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Thrombotic complications after total pancreatectomy with islet autotransplantation (TPIAT) are common. However, the systemic changes to coagulation in the perioperative period have not been well studied. Our objective was to evaluate the derangements in coagulation in the perioperative period for this procedure.This was a prospective observational study of patients undergoing elective TPIAT for chronic pancreatitis. Multiple methods of evaluating coagulation, including 2 viscoelastic assays and standard laboratory assays were obtained at defined intraoperative and postoperative intervals.Fifteen patients were enrolled. Laboratory values demonstrated initial intraoperative hypercoagulability before significant systemic anticoagulation after islet infusion with heparin. Hypercoagulability is again seen at postoperative days 3 and 7. Subgroup analysis did not identify any major coagulation parameters associated with portal vein thrombosis formation.Apart from the immediate period after islet cell and heparin infusion, patients undergoing TPIAT are generally hypercoagulable leading to a high rate of thrombotic complications. Portal vein thrombosis development had minimal association with systemic derangements in coagulation as it is likely driven by localized inflammation at the time of islet cell infusion. This study may provide the groundwork for future studies to identify improvements in thrombotic complications.

Introduction Lung injury has several inciting etiologies ranging from trauma (contusion and hemorrhage) to ischemia reperfusion injury. Reflective of the injury, tissue and cellular injury increases proportionally with the injury stress and is an area of potential intervention to mitigate the injury. This study aims to evaluate the therapeutic benefits of recombinant human MG53 (rhMG53) protein in porcine models of acute lung injury (ALI). Materials and Methods We utilized live cell imaging to monitor the movement of MG53 in cultured human bronchial epithelial cells following mechanical injury. The in vivo efficacy of rhMG53 was evaluated in a porcine model of hemorrhagic shock/contusive lung injury. Varying doses of rhMG53 (0, 0.2, or 1 mg/kg) were administered intravenously to pigs after induction of hemorrhagic shock/contusive induced ALI. Ex vivo lung perfusion system enabled assessment of the isolated porcine lung after a warm ischemic induced injury with rhMG53 supplementation in the perfusate (1 mg/mL). Results MG53-mediated cell membrane repair is preserved in human bronchial epithelial cells. rhMG53 mitigates lung injury in the porcine model of combined hemorrhagic shock/contusive lung injury. Ex vivo lung perfusion administration of rhMG53 reduces warm ischemia-induced injury to the isolated porcine lung. Conclusions MG53 is an endogenous protein that circulates in the bloodstream. Therapeutic treatment with exogenous rhMG53 may be part of a strategy to restore (partially or completely) structural morphology and/or functional lung integrity. Systemic administration of rhMG53 constitutes a potential effective therapeutic means to combat ALI.

Sarcopenia defined as degenerative loss of skeletal muscle mass associated with aging, represents an objective parameter to measure frailty and to estimate patient’s physiologic reserves. It is a robust predictor of post-operative complications in transplantation and major oncologic surgeries. There is no data regarding the prevalence of sarcopenia in chronic pancreatitis or its impact on the outcome of patients undergoing TPIAT for CP. We sought to estimate the prevalence of sarcopenia, its impact on post-operative morbidity and prediction of islet yield and metabolic outcomes in patients undergoing TPIAT. Adult patients undergoing TPIAT between 2008 and 2018 were identified from our prospectively maintained database and were included if they had CT within 6 months before TPIAT. Skeletal muscle index (SMI) was evaluated by pre-operative CT at the level of L3 vertebra. Sarcopenia was defined as SMI

Background: Venovenous extracorporeal membrane oxygenation (VV-ECMO) for select adults with severe acute respiratory distress syndrome (ARDS) cause by coronavirus disease 2019 (COVID-19) infection is a guideline-supported therapy with associated hospital survival of 62%-74%, similar to expected survival with VV-ECMO for other indications. However, ECMO is a resource-heavy intervention, and these patients often require long ECMO runs and prolonged intensive care unit (ICU) care. Identifying factors associated with mortality in VV-ECMO patients with COVID-19 infection can inform the evaluation of ECMO candidates as well as prognostication for those patients on prolonged VV-ECMO. Patients and Methods: This was a retrospective cohort study that included all patients who received either VV- or venoarteriovenous (VAV)-ECMO at one of four ECMO Centers of Excellence in the state of Minnesota between March 1, 2020 and November 1, 2020. The primary outcome was 60-day survival. Secondary outcomes were hospital complications, infectious complications, and complications from ECMO. Results: There were 46 patients who met criteria during this study period and 30 survived to 60-day follow-up (65.2%). Prior to cannulation, older patient age (55.5 in non-survivors vs. 49.1 years in survivors; p = 0.03), lower P/F ratio (62.1 vs. 76.2; p = 0.04), and higher sequential organ failure assessment (SOFA) score (8.1 vs. 6.6; p = 0.02) were identified as risk factors for mortality. After ECMO cannulation, increased mortality was associated with increased number of antibiotic days (25.9 vs. 14.5; p = 0.04), increased number of transfusions (23.9 vs. 9.9; p = 0.03), elevated white blood cell (WBC) count at post-ECMO days one through three, elevated D-dimer at post-ECMO day 21-27, and decreased platelet count from post-ECMO days 14 and onward using univariable analysis. Conclusions: Multiple markers of infection including leukocytosis, thrombocytopenia, and increased antibiotic days are associated with increased mortality in patients placed on VV-ECMO for COVID-19 infection and subsequent ARDS. Knowledge of these factors may assist with determining appropriate candidates for this limited resource as well as direct goals of care in prolonged ECMO courses.

