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Objectives: Total pancreatectomy with islet autotransplantation (TPIAT) is a surgical option for refractory chronic pancreatitis-related pain. Despite the known clinical implications of TPIAT, the molecular effects remain poorly investigated. We performed the first hypothesis-generating study of the urinary proteome before and after TPIAT.Methods: Twenty-two patients eligible for TPIAT were prospectively enrolled. Urine samples were collected the week before and 12 to 18 months after TPIAT. The urine samples were prepared for bottom-up label-free quantitative proteomics using the "MStern" protocol.Results: Using 17 paired samples, we identified 2477 urinary proteins, of which 301 were significantly changed post-TPIAT versus pre-TPIAT. Our quantitative analysis revealed that the molecular response to TPIAT was highly sex-specific, with pronounced sex differences pre-TPIAT but minimal differences afterward. Comparing post-TPIAT versus pre-TPIAT, we found changes in cell-cell adhesion, intracellular vacuoles, and immune response proteins. After surgery, immunoglobulins, complement proteins, and cathepsins were increased, findings that may reflect glomerular damage. Finally, we identified both known and novel markers for immunoglobulin A nephropathy after 1 patient developed the disease 2 years after TPIAT.Conclusions: We found distinct changes in the urinary proteomic profile after TPIAT and the response to TPIAT is highly sex-specific.

Background Prothrombin Complex Concentrates (PCC) are prescribed for emergent warfarin reversal (EWR). The comparative effectiveness and safety among PCC products are not fully understood. Methods Patients in an academic level one trauma center who received PCC3 or PCC4 for EWR were identified. Patient characteristics, PCC dose and time of dose, pre- and post-INR and time of measurement, fresh frozen plasma and vitamin K doses, and patient outcomes were collected. Patients whose pre-PCC International Normalized Ratio (INR) was > 6 h before PCC dose or the pre-post PCC INR was > 12 h were excluded. The primary outcome was achieving an INR ≤ 1.5 post PCC. Secondary outcomes were the change in INR over time, post PCC INR, thromboembolic events (TE), and death during hospital stay. Logistic regression modelled the primary outcome with and without a propensity score adjustment accounting for age, sex, actual body weight, dose, initial INR value, and time between INR measurements. Data are reported as median (IQR) or n (%) with p Results Eighty patients were included (PCC3 = 57, PCC4 = 23). More PCC4 patients achieved goal INR (87.0% vs. 31.6%, odds ratio (OR) = 14.4, 95% CI: 3.80–54.93, p p p = 0.003). Death during hospital stay (p = 0.52) and TE (p = 1.00) were not significantly different. Conclusions PCC4 was associated with a higher achievement of goal INR than PCC3. This relationship was observed in the unadjusted and propensity score adjusted results.

Background\ud Sepsis poses a global threat to millions of lives. The Surviving Sepsis Campaign (SSC) guidelines provide evidence-based recommendations on the recognition and management of sepsis and its complications.\ud Methods\ud We formed a panel of 60 experts from 22 countries and 11 members of the public. The panel prioritized questions that are relevant to the recognition and management of sepsis and septic shock in adults. New questions and sections were addressed, relative to the previous guidelines. These questions were grouped under 6 subgroups (screening and early treatment, infection, hemodynamics, ventilation, additional therapies, and long-term outcomes and goals of care). With input from the panel and methodologists, professional medical librarians performed the search strategy tailored to either specific questions or a group of relevant questions. A dedicated systematic review team performed screening and data abstraction when indicated. For each question, the methodologists, with input from panel members, summarized the evidence assessed and graded the quality of evidence using the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) approach. The panel generated recommendations using the evidence-to-decision framework. Recommendations were either strong or weak, or in the form of best practice statements. When evidence was insufficient to support a recommendation, the panel was surveyed to generate “in our practice” statements.\ud Results\ud The SSC panel issued 93 statements: 15 best practice statements, 15 strong recommendations, and 54 weak recommendations and no recommendation was provided for 9 questions. The recommendations address several important clinical areas related to screening tools, acute resuscitation strategies, management of fluids and vasoactive agents, antimicrobials and diagnostic tests and the use of additional therapies, ventilation management, goals of care, and post sepsis care.\ud Conclusion\ud The SSC panel issued evidence-based recommendations to help support key stakeholders caring for adults with sepsis or septic shock and their families.

