GENETIC ABLATION OF THE C-TYPE LECTIN RECEPTOR CLEC2D INCREASES PERITONITIS MORTALITY, INFLAMMATION AND PHYSIOLOGY WITHOUT DIMINISHING ORGAN INJURY.

BACKGROUND: Sepsis accounts for substantial morbidity and mortality motivating investigators to continue the search for pathways and molecules driving the pathogenesis of the disease. The current study examined if the novel C-type Lectin Receptor (CLR), Clec2d, plays a significant role in the pathogenesis of sepsis. METHODS: Clec2d knockout (KO) mice were fully backcrossed onto the C57\BL6 background. Acute endotoxemia was induced with an intraperitoneal (i.p.) injection of lipopolysaccharide (LPS). Sepsis was induced in two different models, Cecal Ligation and Puncture (CLP) and Pseudomonas aeruginosa pneumonia. Both models were treated with antibiotics and fluid resuscitation. In the sepsis models, physiologic and hematologic measurements were measured at 24 hours by collecting a small sample of peripheral blood. Mortality was followed for 14 days. RESULTS: A total of 197 mice were studied, 58 wild type (WT) and 54 knock-out (KO) in the LPS model; 27 wild type and 21 KO mice in the CLP model; and 22 WT and 15 KO mice in the pneumonia model. Clec2d KO mice had greater mortality in the LPS and CLP studies but not the pneumonia model. There were significant differences in multiple parameters determined 24 hours post sepsis between mice who would subsequently died and those lived. Consistent with previous reports in the CLP model, higher concentrations of IL-6, increased numbers of peripheral blood lymphocytes and greater renal injury were found in the dying mice. In contrast, in the pneumonia model IL-6 was higher in the surviving mice, however, the IL-6 levels in the pneumonia model (0.6 ± 0.3 ng/ml mean ± SEM) were less than 2% of the IL-6 levels of mice that died in the CLP model (41 ± 9 ng/ml, mean ± SEM). There were no differences in the lymphocyte count or renal injury between living and dying mice in the pneumonia model. In both sepsis models dying mice had lower heart rates, respiratory rates, and body temperatures. These values were also lower in the KO mice compared to the WT in CLP, but the breath rate and body temperature were increased in the KO pneumonia mice. CONCLUSION: The C-type lectin receptor Clec2d plays a complicated role in the pathogenesis of sepsis which varies with source of infection as demonstrated in the models used to study the disease. These data highlight the heterogeneity of the responses to sepsis and provide further evidence that a single common pathway driving sepsis organ injury and death likely does not exist.

Application of creatinine height index in patients with trauma for the evaluation of psoas muscle mass: A clinical validation study.

BACKGROUND: The creatinine height index (CHI) is an estimate of lean body mass. We hypothesize that a modified CHI estimate using serum creatinine (sCr) levels in patients with normal renal function when performed soon after injury would reflect preinjury protein nutrition status. METHODS: The urine CHI (uCHI) was calculated using the 24-h urine sample. The serum-derived estimated CHI (sCHI) was calculated using the sCr on admission. Correlation between abdominal computed tomography images at specific lumbar vertebral levels and total body fat and muscle content was used for comparison as an independent measurement of nutrition status unlikely to be substantially altered by trauma. RESULTS: A total of 45 patients were enrolled, all with a significant injury burden (median injury severity score [ISS] = 25; interquartile range, 17-35). The calculated sCHI on admission was 71.0% (SD = 26.9%) and likely underestimates the CHI when compared with uCHI (mean = 112.5%, SD = 32.6%). Stratifying by degree of stress demonstrated that in a group of 23 moderately and severely stressed patients, uCHI (mean = 112.7%, SD = 5.7%) and sCHI (mean = 60.8%, SD = 1.9%) were significantly different and without correlation (r = -0.26, P = 0.91). In patients without stress, there was a significant negative correlation between sCHI and psoas muscle area (r = -0.869, P = 0.03), and in patients with severe stress there was a significant positive correlation between uCHI and psoas muscle area (r = 0.733, P = 0.016). CONCLUSION: The CHI calculated from the initial sCr is not an appropriate estimate of uCHI in critically ill trauma patients and is not a valid measure of psoas muscle mass in this setting.