Circulating microRNAs (miRNAs) can be biomarkers for diagnosis and progression of several pathophysiological conditions. In a cohort undergoing total pancreatectomy with islet autotransplantation (TPIAT) from the multicenter Prospective Observational Study of TPIAT (POST), we investigated associations between a panel of circulating miRNAs (hsa-miR-375, hsa-miR-29b-3p, hsa-miR-148a-3p, hsa-miR-216a-5p, hsa-miR-320d, hsa-miR-200c, hsa-miR-125b, hsa-miR-7-5p, hsa-miR-221-3p, hsa-miR-122-5p) and patient, disease and islet-isolation characteristics. Plasma samples ( n = 139) were collected before TPIAT and miRNA levels were measured by RTPCR. Disease duration, prior surgery, and pre-surgical diabetes were not associated with circulating miRNAs. Levels of hsa-miR-29b-3p ( P = 0.03), hsa-miR-148a-3p ( P = 0.04) and hsa-miR-221-3p ( P = 0.01) were lower in those with genetic risk factors. Levels of hsa-miR-148a-3p ( P = 0.04) and hsa-miR-7-5p ( P = 0.04) were elevated in toxic/metabolic disease. Participants with exocrine insufficiency had lower hsa-miR-29b-3p, hsa-miR-148a-3p, hsa-miR-320d, hsa-miR-221-3p ( P < 0.01) and hsa-miR-375, hsa-miR-200c-3p, and hsa-miR-125b-5p ( P < 0.05). Four miRNAs were associated with fasting C-peptide before TPIAT (hsa-miR-29b-3p, r = 0.18; hsa-miR-148a-3p, r = 0.21; hsa-miR-320d, r = 0.19; and hsa-miR-221-3p, r = 0.21; all P < 0.05), while hsa-miR-29b-3p was inversely associated with post-isolation islet equivalents/kg and islet number/kg ( r = −0.20, P = 0.02). Also, hsa-miR-200c ( r = 0.18, P = 0.03) and hsa-miR-221-3p ( r = 0.19, P = 0.03) were associated with islet graft tissue volume. Further investigation is needed to determine the predictive potential of these miRNAs for assessing islet autotransplant outcomes.

BackgroundTraditionally, patient risk scoring is done by evaluating vital signs and clinical severity scores with clinical intuition. Urinary biomarkers can add objectivity to these models to make risk prediction more accurate. We used metabolomics to identify prognostic urinary biomarkers of mortality or need for renal replacement therapy (RRT). Additionally, we assessed acute kidney injury (AKI) diagnosis, injury severity score (ISS), and AKI stage.MethodsUrine samples (n = 82) from a previous study of combat casualties were evaluated using proton nuclear magnetic resonance (1H-NMR) spectroscopy. Chenomx software was used to identify and quantify urinary metabolites. Metabolite concentrations were normalized by urine output, autoscaled, and log-transformed. Partial least squares discriminant analysis (PLS-DA) and statistical analysis were performed. Receiver operating characteristic (ROC) curves were used to assess prognostic utility of biomarkers for mortality and RRT.ResultsEighty-four (84) metabolites were identified and quantified in each urine sample. Of these, 11 were identified as drugs or drug metabolites and excluded. The PLS-DA models for ISS and AKI diagnosis did not have acceptable model statistics. Therefore, only mortality/RRT and AKI stage were analyzed further. Of 73 analyzed metabolites, 9 were significantly associated with mortality/RRT (p p p p ConclusionsWe identified urinary metabolites associated with AKI stage and the primary outcome of mortality or need for RRT. Lactate, 1-methylnicotinamide, and glycine may be used as a panel of predictive biomarkers for mortality and RRT. 1-Methylnicotinamide is a novel biomarker associated with adverse outcomes. Additional studies are necessary to determine how these metabolites can be utilized in clinically-relevant risk prediction models.

Background: Synchronized circadian rhythms play a key role in coordinating physiologic health. Desynchronized circadian rhythms may predispose individuals to disease or be indicative of underlying disease. Intensive care unit (ICU) patients likely experience desynchronized circadian rhythms due to disruptive environmental conditions in the ICU and underlying pathophysiology. This observational pilot study was undertaken to determine if 24-h rhythms are altered in ICU patients relative to healthy controls by profiling 24-h rhythms in vital signs and plasma metabolites. Methods: We monitored daily rhythms in 5 healthy controls and 5 ICU patients for 24 h. Heart rate and blood pressure were measured every 30 min, temperature was measured every hour, and blood was sampled for mass spectrometry-based plasma metabolomics every 4 h. Bedside sound levels were measured every minute. Twenty-four hours rhythms were evaluated in vitals and putatively identified plasma metabolites individually and in each group using the cosinor method. Results: ICU patient rooms were significantly louder than healthy controls' rooms and average noise levels were above EPA recommendations. Healthy controls generally had significant 24-h rhythms individually and as a group. While a few ICU patients had significant 24-h rhythms in isolated variables, no significant rhythms were identified in ICU patients as a group, except in cortisol. This indicates a lack of coherence in phases and amplitudes among ICU patients. Finally, principal component analysis of metabolic profiles showed surprising patterns in plasma sample clustering. Each ICU patient's samples were clearly discernable in individual clusters, separate from a single cluster of healthy controls. Conclusions: In this pilot study, ICU patients' 24-h rhythms show significant desynchronization compared to healthy controls. Clustering of plasma metabolic profiles suggests that metabolomics could be used to track individual patients' clinical courses longitudinally. Our results show global disordering of metabolism and the circadian system in ICU patients which should be characterized further in order to determine implications for patient care.

Chronic pancreatitis is a painful and life-altering disease. Total pancreatectomy with islet autotransplantation is a treatment option that can remove the source of pain and inflammation (the pancreas) without leading to the complication of brittle diabetes. Postoperative management requires a careful attention to detail, including glucose management, prophylaxis against thrombosis, and monitoring for complications.

Introduction Age and sex affect outcomes from trauma. Older patients tend to be under-triaged, consume more healthcare resources, and experience worse outcomes relative to younger patients. Sex has also been associated with different outcomes, with women experiencing better outcomes than men. While baseline metabolism differs with both age and sex, no study has examined how these differences affect the response to trauma. We used high-throughput metabolomics to assess metabolic differences associated with blunt trauma according to age and sex. Methods Metabolic profiles were constructed using nuclear magnetic resonance spectroscopy for trauma patients age 21–40 years (n = 20, 55% male) and >65 years (n = 22, 41% male) from plasma samples obtained on Day 1 and Day 3 of each patient’s hospital stay. These were compared to profiles constructed from plasma obtained from healthy controls of the same age (21–40: n = 23, 61% male; 65+: n = 26, 50% male). Differences in metabolic profiles were assessed with partial least squares discriminant analysis. Results Trauma elicits an overwhelming global stress response that includes more subtle differences in metabolism related to age and gender. Significant differences due to normal aging were also identified. Many of the metabolites measured were present in similar levels in healthy controls age 65+ as they were in trauma patients of all ages. Sex-based differences in metabolism were observed in younger trauma patients on Day 3 but not in older patients. Conclusions Differences in energy metabolism and oxidative stress were implicated in the response to trauma in all patients. Older trauma patients may enter the trauma state with pre-existing oxidative stress and energy deficits that complicate recovery. Sex-based differences in recovery from trauma support the large body of work demonstrating the role of sex in recovery from trauma.