Background/objectives The effect of total pancreatectomy with islet autotransplantation (TPIAT) on bone mineral density (BMD) in patients with CP is unknown. We aimed to assess bone health in patients with CP after TPIAT. Methods We measured BMD, BMD Z-score, and bone mineral content (BMC) for total body, lumbar spine, right and left hip in 78 patients before and after TPIAT using dual-energy X-ray absorptiometry (DXA, n = 78 pre-TPIAT, n = 65 paired pre- and 12 months post-TPIAT, n = 33 paired 12 and 18 months post-TPIAT), and tested for association with clinical history including age, smoking status, and medications using paired and two-sample t-tests, linear regression, and Fisher's exact test. Laboratory measures related to bone health were also assessed. Results In the patients with pre-TPIAT DXA, 12% had low BMD (Z-score ≤ −2). BMD, BMD Z-score, and BMC all decreased from pre-to 12 months post-TPIAT. BMD declined by 1.7%–4.1% with the greatest change at the hips. Adjusted for change in lean and fat body mass, DXA changes remained significant for total body and hip. Serum carboxy-terminal collagen crosslinks telopeptide and alkaline phosphatase increased at 12 months post-TPIAT, suggesting possible increased bone remodeling. BMD, BMD Z-score, and BMC did not change between 12 months and 18 months in any of the four regions (p > 0.6). Conclusions TPIAT is associated with decreases in BMD in the body, lumbar, and hip regions of patients with CP in the first year after TPIAT but these appear to stabilize between 12 and 18 months after TPIAT.

Objectives Smoking and alcohol use are risk factors for acute and chronic pancreatitis, and their role on anxiety, depression, and opioid use in patients who undergo total pancreatectomy and islet autotransplantation (TPIAT) is unknown. Methods We included adults enrolled in the Prospective Observational Study of TPIAT (POST). Measured variables included smoking (never, former, current) and alcohol abuse or dependency history (yes vs no). Using univariable and multivariable analyses, we investigated the association of smoking and alcohol dependency history with anxiety and depression, opioid use, and postsurgical outcomes. Results Of 195 adults studied, 25 were current smokers and 77 former smokers, whereas 18 had a history of alcohol dependency (of whom 10 were current smokers). A diagnosis of anxiety was associated with current smoking (P = 0.005), and depression was associated with history of alcohol abuse/dependency (P = 0.0001). However, active symptoms of anxiety and depression at the time of TPIAT were not associated with smoking or alcohol status. Opioid use in the past 14 days was associated with being a former smoker (P = 0.005). Conclusions Active smoking and alcohol abuse history were associated with a diagnosis of anxiety and depression, respectively; however, at the time of TPIAT, symptom scores suggested that they were being addressed.

Background Measuring fluid status during intraoperative hemorrhage is challenging, but detection and quantification of fluid overload is far more difficult. Using a porcine model of hemorrhage and over-resuscitation, it is hypothesized that centrally obtained hemodynamic parameters will predict volume status more accurately than peripherally obtained vital signs. Methods Eight anesthetized female pigs were hemorrhaged at 30 ml/min to a blood loss of 400 ml. After each 100 ml of hemorrhage, vital signs (heart rate, systolic blood pressure, mean arterial pressure, diastolic blood pressure, pulse pressure, pulse pressure variation) and centrally obtained hemodynamic parameters (mean pulmonary artery pressure, pulmonary capillary wedge pressure, central venous pressure, cardiac output) were obtained. Blood volume was restored, and the pigs were over-resuscitated with 2,500 ml of crystalloid, collecting parameters after each 500-ml bolus. Hemorrhage and resuscitation phases were analyzed separately to determine differences among parameters over the range of volume. Conformity of parameters during hemorrhage or over-resuscitation was assessed. Results During the course of hemorrhage, changes from baseline euvolemia were observed in vital signs (systolic blood pressure, diastolic blood pressure, and mean arterial pressure) after 100 ml of blood loss. Central hemodynamic parameters (mean pulmonary artery pressure and pulmonary capillary wedge pressure) were changed after 200 ml of blood loss, and central venous pressure after 300 ml of blood loss. During the course of resuscitative volume overload, changes were observed from baseline euvolemia in mean pulmonary artery pressure and central venous pressure after 500-ml resuscitation, in pulmonary capillary wedge pressure after 1,000-ml resuscitation, and cardiac output after 2,500-ml resuscitation. In contrast to hemorrhage, vital sign parameters did not change during over-resuscitation. The strongest linear correlation was observed with pulmonary capillary wedge pressure in both hemorrhage (r2 = 0.99) and volume overload (r2 = 0.98). Conclusions Pulmonary capillary wedge pressure is the most accurate parameter to track both hemorrhage and over-resuscitation, demonstrating the unmet clinical need for a less invasive pulmonary capillary wedge pressure equivalent. Editor’s Perspective What We Already Know about This Topic What This Article Tells Us That Is New