HYDROCORTISONE, ASCORBIC ACID, AND THIAMINE THERAPY DECREASE RENAL OXIDATIVE STRESS AND ACUTE KIDNEY INJURY IN MURINE SEPSIS.

ABSTRACT: Background: Acute kidney injury (AKI) occurs frequently in septic patients and correlates with increased mortality. Because clinical studies investigating hydrocortisone, ascorbic acid, and thiamine (HAT) have demonstrated discordant results, studies were performed using mortality stratification for therapy to identify candidates for therapy and determine mechanisms of organ injury. Methods: Sepsis was induced using the cecal ligation and puncture (CLP) model of sepsis with fluid and antibiotic support. Heart rate (HR) measurements obtained 6 hours after CLP stratified mice into live predicted (P-Live) or die predicted (P-Die). Stratified mice were then randomized for treatment with HAT or vehicle given 7 hours after CLP. Physiologic measurements were taken again at 24 hours, and mice were killed to collect blood and organs. Results: The following five groups were created: (1) P-Live vehicle, (2) P-Live HAT, (3) P-Die vehicle, (4) P-Die HAT, and (5) naive mice. Comparisons were made to test the hypotheses that (1) P-Die vehicle mice will have significant deterioration compared with P-Live mice targeting the kidney and (2) HAT will correct these deleterious changes in P-Die mice. Compared with P-Live, P-Die mice had a significant decline in all measured physiologic parameters (HR, cardiac output, breath rate, and temperature), which were corrected with HAT therapy (P < 0.05 for all parameters). The P-Die mice had declines in the ascorbic acid within the blood, peritoneal lavage, and kidney homogenate compared with P-Live mice indicating consumption, and the decline was corrected with HAT. Elevated IL-6, KC, Macrophage Inflammatory Protein-2, and IL-1RA were found in P-Die mice and decreased with HAT. Markers of endothelial cell injury (glypican 1 and glypican 4) were elevated in the P-Die mice, and these values were decreased with HAT therapy. Low oxygen levels with subsequent oxidative stress (OS) in the kidney were visualized in histologic sections using hypoxyprobe and also with carbonyl proteins and 8-iso-prostaglandin F2α in kidney homogenates. The P-Die mice had significant elevations of renal OSs, which was ameliorated with HAT. Kidney injury was evident in the P-Die mice compared with P-Live mice with elevations in blood urea nitrogen and cystatin C, which were significantly reduced with HAT. There was no evidence of global hypoxia or organ injury because hepatic parameters remained normal. Conclusions: Our data show that in CLP-induced sepsis, P-Die mice have increased inflammation, OS, and kidney injury. Hydrocortisone, ascorbic acid, and thiamine therapy decreased renal OS and injury in the P-Die group when given after the onset of sepsis-induced physiologic changes.

Machine learning and murine models explain failures of clinical sepsis trials.