OBJECTIVE To evaluate initial tissue hemoglobin oxygen saturation (StO2 ) in dogs presenting to an emergency room (ER) for acute hemorrhage. DESIGN Prospective, observational study. SETTING University veterinary teaching hospital. ANIMALS Thirty-eight dogs with acute hemorrhage were enrolled between July 2009 and October 2010. Seventy-eight normal dogs from a previous observational study were included to represent healthy controls ("no shock"). INTERVENTIONS Tissue oxygen saturation measurement was obtained at enrollment on dogs presented to the ER for acute hemorrhage. Baseline clinicopathologic (CBC, serum biochemical profile, prothrombin time, and activated partial thromboplastin time) and physiologic (plasma lactate concentration, venous blood gas, blood pressure, and hemoglobin oxygen saturation by pulse oximetry) data were recorded from all patients with hemorrhage. An ER clinician blinded to the StO2 value guided patient management. Patient survival to discharge from the hospital in the study group was recorded. Once data collection was complete, 3 emergency and critical care clinicians blinded to the StO2 data retrospectively classified patients into 1 of 4 shock categories (no shock, mild, moderate, or severe shock). MEASUREMENTS AND MAIN RESULTS The historical group of healthy dogs had higher StO2 concentrations compared to the dogs classified with shock at all 3 levels (mild, moderate, and severe, P = 0.0006

The quality of prehospital care impacts patient outcomes. Military efforts have focused on training revision and the creation of high-fidelity simulation models to address potentially survivable injuries. We sought to investigate the applicability of models emphasizing hemorrhage control and airway management to a civilian population.Prehospital health care providers (PHPs) undergoing their annual training were enrolled. A trauma scenario was simulated with two modules: hemorrhage control and airway management. Experienced raters used a validated tool to assess performance. Pearson correlation, logistic regression, and χ tests were used for analysis.Ninety-five PHPs participated with a mean experience of 15.9 ± 8.3 years, and 7.4% reported past military training. The PHPs' overall execution rate of the six hemorrhage control measures varied from 38.9% to 88.4%. The median blood loss was 1,700 mL (interquartile range, 1,043-2,000), and the mean global rater score was 25.0 ± 7.4 (scale, 5-40). There was a significant relationship between PHP profession and past military experience to their consideration of blood transfusion and tranexamic acid. An inverse relationship between blood loss and global rater score was found (r = -0.59, n = 88, p = 1.93 × 10). After simulated direct laryngoscope failure in the airway module, 58% of PHPs selected video laryngoscopy over placement of a supraglottic airway. Eighty-six percent of participants achieved bilateral chest rise in the manikin regardless of management method. Participants reported improved comfort with skills after simulation.Our data reveal marginal performance in hemorrhage control regardless of the PHP's prior experience. The majority of PHPs were able to secure an advanced airway if direct laryngoscope was unavailable with a predisposition for video laryngoscopy over supraglottic airway. Our findings support the need for continued training for PHPs highlighting hemorrhage control maneuvers and increased familiarity with airway management options. Improved participant confidence posttraining gives credence to simulation training.Prognostic/epidemiological study, level III.

IntroductionAlthough there are multiple studies regarding the management and outcomes of colonic injuries incurred in combat, the literature is limited with regard to small bowel injuries. This study seeks to provide the largest reported review of the characteristics of combat-associated small bowel injuries.Materials and MethodsThe Department of Defense Trauma Registry was queried for U.S. Armed Forces members who sustained hollow viscus injuries in the years 2007–2012 during Operations Enduring Freedom, Iraqi Freedom, and New Dawn. Concomitant injuries, procedures, and complications were delineated. Fisher’s exact test was used to analyze the relationship of bowel injury pattern to rates of repeat laparotomy, fecal diversion, and complications.ResultsOne hundred seventy-one service members had small bowel injuries. The mean age was 25.8 ± 6.6 yr with a mean injury severity score of 27.9 ± 12.4. The majority of injuries were penetrating (94.2%, n = 161) as a result of explosive devices (61.4%, n = 105). The median blood transfusion requirement in the first 24 h was 6.0 units (interquartile range 1.0–17.3 units). The most frequent concomitant injuries were large bowel (64.3%, n = 110), pelvic fracture (35.7%, n = 61), and perineal (26.3%, n = 45). Fifty patients (29.2%) had a colostomy, and nine patients (5.3%) had an ileostomy; 62.6% (n = 107) of soldiers underwent more than one laparotomy. The mortality rate was 1.8% (n = 3). The most common complications were pneumonia (15.2%, n = 26), deep vein thrombosis (14.6%, n = 25), and wound infection (14.6%, n = 25). The need for repeat laparotomy and fecal diversion was found to be significantly associated with injury pattern (p = 0.00052 and p < 0.0001, respectively).ConclusionWe found that two-thirds of service members with small bowel injuries also had a large bowel injury. One-third of the patients required diversion and two-thirds had more than one laparotomy. The pattern of bowel injury significantly affected the need for repeat laparotomy and fecal diversion.