Context Body composition in total pancreatectomy with islet autotransplantation (TPIAT) has never been studied. Objective Determine whether presurgical body composition is associated with islet function and insulin sensitivity after TPIAT. Methods In 88 adults undergoing TPIAT (median age 41.0 years, IQR 32.8-48.0), beta-cell function and insulin sensitivity were assessed using mixed meal tolerance test and frequent sample intravenous glucose tolerance test before surgery and 12 and 18 months afterward. Body composition was measured by dual x-ray absorptiometry. Analyses used linear and logistic regression. Results Before surgery, 8 individuals (9.1%) were underweight, 40 (45.5%) normal weight, 20 (22.7%) overweight, and 20 (22.7%) obese. Overweight/obese patients had higher area under the curve C-peptide and lower insulin sensitivity index. Baseline body weight was positively associated with first-phase insulin secretion (AIRg) at 12 months (average 38.5 [SE 17.1] mU/L/min higher per extra kg; P = 0.03) and 18 months (38.3 [18.5]; P = 0.04), while baseline lean mass was inversely associated with AIRg at 12 months (−0.05 [0.02] per extra kg; P = 0.01) and 18 months (−0.05 [0.02]; P = 0.03). Percent gynoid fat was inversely associated with disposition index at 18 months (−206.0 [97.2] per extra percent; P = 0.04). Percent body fat and percent gynoid fat were associated with glucose effectiveness index at 18 months (1.9 × 10-3 [0.9 × 10-3] per extra percent; P = 0.04 and −1.96 × 10-3 [0.8 × 10-3]; P = 0.02, respectively). Insulin independence was not significantly associated with body weight or composition. Conclusions Half of these chronic pancreatitis patients were overweight/obese; underweight was uncommon. Preoperative body weight and composition were associated with islet function but not insulin independence after TPIAT.

Background The identification of genetic risk factors for chronic pancreatitis, such as PRSS1, CFTR and SPINK1, provides the opportunity to define key pathologic hallmarks and etiologic-specific changes. For example, pancreata from PRSS1 and CFTR patients exhibit progressive lipomatous atrophy without significant fibrosis. Considering the pathology of SPINK1-associated pancreatitis is ill-defined, we examined the pancreata of SPINK1 patients with chronic pancreatitis. Methods Histologic sections after total pancreatectomy with islet autotransplantation and associated clinicopathologic data were collected from 28 patients with SPINK1 germline alterations. Clinical findings, germline data, anatomic anomalies and pathologic findings were descriptively evaluated. Results Patients ranged in age from 5 to 48 years (median, 21.6 years) with abdominal pain between 2 and 25 years (median, 5.8 years). Most patients were SPINK1 heterozygous and 14 (50%) had co-occurring CFTR (n = 12) and CTRC (n = 2) mutations. Other pancreatitis risk factors included anatomic anomalies (n = 9) and tobacco use (n = 1). Overall, 24 (86%) patients had additional pancreatitis-associated germline alterations, SPINK1 homozygosity, anatomic anomalies or environmental factors. Examination of pancreata revealed a sequential pattern of exocrine parenchymal loss and replacement by prominent fibrosis, dependent on the duration of abdominal pain. No malignancies were identified, but low-grade pancreatic intraepithelial neoplasia was present for 2 cases. Conclusions Within this descriptive study, SPINK1-associated pancreatitis is characterized by parenchymal fibrosis and suggests divergent pathophysiologic mechanisms from PRSS1 and CFTR-associated pancreatitis. Moreover, SPINK1 patients frequently had additional etiologic factors that did not impact the development of pancreatic fibrosis and may implicate SPINK1 as a disease modifier gene.