BACKGROUND: Multiple clinical trials failed to demonstrate the efficacy of hydrocortisone, ascorbic acid, and thiamine (HAT) in sepsis. These trials were dominated by patients with pulmonary sepsis and have not accounted for differences in the inflammatory responses across varying etiologies of injury/illness. Hydrocortisone, ascorbic acid, and thiamine have previously revealed tremendous benefits in animal peritonitis sepsis models (cecal ligation and puncture [CLP]) in contradiction to the various clinical trials. The impact of HAT remains unclear in pulmonary sepsis. Our objective was to investigate the impact of HAT in pneumonia, consistent with the predominate etiology in the discordant clinical trials. We hypothesized that, in a pulmonary sepsis model, HAT would act synergistically to reduce end-organ dysfunction by the altering the inflammatory response, in a unique manner compared with CLP. METHODS: Using Pseudomonas aeruginosa pneumonia, a pulmonary sepsis model (pneumonia [PNA]) was compared directly to previously investigated intra-abdominal sepsis models. Machine learning applied to early vital signs stratified animals into those predicted to die (pDie) versus predicted to live (pLive). Animals were then randomized to receive antibiotics and fluids (vehicle [VEH]) vs. HAT). Vitals, cytokines, vitamin C, and markers of liver and kidney function were assessed in the blood, bronchoalveolar lavage, and organ homogenates. RESULTS: PNA was induced in 119 outbred wild-type Institute of Cancer Research mice (predicted mortality approximately 50%) similar to CLP. In PNA, interleukin 1 receptor antagonist in 72-hour bronchoalveolar lavage was lower with HAT (2.36 ng/mL) compared with VEH (4.88 ng/mL; p = 0.04). The remaining inflammatory cytokines and markers of liver/renal function showed no significant difference with HAT in PNA. PNA vitamin C levels were 0.62 mg/dL (pDie HAT), lower than vitamin C levels after CLP (1.195 mg/dL). Unlike CLP, PNA mice did not develop acute kidney injury (blood urea nitrogen: pDie, 33.5 mg/dL vs. pLive, 27.6 mg/dL; p = 0.17). Furthermore, following PNA, HAT did not significantly reduce microscopic renal oxidative stress (mean gray area: pDie, 16.64 vs. pLive, 6.88; p = 0.93). Unlike CLP where HAT demonstrated a survival benefit, HAT had no impact on survival in PNA. CONCLUSION: Hydrocortisone, ascorbic acid, and thiamine therapy has minimal benefits in pneumonia. The inflammatory response induced by pulmonary sepsis is unique compared with the response during intra-abdominal sepsis. Consequently, different etiologies of sepsis respond differently to HAT therapy.

Defining Sepsis Phenotypes-Two Murine Models of Sepsis and Machine Learning.

INTRODUCTION: The immunobiology defining the clinically apparent differences in response to sepsis remains unclear. We hypothesize that in murine models of sepsis we can identify phenotypes of sepsis using non-invasive physiologic parameters (NIPP) early after infection to distinguish between different inflammatory states. METHODS: Two murine models of sepsis were used: gram-negative pneumonia (PNA) and cecal ligation and puncture (CLP). All mice were treated with broad spectrum antibiotics and fluid resuscitation. High-risk sepsis responders (pDie) were defined as those predicted to die within 72 h following infection. Low-risk responders (pLive) were expected to survive the initial 72 h of sepsis. Statistical modeling in R was used for statistical analysis and machine learning. RESULTS: NIPP obtained at 6 and 24 h after infection of 291 mice (85 PNA and 206 CLP) were used to define the sepsis phenotypes. Lasso regression for variable selection with 10-fold cross-validation was used to define the optimal shrinkage parameters. The variables selected to discriminate between phenotypes included 6-h temperature and 24-h pulse distention, heart rate (HR), and temperature. Applying the model to fit test data (n = 55), area under the curve (AUC) for the receiver operating characteristics (ROC) curve was 0.93. Subgroup analysis of 120 CLP mice revealed a HR of <620 bpm at 24 h as a univariate predictor of pDie. (AUC of ROC curve = 0.90). Subgroup analysis of PNA exposed mice (n = 121) did not reveal a single predictive variable highlighting the complex physiological alterations in response to sepsis. CONCLUSION: In murine models with various etiologies of sepsis, non-invasive vitals assessed just 6 and 24 h after infection can identify different sepsis phenotypes. Stratification by sepsis phenotypes can transform future studies investigating novel therapies for sepsis.

The impact of English proficiency on outcomes after bariatric surgery.