Sepsis accounts for 10% of intensive care unit admissions and significant healthcare costs. Although the mortality rate from sepsis has been decreasing with better critical care, early identification of septic patients, and prompt interventions, the mortality rate remains 20%-30%.Review of the English-language literature.Norepinephrine is the first-line vasopressor in shock and is associated with a lower mortality rate as well as fewer adverse effects. Dopamine has similar actions but is associated with significantly more tachydysrhythmias and should be reserved for patients with bradycardia. Epinephrine and vasopressin are appropriate second-line vasopressors and may enable use of lower doses of norepinephrine while improving hemodynamics. Inotropes may be added in patients with cardiac dysfunction.Appropriate treatment of sepsis includes prompt identification, early antimicrobial drug therapy, appropriate fluid resuscitation, and initiation of vasopressors in the presence of continued septic shock. Further research needs to be done to better understand the ideal timing of the addition of a second agent and the optimal combinations of vasopressors for individual patients.

Our objectives were to characterize injury, complications, and outcomes for older riders after motorcycle accidents due to the rising trend in advanced-age motorcyclists.From 2008 to 2013, injured motorcyclists were compared by age group: younger (0 to 54 years) vs older (≥55 years) in a retrospective review of the trauma databank at North Memorial Medical Center, a Level-1 trauma center.Of 432 patients, the older group (n = 100) had more fractures (60% vs 42%), injuries per patient (2 vs 1), intensive care unit admissions (48% vs 32%), ventilator days (8 vs 5), in-hospital complications (16% vs 8%), and hospital days (5.5 vs 3) than the younger group (n = 332), P .01. The older group was also more likely to be discharged to a destination other than home, 35% vs 18%, P.01.Older riders are at risk for more severe injury, longer and more complex hospitalizations, and higher care demands after discharge. Both age-specific treatment and care systems will need to evolve to accommodate the needs of the aging trauma population.

During unresolved infections, some viruses escape immunological control and establish a persistant reservoir in certain cell types, such as human immunodeficiency virus (HIV), which persists in follicular helper T cells (TFH cells), and Epstein-Barr virus (EBV), which persists in B cells. Here we identified a specialized group of cytotoxic T cells (TC cells) that expressed the chemokine receptor CXCR5, selectively entered B cell follicles and eradicated infected TFH cells and B cells. The differentiation of these cells, which we have called 'follicular cytotoxic T cells' (TFC cells), required the transcription factors Bcl6, E2A and TCF-1 but was inhibited by the transcriptional regulators Blimp1, Id2 and Id3. Blimp1 and E2A directly regulated Cxcr5 expression and, together with Bcl6 and TCF-1, formed a transcriptional circuit that guided TFC cell development. The identification of TFC cells has far-reaching implications for the development of strategies to control infections that target B cells and TFH cells and to treat B cell-derived malignancies.

Total pancreatectomy and islet autotransplantation (TPIAT) is an effective treatment for selected patients with chronic pancreatitis. The portal circulation is the standard infusion site for islet transplant, but marked elevation of portal pressures may prevent complete islet infusion. Herein we report a novel technique of combined site islet autotransplantation using an omental pouch. This technique may be useful when technical limitations prevent complete intraportal transplantation. In four TPIAT recipients with intraoperative issues precluding the complete intraportal infusion of islets, an omental pouch was created to contain the remaining islet mass. Patients were monitored for complications, and islet graft function was assessed using mixed meal tolerance testing and compared with matched controls who received only intraportally transplanted islets. All patients had decreasing insulin requirements as their recovery progressed. At 3 months follow-up there were no significant differences in glycemic control or graft function for the combined site recipients compared with their matched controls who only received an intraportal islet infusion. The omentum has potentially desirable qualities such as accessibility, capacity, and systemic/portal vascularity comparable to the native pancreas. The omental pouch technique may represent a safe and effective alternate site for islet autotransplantation. Further study is needed to confirm these findings.

Obstructive sleep apnea (OSA) is associated with increased systemic oxidative stress, endothelial dysfunction, and activation of pro-inflammatory cascades, which increase host susceptibility to infection. OSA has not been evaluated as a risk factor for surgical site infection (SSI) following colectomy. We hypothesized that OSA increases the risk for SSI after colectomy.We performed a retrospective review of 507 colectomies that took place between August 2011 and September 2013. Forty-two patients carried the diagnosis of OSA prior to surgery. These 42 patients were matched to 68 patients with no OSA for age, body mass index (BMI), diabetes mellitus (DM), reason for surgery and surgical approach.The rate of SSI was 28.6% (12 of 42) in the patients with and 10.3% (7 of 68) in the patients without OSA (p=0.03). Using logistic regression, the predictors of SSI following colectomy were found to be OSA (odds ratio [OR] of 3.98, 95% confidence interval [CI]=1.29-12.27), and DM (OR of 7.16, 95% CI=2.36-21.96). The average hospital stay after colectomy for patients with OSA complicated with SSI was 16.7 d whereas patients with OSA without SSI stayed 7.4 d (p0.001). The rate of organ space infections was 9.5% (4 of 42) in the patients with OSA compared with 0 (p=0.02) in patients without OSA.OSA is an independent risk factor for SSI following colectomy. Patients with OSA have substantially greater rates of organ space SSI and longer hospital stay.

Identifying biomarkers that are indicative of a phenotypic state is difficult because of the amount of natural variability which exists in any population. While there are many different algorithms to select biomarkers, previous investigation shows the sensitivity and flexibility of support vector machines (SVM) make them an attractive candidate. Here we evaluate the ability of support vector machine recursive feature elimination (SVM-RFE) to identify potential metabolic biomarkers in liquid chromatography mass spectrometry untargeted metabolite datasets. Two separate experiments are considered, a low variance (low biological noise) prokaryotic stress experiment, and a high variance (high biological noise) mammalian stress experiment. For each experiment, the phenotypic response to stress is metabolically characterized. SVM-based classification and metabolite ranking is undertaken using a systematically reduced number of biological replicates to evaluate the impact of sample size on biomarker reproducibility and robustness. Our results indicate the highest ranked 1 % of metabolites, the most predictive of the physiological state, were identified by SVM-RFE even when the number of training examples was small (≥3) and the coefficient of variation was high (>0.5). An accuracy analysis shows filtering with recursive feature elimination measurably improves SVM classification accuracy, an effect that is pronounced when the number of training examples is small. These results indicate that SVM-RFE can be successful at biomarker identification even in challenging scenarios where the training examples are noisy and the number of biological replicates is low.