Background: The burden of surgical infections in low- and middle-income countries (LMICs) remains poorly defined compared with high-income countries. Although there are common infections necessitating surgery prevalent across the world, such as appendicitis and peptic ulcer disease, other conditions are more localized geographically. To date, comprehensive assessment of the burden of surgically treatable infections or sequelae of surgical infections in LMICs is lacking. Methods: We reviewed the literature to define the burden of surgical infections in LMICs and characterize the needs and challenges of addressing this issue. Results: Surgical infections comprise a broad range of diseases including intra-abdominal, skin and soft tissue, and healthcare-associated infections and other infectious processes. Treatment of surgical infections requires a functional surgical ecosystem, microbiology services, and appropriate and effective antimicrobial therapy. Systems must be developed and maintained to evaluate screening, prevention, and treatment strategies. Solutions and interventions are proposed focusing on reducing the burden of disease, improving surveillance, strengthening antibiotic stewardship, and enhancing the management of surgical infections. Conclusions: Surgical infections constitute a large burden of disease globally. Challenges to management in LMICs include a shortage of trained personnel and material resources. The increasing rate of antimicrobial drug resistance, likely related to antibiotic misuse, adds to the challenges. Development of surveillance, infection prevention, and antimicrobial stewardship programs are initial steps forward. Education is critical and should begin early in training, be an active process, and be sustained through regular programs.

Objectives A selective therapy for pancreatitis is total pancreatectomy and islet autotransplantation. Outcomes and geographical variability of patients who had total pancreatectomy (TP) alone or total pancreatectomy with islet autotransplantation (TPIAT) were assessed. Methods Data were obtained from the Healthcare Cost and Utilization Project National Inpatient Sample database. Weighed univariate and multivariate analyses were performed to determine the effect of measured variables on outcomes. Results Between 2002 and 2013, there were 1006 TP and 825 TPIAT in patients with a diagnosis of chronic pancreatitis, and 1705 TP and 830 TPIAT for any diagnosis of pancreatitis. The majority of the TP and TPIAT were performed in larger urban hospitals. Costs were similar for TP and TPIAT for chronic pancreatitis but were lower for TPIAT compared with TP for any type of pancreatitis. The trend for TP and TPIAT was significant in all geographical areas during the study period. Conclusions There is an increasing trend of both TP and TPIAT. Certain groups are more likely to be offered TPIAT compared with TP alone. More data are needed to understand disparities and barriers to TPIAT, and long-term outcomes of TPIAT such as pain control and glucose intolerance need further study.

Burn injury initiates a hypermetabolic response leading to muscle catabolism and organ dysfunction but has not been well-characterized by high-throughput metabolomics. We examined changes in metabolism over the first 72 h post-burn using proton nuclear magnetic resonance (1H-NMR) spectroscopy and serum from a porcine model of severe burn injury. We sought to quantify the changes in metabolism that occur over time in response to severe burn and smoke inhalation in this preliminary study. Fifteen pigs received 40% total body surface area (TBSA) burns with additional pine bark smoke inhalation. Arterial blood was drawn at baseline (pre-burn) and every 24 h until 72 h post-injury or death. The aqueous portion of each serum sample was analyzed using 1H-NMR spectroscopy and metabolite concentrations were used for principal component analysis (PCA). Thirty-eight metabolites were quantified in 39 samples. Of these, 31 showed significant concentration changes over time (p &lt, 0.05). PCA revealed clustering of samples by time point on a 2D scores plot. The first 48 h post-burn were characterized by high concentrations of histamine, alanine, phenylalanine, and tyrosine. Later timepoints were characterized by rising concentrations of 2-hydroxybutyrate, 3-hydroxybutyrate, acetoacetate, and isovalerate. No significant differences in metabolism related to mortality were observed. Our work highlights the accumulation of organic acids resulting from fatty acid catabolism and oxidative stress. Further studies will be required to relate accumulation of the four organic carboxylates identified in this analysis to outcomes from burn injury.