BACKGROUND: Several studies demonstrated language that discordant care between may lead to mixed outcomes and increased use of hospital-resources. In the setting of bariatric surgery, which relies heavily on intensive pre-operative and post-operative counseling, we hypothesized that patients with LEP would have less favorable outcomes compared to English-proficient (EP) patients. METHODS: All patients 18 years and older, who underwent laparoscopic sleeve gastrectomy (SG) or laparoscopic gastric bypass (LGBP) from January 2013 to December 2017 were included. Language proficiency was determined by chart review for the use of an interpreter at least once during the study period. Outcomes of interest at 30-days and 1 year included: emergency department (ED) visits, readmission, length of stay (LOS), chief-complaint on readmission, and post-operative complications. Additionally, comorbidity remission and weight loss at one year was recorded. RESULTS: A total of 671 patients were categorized as LEP (40%) and spoke 6 unique languages. Within the 1 year post-operative period, EP patients presented to the ED more than LEP patients (23% vs. 14% p < 0.001). After multivariable regression for potential confounders this difference persisted; adjusted OR = 0.65 (95% CI 0.43-0.95; p = 0.029). However, despite more frequent ED visits by EP patients, there was no significant difference in readmission within one year; adjusted OR = 0.94 (95% CI 0.56-1.55; p = 0.50). Both groups demonstrated similar successful weight loss at 1 year: EP-31.85% (LGBP) and - 28.02% (SG) vs. LEP-30.17% (LGBP) and - 28.36% (SG). EP and LEP patients also had similar remission of obesity-related comorbidities. CONCLUSION: There were no differences in outcomes following bariatric surgery when comparing patients with limited English proficiency to those who are proficient in English. Bariatric surgical care can be delivered in a safe and effective manner with equivalent outcomes between patients who are and are not English-language proficient.

Early metabolic support for critically ill trauma patients: A prospective randomized controlled trial.

BACKGROUND: There is a lack of consensus regarding the optimal nutritional support for trauma patients. We hypothesize that early postinjury metabolic support focusing on adequate protein would modify the metabolic signature and alter the inflammatory environment for critically ill trauma patients. METHODS: We conducted a prospective randomized controlled pilot trial for adult patients admitted to the surgical intensive care unit following traumatic injury. Patients were randomized to receive early metabolic support (EMS) (peripheral amino acid infusions) or standard of care (enteral nutrition as soon as feasible). Routine laboratory assessments, nitrogen balance, cytokines, and metabolomic analyses were assessed at baseline and day 5 after intervention. RESULTS: A total of 42 trauma patients were randomized into well-balanced groups with similar age (32 years), Injury Severity Score (25), and body mass index (27.4 kg/m2). Early metabolic support provided significantly more protein (1.43 g/kg vs. 0.35 g/kg; p < 0.0001) and more calories (12.6 kcal/kg vs. 7.5 g/kg; p = 0.0012) over the first 5 days as compared with the standard of care. Early metabolic support modified protein catabolism and synthesis as demonstrated by a larger median negative nitrogen balance (-16.3 g vs. -5.3 g; p = 0.03) and a unique metabolomic profile at day 5. The biochemical profile of patients who received EMS was defined by greater declines in circulating levels of stress hormone precursors and increased levels of amino acids. The inflammatory response following EMS resulted in a greater decrease in interleukin-1B (p = 0.02) and increase in soluble interleukin-6 receptor (p = 0.01) between baseline and day 5 as compared with the standard of care. The EMS group had a decreased length of stay (15 vs. 22 days) and decreased surgical intensive care unit length of stay (8 vs. 9 days); however, this disappeared after adjustment for Injury Severity Score in this small population. CONCLUSIONS: Early metabolic support with amino acid is safe, modifies metabolism, and may downregulate the inflammatory state associated with significant trauma, warranting a larger trial to assess for improved outcomes. LEVEL OF EVIDENCE: Therapeutic/Care Management; Level II.

Cytokine Drizzle-The Rationale for Abandoning "Cytokine Storm".