The potential for using serum albumin (SA) as a broadly applicable molecular sensor was explored in an effort to develop a method for rapid analysis of complex metabolite samples. SA is a protein present at high concentration in blood, which transports a diverse set of compounds including fatty acids, hormones, and drugs. The effectiveness of the bovine ortholog (BSA) as a molecular sensor was tested by analyzing the pool of small molecules bound to the protein after a brief incubation with complex fluids of biological origin. As an initial test, three varietals of red wine were readily distinguished. Further analysis using four varietals of white wine also showed clear separation. In a second analysis using urine, animals in hemorrhagic shock were separated from a group of comparably treated controls. A time course analysis showed that recovery from injury could also be followed using the assay. This finding is significant as there currently is no method or biomarker for predicting the onset of shock. Comparison of samples was based on liquid chromatography mass spectrometry (LCMS) analysis of compounds selectively bound by BSA. Analysis of the samples after protein selection revealed a significant reduction in complexity and clear separation of groups by Principle Component Analysis (PCA). These results show the potential for using cargo-carrying proteins as molecular sensors for screening complex samples without the need for prior knowledge of sample composition or concentration and may streamline elucidation of biomarkers.

Antiretroviral therapy can reduce HIV-1 to undetectable levels in peripheral blood, but the effectiveness of treatment in suppressing replication in lymphoid tissue reservoirs has not been determined. Here we show in lymph node samples obtained before and during 6 mo of treatment that the tissue concentrations of five of the most frequently used antiretroviral drugs are much lower than in peripheral blood. These lower concentrations correlated with continued virus replication measured by the slower decay or increases in the follicular dendritic cell network pool of virions and with detection of viral RNA in productively infected cells. The evidence of persistent replication associated with apparently suboptimal drug concentrations argues for development and evaluation of novel therapeutic strategies that will fully suppress viral replication in lymphatic tissues. These strategies could avert the long-term clinical consequences of chronic immune activation driven directly or indirectly by low-level viral replication to thereby improve immune reconstitution.

Hemorrhagic shock with injury results in alterations of the metabolic state of an organism, which contribute to organ dysfunction and death. Previous investigations have explored the effects of carbohydrate prefeed in murine models but few in clinically relevant large animal models. We performed carbohydrate prefeed in pigs undergoing simulated polytrauma and hemorrhagic shock with resuscitation to determine if carbohydrate prefeeding if the metabolic response to shock is dependent on fed state. Sixty-four Yorkshire pigs were divided into two experimental groups: fasted (32) and prefed (32). Experimental animals were subjected to a standardized hemorrhagic shock protocol, including pulmonary contusion and liver crush injury. To determine molecular alterations in response to trauma as a result of prefeeding, liver biopsies were obtained at set timepoints throughout the procedure. Fifty-one metabolites were profiled for each sample via proton nuclear magnetic resonance spectroscopy (1H NMR). Partial-Least Squared Discriminant Analysis (PLS-DA) was used to examine clustering of the data with respect to fed state. Cross-validated models separated the fed from fasted animals. Metabolites contributing to the separation have known relationships to alternate carbon energy sources, amino acid metabolism, oxidative stress response, and membrane maintenance. In conclusion, metabolomic techniques allowed identification of an alternate response to shock and resuscitation, dependent upon fed state, through the use of metabolomics.

Introduction: Advances in care of the critically ill patient have promoted growth in the number of “chronically critically ill”-patients who survive acute medical crisis only to require weeks of intensive monitoring. This population accounts for a small fraction of admissions yet a disproportionately large fraction of healthcare resources. Despite this allocation, long-term outcomes are poorly understood. The goal of this study is to determine the rate of mortality in the 3 years following prolonged admission to the surgical intensive care unit. Methods: This retrospective study includes patients discharged from a twenty-bed surgical intensive care unit in an 874-bed tertiary care academic hospital. All patients who were at least 18 years old, spent at least 30 consecutive days in the surgical intensive care unit, and were discharged during 2002-2009 were eligible for inclusion in the study. Patients were followed for 3 years following discharge. Age, sex, length of hospital stay, length of surgical intensive care unit stay, and admitting diagnosis were abstracted from medical records. For living patients, ventilator-dependence at discharge and disposition to rehabilitation facility were documented. Date of death was determined from medical records and the Social Security Death Master File. Using a proportional hazards model, these patient variables were analyzed for their contribution to mortality during admission as well as at 1 year and 3 years post discharge. Results: Sixty-four patients were included in the study: 35 males and 29 females with a mean age of 59 (21 - 83) years, surgical intensive care unit stay of 47 (30 - 125) days, and hospital stay of 58 (30 - 178) days. Thirty patients died during admission, 16 died within 1 year of discharge, and an additional 4 patients died within 3 years. Among those discharged, 70% of deaths occurred within 3 months. No variables were identified as independent risk factors for mortality. Conclusions: An increasing number of patients are admitted for prolonged stays in the surgical intensive care unit. The human cost of prolonged surgical intensive care unit admission is high with 70% of patients succumbing during admission or within the first year after discharge.

Background Previous studies have indicated that hemorrhagic shock and injury cause significant early changes in metabolism. Recently, global changes in metabolism have been described using metabolomics in animal models and civilian trauma. We evaluated metabolic changes associated with combat injury to identify early biomarkers and aid in triage. Methods Plasma obtained at emergency department presentation and intervals thereafter from patients injured during combat operations in Iraq (n = 78) were compared with healthy control subjects (n = 40). Using proton Nuclear Magnetic Resonance (NMR), water-soluble metabolites were detected and quantified. Resulting metabolic profiles were analyzed with partial least squares discriminant analysis, Receiver Operating Characteristic (ROC), and cluster analyses to identify features of combat injury and mortality. Results Significant alterations to metabolism resulted from traumatic injury. Metabolic profiles of injured patients differed from those of healthy controls, driven by increased 5-aminolevulinate and hypoxanthine that persisted through 24 hours. Among combat-injured patients, increased succinate and malonate best discriminated between those who survived from those who did not. Higher levels of succinate and hypoxanthine were associated with increased injury severity. ROC analysis showed that these metabolites had equivalent or superior performance to lactate in distinguishing the presence of trauma, injury severity, and mortality. Conclusion Combat injury is associated with several changes at the metabolic level compared with healthy individuals. Novel potential biomarkers of mortality (succinate, malonate), injury severity (succinate, hypoxanthine), and the presence of trauma (hypoxanthine, 5-aminolevulinate) perform as well as or better than the common clinical standard, lactate. Level of evidence Prognostic study, level III.