BACKGROUND: In critically ill patients, muscle loss is associated with adverse outcomes. Raw bioelectrical impedance analysis (BIA) parameters (eg, phase angle [PA] and impedance ratio [IR]) have received attention as potential markers of muscularity, nutrition status, and clinical outcomes. Our objective was to test whether PA and IR could be used to assess low muscularity and predict clinical outcomes.METHODS: Patients (≥18 years) having an abdominal computed tomography (CT) scan and admitted to intensive care underwent multifrequency BIA within 72 hours of scan. CT scans were landmarked at the third lumbar vertebra and analyzed for skeletal muscle cross-sectional area (CSA). CSA ≤170 cm(2) for males and ≤110 cm(2) for females defined low muscularity. The relationship between PA (and IR) and CT muscle CSA was evaluated using multivariate regression and included adjustments for age, sex, body mass index, Charlson Comorbidity Index, and admission type. PA and IR were also evaluated for predicting discharge status using dual-energy X-ray absorptiometry-derived cut-points for low fat-free mass index.RESULTS: Of 171 potentially eligible patients, 71 had BIA and CT scans within 72 hours. Area under the receiver operating characteristic (c-index) curve to predict CT-defined low muscularity was 0.67 (P ≤ .05) for both PA and IR. With covariates added to logistic regression models, PA and IR c-indexes were 0.78 and 0.76 (P < .05), respectively. Low PA and high IR predicted time to live ICU discharge.CONCLUSION: Our study highlights the potential utility of PA and IR as markers to identify patients with low muscularity who may benefit from early and rigorous intervention.

Blood is an ideal body fluid for the discovery or monitoring of diagnostic and prognostic protein biomarkers. However, discovering robust biomarkers requires the analysis of large numbers of samples to appropriately represent interindividual variability. To address this analytical challenge, we established a high-throughput and cost-effective proteomics workflow for accurate and comprehensive proteomics at an analytical depth applicable for clinical studies. For validation, we processed one μL each from 62 plasma samples in 96-well plates and analyzed the product by quantitative data-independent acquisition (DIA) liquid chromatography/mass spectrometry (LC/MS); the data were queried using feature quantification with Spectronaut. To show the applicability of our workflow to serum, we analyzed a unique set of samples from 48 chronic pancreatitis patients, pre- and post Total Pancreatectomy with Islet AutoTransplantation (TPIAT) surgery. We identified 16 serum proteins with a statistically significant abundance alteration, representing a molecular signature distinct from that of chronic pancreatitis. In summary, we established a cost-efficient high throughput workflow for comprehensive proteomics using PVDF-membrane-based digestion that is robust, automatable, and applicable to small plasma- and serum volumes, e.g. fingerstick. Application of this plasma/serum proteomics workflow resulted in the first mapping of the molecular implications of TPIAT on the serum proteome.

There is marked variability in vaccine efficacy among global populations. In particular, individuals in low- to middle-income countries have been shown to be less responsive to vaccines than those from developed nations. Several factors, including endemic infections, nutrition, genetics, and gut microbiome composition, have been proposed to underlie discrepancies in vaccine response. In this issue of the JCI, Kityo et al. evaluated response to yellow fever virus vaccine, inflammation, and lymphatic tissue architecture and fibrosis in three cohorts: two from the U.S. and one from Uganda. Compared with the U.S. subjects, the Ugandan cohort exhibited enhanced cytokine responses, increased lymph node fibrosis, reduced CD4(+) T cell levels, and reduced vaccine response. Together, these results provide a link among chronic inflammation, damaged lymphoid architecture, and poor vaccine outcome, and set the stage for future studies to identify strategies to overcome these barriers.