BACKGROUND: "Cytokine storm" has been used to implicate increased cytokine levels in the pathogenesis of serious clinical conditions. Similarities with Severe Acute Respiratory Syndrome Coronoavirus-2 (SARS CoV-2) and the 2012 Middle Eastern Respiratory Syndrome led early investigators to suspect a "cytokine storm" resulting in an unregulated inflammatory response associated with the significant morbidity and mortality induced by SARS CoV-2. The threshold of blood cytokines necessary to qualify as a "cytokine storm" has yet to be defined. METHODS: A literature review was conducted to identify cytokine levels released during 11 assorted clinical conditions or diseases. Weighted averages for various cytokines were calculated by multiplying the number of patients in the paper by the average concentration of each cytokine. Correlation between cytokine levels for individual conditions or diseases were assessed using Pearson correlation coefficient. RESULTS: The literature was reviewed to determine blood levels of cytokines in a wide variety of clinical conditions. These conditions ranged from exercise and autoimmune disease to septic shock and therapy with chimeric antigen receptor T cells. The most frequently measured cytokine was IL-6 which ranged from 24,123 pg/mL in septic shock to 11 pg/mL after exercise. In patients with severe SARS CoV-2 infections, blood levels of IL-6 were only 43 pg/mL, nearly three magnitudes lower than IL-6 levels in patients with septic shock. The clinical presentations of these different diseases do not correlate with blood levels of cytokines. Additionally, there is poor correlation between the concentrations of different cytokines among the different diseases. Specifically, blood levels of IL-6 did not correlate with levels of IL-8, IL-10, or TNF. Septic shock had the highest concentrations of cytokines, yet multiple cytokine inhibitors have failed to demonstrate improved outcomes in multiple clinical trials. Patients with autoimmune diseases have very low blood levels of cytokines (rheumatoid arthritis, IL-6 = 34 pg/mL; Crohn's disease, IL-6 = 5 pg/mL), yet respond dramatically to cytokine inhibitors. CONCLUSION: The misleading term "cytokine storm" implies increased blood levels of cytokines are responsible for a grave clinical condition. Not all inflammatory conditions resulting in worsened disease states are correlated with significantly elevated cytokine levels, despite an association with the term "cytokine storm". "Cytokine storm" should be removed from the medical lexicon since it does not reflect the mediators driving the disease nor does it predict which diseases will respond to cytokine inhibitors.

Amplifying inequity: The compounding impact of COVID-19 and violence.

While "stay-at-home" orders for COVID-19 were in effect, many American cities witnessed a rise in community and interpersonal violence. Our own institution, the largest regional trauma facility and Boston's safety net hospital, saw a paradoxical rise in penetrating violent trauma admissions despite decreases in other hospital admissions, leading to our most violent summer in five years. It has been established that minoritized and marginalized communities have faced the harshest impacts of the pandemic. Our findings suggest that the conditions created by the COVID-19 pandemic have amplified the inequities that exist in communities of color that place them at risk for exposure to violence. The pandemic has served to potentiate the impacts of violence already plaguing the communities and patients we serve.

Mentoring experience of new surgeons during their transition to independent practice: A nationwide survey.

BACKGROUND: New surgeons are faced with inadequate mentoring when first entering practice. Our study examined challenges faced by young surgeons during their transition in practice and their mentoring experience when entering practice. METHODS: An article-based survey was mailed in August 2019 to general, colorectal, vascular, and cardiothoracic surgeons that became members of the American College of Surgeons within the past 5 years. RESULTS: A total of 853 of 2,915 surveys were completed (29.3% response rate). Both female (38%) and male (62%) surgeons participated. The 3 most common challenges during the transition to practice were confidence building (26.0%), adjusting to a new institutional culture (16.9%), and business and administrative aspects of practice (16.3%). First job attrition rate 44.2%, with the mean duration of the first job being 3.28 ± 0.17 years. Nearly one-third (28.3%) of respondents were not mentored when they first entered practice. The proportion of nonmentored young surgeons leaving their first job (64.3%) was almost twice as that of surgeons who received mentoring (36.3%). Furthermore, the mean duration of the first job was significantly shorter in nonmentored versus mentored surgeons (3.16 ± 0.26 vs 3.76 ± 0.25 years; P < .05). A significant number (43.3%) of respondents reported a desire to be mentored by retired surgeons. CONCLUSION: Our survey highlights the importance of mentoring for young surgeons during their transition into practice. With many young surgeons being enthusiastic about mentoring by retired surgeons, specific programs are necessary to better use their expertise.