Pseudocholinesterase deficiencies occur because of both genetic and acquired factors. We present the case of a patient with a history of bariatric surgery and severe malnutrition who subsequently developed prolonged neuromuscular blockade after succinylcholine administration. She had markedly decreased pseudocholinesterase levels at the time of the incident, but her motor function returned to normal with supportive care. After aggressive nutritional support over multiple weeks, her pseudocholinesterase levels drastically improved. For those patients in a poor nutritional state who experience an unexpected episode of apnea or prolonged neuromuscular blockade, practitioners must always consider malnutrition-induced pseudocholinesterase deficiency as a possible etiology.

Background Deep Vein Thrombosis (DVT) is a common complication in trauma patients. Venous duplex surveillance is used widely for the diagnosis of DVT, however, there is controversy concerning its appropriate use. The Wells criterion is a clinically validated scoring system in an outpatient setting, but its use in trauma patients has not been studied. This study evaluated the application of the Wells scoring system in trauma population. Methods Wells scores were calculated retrospectively for all patients who were admitted to the trauma service and underwent Venous Duplex Scanning (VDS) at the author’s institution between 2012 and 2013. Correlation of Wells score with DVT and its efficacy in risk stratifying the patients after trauma was analyzed using linear correlation and receiver operating characteristic (ROC) curve. Sensitivity and specificity of Wells score in ruling out or ruling in DVT were calculated in various risk groups. Results Of 298 patients evaluated, 18 (6 %) patients were positive for DVT. A linear correlation was present between Wells score and DVT with R2 = 0.88 (p = 0.0016). Median Wells score of patients without DVT was 1 (1–3) compared to a median score of 2 (1–5) in those with DVT (p

To evaluate initial tissue hemoglobin oxygen saturation (StOProspective, observational study.University veterinary teaching hospital.Thirty-eight dogs with acute hemorrhage were enrolled between July 2009 and October 2010. Seventy-eight normal dogs from a previous observational study were included to represent healthy controls ("no shock").Tissue oxygen saturation measurement was obtained at enrollment on dogs presented to the ER for acute hemorrhage. Baseline clinicopathologic (CBC, serum biochemical profile, prothrombin time, and activated partial thromboplastin time) and physiologic (plasma lactate concentration, venous blood gas, blood pressure, and hemoglobin oxygen saturation by pulse oximetry) data were recorded from all patients with hemorrhage. An ER clinician blinded to the StOThe historical group of healthy dogs had higher StODogs with hemorrhagic shock have lower StO

BACKGROUND: Early recognition and intervention in hemorrhagic shock is essential to improved outcomes. However, the lack of robust diagnostic tools readily available to identify patients in the field inhibits the ability to provide timely intervention. Therefore, the development of a reliable prognostic indicator, such as a serum biomarker or a metabolic profile, has significant potential to improve far-forward trauma care. In this study, we used metabolomics as a tool to identify a metabolic state associated with the hemorrhagic shock and outcome in our porcine model of multiple injuries, shock, and resuscitation. METHODS: Proton nuclear magnetic resonance spectroscopy was used to evaluate serum metabolites from 23 animals that underwent multiple injuries, controlled hemorrhage, and 20 hours of a standard resuscitation protocol. Serum samples were collected from the animals at baseline (before hemorrhage), at shock (after 45 minutes of shock), and at 8 hours of full resuscitation. RESULTS: We were able to demonstrate shifts in the metabolome throughout different time points and construct a metabolic profile associated with mortality using partial least squares discriminate analysis. The metabolites most responsible for the classification of hemorrhagic shock in our model serve as markers for ischemia, changes in energy production, and cellular damage. Hemorrhagic shock was characterized by marked increases in tricarboxylic acid cycle intermediates, glycolytic-gluconeogenic by-products, purine-pyrimidine catabolism, and fatty acid oxidation. CONCLUSION: The results of this study demonstrate the potential for metabolomics as a tool to classify the metabolic flux, to identify relevant biochemical pathways, and to identify clinically useful biomarkers.

Hemorrhagic shock, often a result of traumatic injury, is a condition of reduced perfusion that results in diminished delivery of oxygen to tissues. The disruption in oxygen delivery induced by both ischemia (diminished oxygen delivery) and reperfusion (restoration of oxygen delivery) has profound consequences for cellular metabolism and the maintenance of homeostasis. The pathophysiologic state associated with traumatic injury and hemorrhagic shock was studied with a scale-invariant metabolic network. Urinary metabolic profiles were constructed from NMR spectra of urine samples collected at set timepoints in a porcine model of hemorrhagic shock that included a pulmonary contusion, a liver crush injury, and a 35 % controlled bleed. The network was constructed from these metabolic profiles. A partial least squares discriminant analysis (PLS-DA) model that discriminates by experimental timepoint was also constructed. Comparisons of the network (functional relationships among metabolites) and PLS-DA model (observable relationships to experimental time course) revealed complementary information. First, ischemia/reperfusion injury and evidence of cell death due to hemorrhage was associated with early resuscitation timepoints. Second, evidence of increased protein catabolism and traumatic injury was associated with late resuscitation timepoints. These results are concordant with generally accepted views of the metabolic progression of shock.

BACKGROUND: Blood operations are constrained by many limitations in combat settings. As a result there are many challenges that require innovative solutions. STUDY DESIGN AND METHODS: This is a descriptive overview of blood product usage and transfusion medicine adaptations that have been employed by the US military to support combat operations in Iraq and Afghanistan between November 2001 and December 2010. RESULTS: Transfusion medicine challenges have included the need for rapid transport of large quantities of blood products from the United States to Iraq and Afghanistan, risks and appropriate countermeasures associated with blood products collected in the theater of operations, availability of fresh-frozen plasma at forward surgical facilities, need for platelets (PLTs) in combat, and the need to support constant and evolving changes in transfusion and resuscitation protocols. A decrease in the storage age of red blood cells (RBCs) transfused to combat casualties has been achieved. There has been an increase in the ratio of plasma and PLTs to RBCs transfused, increased availability of plasma and apheresis PLTs to facilitate this approach, and a continuous effort to improve the safety of using fresh whole blood and apheresis PLTs collected in combat. A number of clinical practice guidelines are in place to address these processes. CONCLUSION: This multidisciplinary approach has successfully addressed many complicated and challenging issues regarding blood operations and transfusion practices for combat casualties.