OBJECTIVES Approximately two thirds of patients will remain on insulin therapy after total pancreatectomy with islet autotransplant (TPIAT) for chronic pancreatitis. We investigated the relationship between measured pancreas volume on computerized tomography or magnetic resonance imaging and features of chronic pancreatitis on imaging, with subsequent islet isolation and diabetes outcomes. METHODS Computerized tomography or magnetic resonance imaging was reviewed for pancreas volume (Vitrea software) and presence or absence of calcifications, atrophy, and dilated pancreatic duct in 97 patients undergoing TPIAT. Relationship between these features and (1) islet mass isolated and (2) diabetes status at 1-year post-TPIAT were evaluated. RESULTS Pancreas volume correlated with islet mass measured as total islet equivalents (r = 0.50, P < 0.0001). Mean islet equivalents were reduced by more than half if any one of calcifications, atrophy, or ductal dilatation were observed. Pancreatic calcifications increased the odds of insulin dependence 4.0 fold (1.1, 15). Collectively, the pancreas volume and 3 imaging features strongly associated with 1-year insulin use (P = 0.07), islet graft failure (P = 0.003), hemoglobin A1c (P = 0.0004), fasting glucose (P = 0.027), and fasting C-peptide level (P = 0.008). CONCLUSIONS Measures of pancreatic parenchymal destruction on imaging, including smaller pancreas volume and calcifications, associate strongly with impaired islet mass and 1-year diabetes outcomes.

Total pancreatectomy with islet autotransplantation (TPIAT) is being used increasingly as a definitive treatment for chronic pancreatitis. Patients with chronic pancreatitis have an elevated risk of pancreatic cancer, which can also masquerade as acute or chronic pancreatitis, making the diagnosis challenging. We describe here the first case of pancreatic ductal adenocarcinoma developing in the liver of a patient after TPIAT for presumed benign chronic pancreatitis. Retrospective analysis of the patient's preoperative serum revealed normal carbohydrate antigen 19-9 and carcinoembryonic antigen levels but elevated levels of microRNAs -10b, -30c, and -106b compared with controls. Screening guidelines are important to reduce the risk of transplantation of malignant tissue. More sensitive screening tools, including the potential use of microRNAs, are needed to detect early preclinical disease, given the highly malignant nature of pancreatic cancer.

Hemorrhagic shock, a result of extensive blood loss, is a dominant factor in battlefield morbidity and mortality. Early rodent studies in hemorrhagic shock reported carbohydrate feeding prior to the induction of hemorrhagic shock decreased mortality. When repeated in our laboratory with a porcine model, carbohydrate pre-feed resulted in a 60% increase in death rate following hemorrhagic shock with trauma when compared to fasted animals (15/32 or 47% vs. 9/32 or 28%). In an attempt to explain the unexpected death rate for pre-fed animals, we further investigated the metabolic profiles of pre-fed non-survivors (n = 15) across 4 compartments (liver, muscle, serum, and urine) at specific time intervals (pre-shock, shock, and resuscitation) and compared them to pre-fed survivors (n = 17). As hypothesized, pre-fed pigs that died as a result of hemorrhage and trauma showed differences in their metabolic and physiologic profiles at all time intervals and in all compartments when compared to pre-fed survivors. Our data suggest that, although all animals were subjected to the same shock and trauma protocol, non-survivors exhibited altered carbohydrate processing as early as the pre-shock sampling point. This was evident in (for example) the higher levels of ATP and markers of greater anabolic activity in the muscle at the pre-shock time point. Based on the metabolic findings, we propose two mechanisms that connect pre-fed status to a higher death rate: (1) animals that die are more susceptible to opening of the mitochondrial permeability transition pore, a major factor in ischemia/reperfusion injury; and (2) loss of fasting-associated survival mechanisms in pre-fed animals.

Our objective was to analyze factors predicting outcomes after a total pancreatectomy and islet autotransplantation (TP-IAT).Chronic pancreatitis (CP) is increasingly treated by a TP-IAT. Postoperative outcomes are generally favorable, but a minority of patients fare poorly.In our single-centered study, we analyzed the records of 581 patients with CP who underwent a TP-IAT. Endpoints included persistent postoperative "pancreatic pain" similar to preoperative levels, narcotic use for any reason, and islet graft failure at 1 year.In our patients, the duration (mean ± SD) of CP before their TP-IAT was 7.1 ± 0.3 years and narcotic usage of 3.3 ± 0.2 years. Pediatric patients had better postoperative outcomes. Among adult patients, the odds of narcotic use at 1 year were increased by previous endoscopic retrograde cholangiopancreatography (ERCP) and stent placement, and a high number of previous stents (3). Independent risk factors for pancreatic pain at 1 year were pancreas divisum, previous body mass index30, and a high number of previous stents (3). The strongest independent risk factor for islet graft failure was a low islet yield-in islet equivalents (IEQ)-per kilogram of body weight. We noted a strong dose-response relationship between the lowest-yield category (2000 IEQ) and the highest (≥5000 IEQ or more). Islet graft failure was 25-fold more likely in the lowest-yield category.This article represents the largest study of factors predicting outcomes after a TP-IAT. Preoperatively, the patient subgroups we identified warrant further attention.