Addressing General Surgery Residents' Concerns in the Early Phase of the COVID-19 Pandemic.

OBJECTIVE: The purpose of this study was to determine the concerns of General Surgery residents as they prepare to be in the frontlines of the response against coronavirus disease 2019 (COVID-19_). DESIGN, SETTING, AND PARTICIPANTS: A qualitative study with voluntary dyadic and focus group interviews with a total of 30 General Surgery residents enrolled at 2 academic medical centers in Boston, Massachusetts was conducted between March 12 to 16, 2020. RESULTS: The most commonly reported personal concern related to the COVID-19 outbreak was the health of their family (30 of 30 [100%]), followed by the risk of their transmitting COVID-19 infection to their family members (24 of 30 [80%]); risk of their transmitting COVID-19 infection their patients (19 of 30 [63%]); anticipated overwork for taking care of a high number of patients (15 of 30 [50%]); and risk of their acquiring COVID-19 infection from their patients (8 of 30 [27%]) . The responses were comparable when stratified by sex, resident training level, and residency program. All residents self-expressed their readiness to take care of COVID-19 patients despite the risk of personal or familial harm . To improve their preparedness, they recommend increasing testing capacity, ensuring personal protective equipment availability, and transitioning to a shift schedule in order to minimize exposure risk and prevent burnout. CONCLUSIONS: General Surgery residents are fully dedicated to taking care of patients with COVID-19 infection despite the risk of personal or familial harm. Surgery departments should protect the physical and psychosocial wellbeing of General Surgery residents in order to increase their ability to provide care in the frontlines of the COVID-19 pandemic.

Mentorship of Surgical Interns: Are We Failing to Meet Their Needs?

OBJECTIVE: This study aimed to determine the challenges faced by surgical trainees during their internship and to explore their experience with mentoring. DESIGN: An internet-based survey comprised of 30 questions was distributed to 59 surgical interns to evaluate their internship experience at the conclusion of the academic year 2018 to 2019. SETTING: Four academic medical centers in Boston, Massachusetts. PARTICIPANTS: Both preliminary as well as categorical general surgery interns were included in the study. Twenty-five responses were received (response rate of 42.4%). RESULTS: The majority of surgical interns (80%) reported having a mentor during their intern year. Gender as well as mentor career status/prestige were both the highest rated factors in selection of a mentor, (4.67/5 and 4.33/5 respectively). Mentoring topics varied by the career status of the mentor, with most surgical interns (80%) selecting senior faculty members for mentoring on career planning, clinical training, and research. Surgical interns relied only on junior faculty members to discuss work-life integration. Very few surveyed interns (only 1 in 10) discussed work-life integration with their mentors despite this being reported as the most significant challenge of their internship year. Only 15% of the interns reported that the effectiveness of the mentor-mentee relationship was reviewed by program administration. About one third (30%) of interns reported that they would not feel comfortable reporting a failed mentorship to their program director. Furthermore, 40% of the surgical interns were not given an option to choose a new mentor in case of failed mentoring. CONCLUSIONS: Surgical interns report high work demands and challenges with worklife integration in their first year of surgical training, however only a small minority of interns discuss this with their mentors. Surgical residency programs should better supervise and adjust mentoring of surgical interns in order to maximize their performance and wellness.