Background Despite ongoing advances in treatment, thousands of patients still die annually from complications due to hemorrhagic shock, a condition causing dramatic physiologic and metabolic changes as cells switch to anaerobic metabolism in response to oxygen deprivation. As the shift from aerobic to anaerobic metabolism occurs in the peripheral tissues during shock, the liver must increase production of endogenous glucose as well as process excess lactate produced in the periphery. This places the liver at the center of metabolic regulation in the body during hemorrhagic shock. Therefore, we hypothesized that liver tissue from pigs during an in vivo model of hemorrhagic shock ( n = 6) would reflect resultant metabolic changes. Materials and Methods The in vivo model of shock consisted of 45 min of shock followed by 8 h of hypotensive resuscitation (80 mmHg) and subsequent normotensive resuscitation (90 mmHg) ending 48 h after the shock period. Control groups of pigs ( n = 3) (1) shock with no resuscitation, and (2) only anesthesia and instrumentation, also were included. Metabolic changes within the liver after shock and during resuscitation were investigated using both proton ( 1 H) and phosphorous ( 31 P) nuclear magnetic resonance (NMR) spectroscopy. Results Concentrations of glycerylphosphorylcholine (GPC) and glycerylphosphorylethanolamine (GPE) were significantly lower at 8 h after shock, with recovery to baseline by 23 and 48 h after shock. Uridine diphosphate-glucose (UDP-glucose), and phosphoenolpyruvate (PEP) were elevated 23 h after shock. Conclusions These results indicate that 1 H and 31 P NMR spectroscopy can be used to identify differences in liver metabolites in an in vivo model of hemorrhagic shock, indicating that metabolomic analysis can be used to elucidate biochemical events occurring during this complex disease process.

Objectives: The aim of this study was to compare hypotensive and normotensive resuscitation in a porcine model of hemorrhagic shock. Methods: This was a prospective, comparative, randomized survival study of controlled hemorrhagic shock using 28 male Yorkshire-Landrace pigs (15 to 25 kg). In 24 splenectomized pigs, the authors induced hemorrhagic shock to a systolic blood pressure (sBP) of 48 to 58 mm Hg (∼35% bleed). Pigs were randomized to undergo normotensive resuscitation (sBP of 90 mm Hg, n = 7), mild hypotensive resuscitation (sBP of 80 mm Hg, n = 7), severe hypotensive resuscitation (sBP of 65 mm Hg, n = 6), or no resuscitation (n = 4). The authors also included a sham group of animals that were instrumented and splenectomized, but that did not undergo hemorrhagic shock (n = 4). After the initial 8 hours of randomized pressure-targeted resuscitation, all animals were resuscitated to a sBP of 90 mm Hg for 16 hours. Results: Animals that underwent severe hypotensive resuscitation were less likely to survive, compared with animals that underwent normotensive resuscitation. Mean arterial pressure (MAP) decreased with hemorrhage and increased appropriately with pressure-targeted resuscitation. Base excess (BE) and tissue oxygen saturation (StO2) decreased in all animals that underwent hemorrhagic shock. This decrease persisted only in animals that were pressure target resuscitated to a sBP of 65 mm Hg. Conclusions: In this model of controlled hemorrhagic shock, initial severe hypotensive pressure-targeted resuscitation for 8 hours was associated with an increased mortality rate and led to a persistent base deficit (BD) and to decreased StO2, suggesting persistent metabolic stress and tissue hypoxia. However, mild hypotensive resuscitation did not lead to a persistent BD or to decreased StO2, suggesting less metabolic stress and less tissue hypoxia.

Clinical studies have caused blood transfusion practices in critically ill patients to become more conservative in the last decade. However, few studies have focused on trauma patients, particularly those with severe isolated traumatic brain injury.We conducted a retrospective study to test the hypothesis that patients with severe brain injury would not benefit from aggressive red blood cell transfusion (RBCT). End points of the study were in-hospital mortality and morbidity (pneumonia, urinary tract infection, deep venous thrombosis, pulmonary embolus, decubitus ulcer, bacteremia, septic shock, myocardial infarction, and seizure). Included in our retrospective study were patients at two urban, level I trauma centers who were admitted with a diagnosis of isolated head injury and with a Glasgow Coma Scale (GCS) score of 8 or less. We recorded demographic, interventional, and outcome variables.In 289 patients, 24 of 25 (96%) were transfused if their lowest recorded intensive care unit (ICU) hemoglobin level was 8.0 g/dl or less. In contrast, only 9/182 (5%) of these 289 patients were transfused if the hemoglobin levels were 10.0 g/dl or greater. In the remaining 82 patients with lowest ICU hemoglobin levels of 8.0-10.0 g/dl, 52% were transfused. These 82 patients (43 underwent RBCT and 39 did not) were included in our analysis.The overall in-hospital mortality rate was 32%; rates were similar between the two groups (29%, non-RBCT; 35%, RBCT) (P = 0.64). Likewise, in-hospital morbidity was similar between groups. Logistic and proportional hazard regression analyses identified RBCT as one predictor of mortality.Our results suggest that a restrictive transfusion practice is safe for severely head-injured patients.