Lymph nodes and gut-associated lymphatic tissue are important reservoirs of the human immunodeficiency virus (HIV). Little is known about these reservoirs in different geographic populations. We report the surgical outcomes of excisional lymph node and anorectal mucosal biopsies performed internationally and describe the lessons learned.Patients were recruited through the Joint Clinical Research Center (JCRC) in Kampala, Uganda, where procedures were performed. Studies were approved by the Institutional Review Boards of the JCRC and the University of Minnesota. Instruments and supplies were shipped to Uganda and prepared onsite. Drugs and skin preparations were purchased locally. Lymph nodes were removed through 1-3 cm incisions with ligatures on lymphovascular pedicles. Incisions were closed with subcuticular sutures and epidermal tape. Two to four pieces of anorectal mucosa were obtained through anoscopes using biopsy forceps.One hundred thirty-eight lymph node biopsies and 98 anorectal mucosal biopsies were performed on 71 patients. Forty-one patients were HIV-positive. Many patients had multiple procedures. Two minor complications resulted: One hematoma and one lymphocele. Despite the cost of travel and lodging, cost per biopsy was lower in Uganda compared with the United States.Invasive clinical research can be performed with minimal morbidity in emerging nations with outcomes similar to those found in the United States, but with lower cost.

Background: Patients admitted to the intensive care unit with alcohol use disorders have increased morbidity and mortality. The purpose of this study was to determine how chronic alcohol ingestion alters the host response to sepsis in mice. Methods: Mice were randomized to receive either alcohol or water for 12 weeks and then subjected to cecal ligation and puncture. Mice were sacrificed 24 hours post-operatively or followed seven days for survival. Results: Septic alcohol-fed mice had a significantly higher mortality than septic water-fed mice (74% vs. 41%, p=0.01). This was associated with worsened gut integrity in alcohol-fed mice with elevated intestinal epithelial apoptosis, decreased crypt proliferation and shortened villus length. Further, alcohol-fed mice had higher intestinal permeability with decreased ZO-1 and occludin protein expression in the intestinal tight junction. The frequency of splenic and bone marrow CD4+ T cells was similar between groups; however, splenic CD4+ T cells in septic alcohol-fed mice had a marked increase in both TNF and IFN-c production following ex vivo stimulation. Neither the frequency nor function of CD8+ T cells differed between alcoholfed and water-fed septic mice. NK cells were decreased in both the spleen and bone marrow of alcohol-fed septic mice. Pulmonary myeloperoxidase levels and BAL levels of G-CSF and TFG-b were higher in alcohol-fed mice. Pancreatic metabolomics demonstrated increased acetate, adenosine, xanthine, acetoacetate, 3-hydroxybutyrate and betaine in alcohol-fed mice and decreased cytidine, uracil, fumarate, creatine phosphate, creatine, and choline. Serum and peritoneal cytokines were generally similar between alcohol-fed and water-fed mice, and there were no differences in bacteremia, lung wet to dry weight, or pulmonary, liver or splenic histology. Conclusions: When subjected to the same septic insult, mice with chronic alcohol ingestion have increased mortality. Alterations in intestinal integrity, the host immune response, and pancreatic metabolomics may help explain this differential response.

Lymphatic tissues (LTs) are structurally organized to promote interaction between antigens, chemokines, growth factors, and lymphocytes to generate an immunologic response and maintain normal-sized populations of CD4(+) and CD8(+) T cells. Inflammation and tissue remodeling that accompany local innate and adaptive immune responses to HIV-1 replication cause damage to the LT architecture. As a result, normal populations of CD4(+) and CD8(+) T cells cannot be supported and antigen-lymphocyte interactions are impaired. This conclusion is supported herein following LT sampling before and during anti-HIV therapy in persons with acute, chronic, and late-stage HIV-1 infection. Among seven individuals treated with anti-retroviral therapy (ART) and four individuals deferring therapy we found evidence of significant paracortical T cell zone damage associated with deposition of collagen, the extent of which was inversely correlated with both the size of the LT CD4(+) T cell population and the change in peripheral CD4(+) T cell count with anti-HIV therapy. The HIV-1-associated inflammatory changes and scarring in LT both limit the ability of the tissue to support and reestablish normal-sized populations of CD4(+) T cells and suggest a novel mechanism of T cell depletion that may explain the failure of ART to significantly increase CD4(+) T cell populations in some HIV-1-infected persons.

The objective was to determine the relationship of early hypothermia to multiple organ failure and mortality in severely injured trauma patients.

Background We evaluated the ability of experienced trauma surgeons to accurately predict specific blunt injuries, as well as patient disposition from the emergency department (ED), based only on the initial clinical evaluation and prior to any imaging studies. It would be hypothesized that experienced trauma surgeons’ initial clinical evaluation is accurate for excluding life-threatening blunt injuries and for appropriate admission triage decisions. Methods Using only their history and physical exam, and prior to any imaging studies, three (3) experienced trauma surgeons, with a combined Level 1 trauma experience of over 50 years, predicted injuries in patients with an initial GCS (Glasgow Coma Score) of 14–15. Additionally, ED disposition (ICU, floor, discharge to home) was also predicted. These predictions were compared to actual patient dispositions and to blunt injuries documented at discharge. Results A total of 101 patients with 92 blunt injuries were studied. 43/92 (46.7 %) injuries would have been missed by only performing an initial history and physical exam (“Missed injury”). A change in treatment, though often minor, was required in 19/43 (44.2 %) of the missed injuries. Only 1/43 (2.3 %) of these “missed injuries” (blunt aortic injury) required surgery. Sensitivity, specificity, and accuracy for injury prediction were 53.2, 95.9, and 92.3 % respectively. Positive and negative predictive values were 53.8 and 95.8 % respectively. Prediction of disposition from the ED was 77.8 % accurate. In 7/34 (20.6 %) patients, missed injuries led to changes in disposition. “Undertriage” occurred in 9/99 (9.1 %) patients (Predicted for floor but admitted to ICU). Additionally, 8/84 (9.5 %) patients predicted for floor admission were sent home from the ED; and 5/13 (38.5 %) patients predicted for ICU admission were actually sent to the floor after complete evaluations, giving an “overtriage” rate of 13/99 (13.1 %) patients. Conclusions In a neurologically-intact group of trauma patients, experienced trauma surgeons would have missed 46.7 % of the actual injuries, based only on their history and physical exam. Once accurate diagnoses of injuries were completed, usually with the help of CT scans, admission dispositions changed in 20.6 % of patients. Treatment changes occurred in 44.2 % of the missed injuries, though usually minimal. Broad elimination of early imaging studies in alert, blunt trauma patients cannot be advocated.

Background Near-infrared spectroscopy technology has been utilized to monitor perfusion status in animal models of hemorrhagic shock and in human traumatic injury. To observe the effectiveness of such a device in a combat setting, an FDA-approved device was used in conjunction with standard resuscitation and therapy of wounded patients presenting to the 228th Combat Support Hospital (CSH), Company B, over a three-month period. Materials and methods These observations were performed on patients presenting to the 228th CSH, Co B, at Forward Operating Base Speicher, outside of Tikrit, Iraq, between the dates of June 15 and September 11, 2005. We utilized the Inspectra™ 325 tissue oxygen saturation (StO2) monitor (Hutchinson Technology, Inc; Hutchinson, MN, USA) with the probe placed on the thenar eminence or on another appropriate muscle bed, and used to monitor StO2 during early resuscitation and stabilization of patients. Results During the above time period, 161 patients were evaluated at the CSH as a result of traumatic injury and the device was placed on approximately 40 patients. In most patients, StO2 readings of greater than 70% were noted during the initial evaluation. No further information was collected from these patients. In 8 patients, convenience samples of StO2 data were collected along with pertinent physiologic data. In these patients, StO2 levels of below 70% tracked with hypotension, tachycardia, and clinical shock resulted in increases in StO2 after resuscitation maneuvers. Conclusion Near-infrared spectroscopy-derived StO2 reflected and tracked the resuscitation status of our patients with battlefield injuries. StO2 has significant potential for use in resuscitation and care of patients with battlefield injuries.