Colon surgical site infections (SSIs) are being utilized increasingly as a quality measure for hospital reimbursement and public reporting. The Centers for Medicare and Medicaid Services (CMS) now require reporting of colon SSI, which is entered through the U.S. Centers for Disease Control and Prevention's National Healthcare Safety Network (NHSN). However, the CMS's model for determining expected SSIs uses different risk adjustment variables than does NHSN. We hypothesize that CMS's colon SSI model will predict lower expected infection rates than will NHSN.Colon SSI data were reported prospectively to NHSN from 2012-2014 for the six Fairview Hospitals (1,789 colon procedures). We compared expected quarterly SSIs and standardized infection ratios (SIRs) generated by CMS's risk-adjustment model (age and American Society of Anesthesiologist [ASA] classification) vs. NHSN's (age, ASA classification, procedure duration, endoscope [including laparoscope] use, medical school affiliation, hospital bed number, and incision class).The patients with more complex colon SSIs were more likely to be male (60% vs. 44%; p = 0.011), to have contaminated/dirty incisions (21% vs. 10%; p = 0.005), and to have longer operations (235 min vs. 156 min; p 0.001) and were more likely to be at a medical school-affiliated hospital (53% vs. 40%; p = 0.032). For Fairview Hospitals combined, CMS calculated a lower number of expected quarterly SSIs than did the NHSN (4.58 vs. 5.09 SSIs/quarter; p = 0.002). This difference persisted in a university hospital (727 procedures; 2.08 vs. 2.33; p = 0.002) and a smaller, community-based hospital (565 procedures; 1.31 vs. 1.42; p = 0.002). There were two quarters in which CMS identified Fairview's SIR as an outlier for complex colon SSIs (p = 0.05 and 0.04), whereas NHSN did not (p = 0.06 and 0.06).The CMS's current risk-adjustment model using age and ASA classification predicts lower rates of expected colon SSIs than does NHSN. This may lead to financial penalties because of the use of limited risk factors. Further efforts at elucidating appropriate risk adjustment measures without unnecessarily burdening hospitals with expensive data collection are necessary.

Background Treatment with oral carbohydrate prior to trauma and hemorrhage confers a survival benefit in small animal models. The impact of fed states on survival in traumatically injured humans is unknown. This work uses regulatory networks to examine the effect of carbohydrate pre-feeding on metabolic response to polytrauma and hemorrhagic shock in a clinically-relevant large animal model. Methods Male Yorkshire pigs were fasted overnight (n = 64). Pre-fed animals (n = 32) received an oral bolus of Karo\textregistered\syrup before sedation. All animals underwent a standardized trauma, hemorrhage, and resuscitation protocol. Serum samples were obtained at set timepoints. Proton NMR was used to identify and quantify serum metabolites. Metabolic regulatory networks were constructed from metabolite concentrations and rates of change in those concentrations to identify controlled nodes and controlling nodes of the network. Results Oral carbohydrate pre-treatment was not associated with survival benefit. Six metabolites were identified as controlled nodes in both groups: adenosine, cytidine, glycerol, hypoxanthine, lactate, and uridine. Distinct groups of controlling nodes were associated with controlled nodes; however, the composition of these groups depended on feeding status. Conclusions A common metabolic output, typically associated with injury and hypoxia, results from trauma and hemorrhagic shock. However, this output is directed by different metabolic inputs depending upon the feeding status of the subject. Nodes of the network that are related to mortality can potentially be manipulated for therapeutic effect; however, these nodes differ depending upon feeding status. Electronic supplementary material The online version of this article (doi:10.1186/s12873-015-0038-1) contains supplementary material, which is available to authorized users.

Chronic pancreatitis is a painful and often debilitating disease. Total pancreatectomy with intra-portal islet autotransplantation (TP-IAT) is a treatment option that allows for pain relief and preservation of beta-cell mass, thereby minimizing the complication of diabetes mellitus. Cultures of harvested islets are often positive for bacteria, possibly due to frequent procedures prior to TP-IAT, such as endoscopic retrograde cholangiopancreatography (ERCP), stenting, or other operative drainage procedures. It is unclear if these positive cultures contribute to post-operative infections.We hypothesized that positive cultures of transplant solutions will not be associated with increased infection risk.We reviewed retrospectively the sterility cultures from both the pancreas preservation solution used to transport the pancreas and the final islet preparation for intra-portal infusion of patients who underwent TP-IAT between April 2006 and November 2012. Two hundred fifty-one patients underwent total, near-total, or completion pancreatectomy with IAT and had complete sterility cultures. All patients received prophylactic peri-operative antibiotics. Patients with positive pancreas preservation solution or islet sterility cultures received further antibiotics for 5-7 d. Patients' medical records were reviewed for post-operative infections and causative organisms.Of the 251 patients included, 151 (61%) had one or more positive bacterial cultures from the pancreas preservation solution or final islet product. Seventy-three of the 251 patients (29%) had an infectious complication. Thirty-four of the 73 (22%) patients with a post-operative infectious complication also had positive cultures. Only seven of 151 patients with positive cultures (4.7%) had an infectious complication caused by the same organism as that isolated from their pancreas or islet cell preparation.In autologous islet preparations, isolation solutions frequently have positive cultures, but this finding is associated infrequently with clinical infection.

INTRODUCTION Hemorrhagic shock and injury lead to dramatic changes in metabolic demands and continue to be a leading cause of death. We hypothesized that altering the preinjury metabolic state with a carbohydrate load prior to injury would affect subsequent metabolic responses to injury and lead to improved survival. METHODS Sixty-four pigs were randomized to fasted (F) or carbohydrate prefeeding (CPF) groups and fasted 12 h prior to experiment. The CPF pigs received an oral carbohydrate load 1 h prior to anesthesia. All pigs underwent a standardized injury/hemorrhagic shock protocol. Physiologic parameters and laboratory values were obtained at set time points. RESULTS Carbohydrate prefeeding did not convey a survival benefit; instead, CPF animals had greater mortality rates (47% vs. 28%; P = 0.153; log-rank [Mantel-Cox]). Carbohydrate prefeeding animals also had higher rates of acute lung injury (odds ratio, 4.23; 95% confidence interval, 1.1-16.3) and altered oxygen utilization. Prior to shock and throughout resuscitation, CPF animals had significantly higher serum glucose levels than did the F animals. CONCLUSIONS Carbohydrate prefeeding did not provide a survival benefit to swine subjected to hemorrhagic shock and polytrauma. Carbohydrate prefeeding led to significantly different metabolic profile than in fasted animals, and prefeeding led to a greater incidence of lung injury, increased multiorgan dysfunction, and altered oxygen utilization.