The Surgical Infection Society Guidelines on the Management of Intra-Abdominal Infection: 2024 Update.

Background: The Surgical Infection Society (SIS) published evidence-based guidelines for the management of intra-abdominal infection (IAI) in 1992, 2002, 2010, and 2017. Here, we present the most recent guideline update based on a systematic review of current literature. Methods: The writing group, including current and former members of the SIS Therapeutics and Guidelines Committee and other individuals with content or guideline expertise within the SIS, working with a professional librarian, performed a systematic review using PubMed/Medline, the Cochrane Library, Embase, and Web of Science from 2016 until February 2024. Keyword descriptors combined "surgical site infections" or "intra-abdominal infections" in adults limited to randomized controlled trials, systematic reviews, and meta-analyses. Additional relevant publications not in the initial search but identified during literature review were included. The Grading of Recommendations, Assessment, Development, and Evaluations (GRADE) system was utilized to evaluate the evidence. The strength of each recommendation was rated strong (1) or weak (2). The quality of the evidence was rated high (A), moderate (B), or weak (C). The guideline contains new recommendations and updates to recommendations from previous IAI guideline versions. Final recommendations were developed by an iterative process. All writing group members voted to accept or reject each recommendation. Results: This updated evidence-based guideline contains recommendations from the SIS for the treatment of adult patients with IAI. Evidence-based recommendations were developed for antimicrobial agent selection, timing, route of administration, duration, and de-escalation; timing of source control; treatment of specific pathogens; treatment of specific intra-abdominal disease processes; and implementation of hospital-based antimicrobial agent stewardship programs. Summary: This document contains the most up-to-date recommendations from the SIS on the prevention and management of IAI in adult patients.

invariant Natural Killer T Cells Modulate the Peritoneal Macrophage Response to Polymicrobial Sepsis.

INTRODUCTION: A dysregulated immune system is a major driver of the mortality and long-term morbidity from sepsis. With respect to macrophages, it has been shown that phenotypic changes are critical to effector function in response to acute infections, including intra-abdominal sepsis. Invariant natural killer T cells (iNKT cells) have emerged as potential central regulators of the immune response to a variety of infectious insults. Specifically, various iNKT cell:macrophage interactions have been noted across a spectrum of diseases, including acute events such as sepsis. However, the potential for iNKT cells to affect peritoneal macrophages during an abdominal septic event is as yet unknown. METHODS: Cecal ligation and puncture (CLP) was performed in both wild type (WT) and invariant natural killer T cell knockout (iNKT-/-) mice. 24 h following CLP or sham operation, peritoneal macrophages were collected for analysis. Analysis of macrophage phenotype and function was undertaken to include analysis of bactericidal activity and cytokine or superoxide production. RESULTS: Within iNKT-/- mice, a greater degree of intraperitoneal macrophages in response to the sepsis was noted. Compared to WT mice, within iNKT-/- mice, CLP did induce an increase in CD86+ and CD206+, but no difference in CD11b+. Unlike WT mice, intra-abdominal sepsis within iNKT-/- mice induced an increase in Ly6C-int (5.2% versus 14.9%; P < 0.05) and a decrease in Ly6C-high on peritoneal macrophages. Unlike phagocytosis, iNKT cells did not affect macrophage bactericidal activity. Although iNKT cells did not affect interleukin-6 production, iNKT cells did affect IL-10 production and both nitrite and superoxide production from peritoneal macrophages. CONCLUSIONS: The observations indicate that iNKT cells affect specific phenotypic and functional aspects of peritoneal macrophages during polymicrobial sepsis. Given that pharmacologic agents that affect iNKT cell functioning are currently in clinical trial, these findings may have the potential for translation to critically ill surgical patients with abdominal sepsis.

INHIBITION OF INTEGRIN VLA-3 AND TETRASPANIN CD151 PROTECTS AGAINST NEUTROPHIL-MEDIATED ENDOTHELIAL DAMAGE.

ABSTRACT: Background: The recruitment of neutrophils to sites of localized injury or infection is initiated by changes on the surface of endothelial cells located in proximity to tissue damage. Inflammatory mediators, such as TNF-α, increase surface expression of adhesive ligands and receptors on the endothelial surface to which neutrophils tether and adhere. Neutrophils then transit through the activated endothelium to reach sites of tissue injury with little lasting vascular injury. However, in cases of sepsis, the interaction of endothelial cells with highly activated neutrophils can cause damage vascular damage. The identification of molecules that are essential for neutrophil diapedesis may reveal targets of therapeutic opportunity for preservation of endothelial function in the presence of critical illness. We tested the hypothesis that inhibition of neutrophil ß1 integrin very late antigen-3 (VLA-3; α3ß1) and/or inhibition of the tetraspanin (TM4) family member CD151 would protect against neutrophil-mediated loss of endothelial function. Methods: Blood was obtained from septic patients or healthy donors. Neutrophils were purified, and aliquots were treated with/without proinflammatory molecules. Confluent human umbilical vascular endothelial cells were activated with TNF-α. Electric cell impedance sensing was used to determine monolayer resistance over time after the addition of neutrophils that were treated with blocking antibodies against VLA-3 and/or CD151 or isotype controls. Groups (depending on relevancy) were analyzed by Mann-Whitney U test, Wilcoxon test, or repeated-measures one-way ANOVA. Results: Neutrophils from septic patients and neutrophils activated ex vivo reduced endothelial monolayer resistance to a greater extent than neutrophils from healthy donors. Antibody blockade of VLA-3 and/or CD151 significantly reduced activation-associated endothelial damage. Similar findings were demonstrated on fibronectin, collagen I, collagen IV, and laminin, suggesting that neutrophil surface VLA-3 and CD151 are responsible for endothelial damage regardless of substrata and are likely to be operative in all bodily tissues. Conclusion: This report identifies VLA-3 and CD151 on the activated human neutrophil, which are responsible for damage to endothelial function. Targeting these molecules in vivo may demonstrate preservation of organ function during critical illness.

Severity of critical illness correlates with CD3-low expression on iNKT-cells among septic surgical patients.

BACKGROUND: iNKT-cells are innate regulatory lymphocytes capable of directing immune and inflammatory responses to sepsis. Repeat stimulation of iNKT-cells leads to the induction of anergy with the emergence of a hyporesponsive CD3low iNKT-cell subpopulation. METHODS: iNKT-cells were isolated from critical ill surgical patients with sepsis and phenotyped for CD3 expression. This was correlated with degree of severity of illness, as denoted by APACHE-II score. RESULTS: Comparing healthy volunteers to critically ill septic patients, it was noted that increasing severity of sepsis was associated with increasing frequency of circulating CD3low-iNKT-cell populations. CONCLUSION: The emergence of CD3low -iNKT-cells may serve as a clinically translatable marker of degree of sepsis-induced immune dysfunction.

SPLENIC INVARIANT NATURAL KILLER T CELLS PLAY A SIGNIFICANT ROLE IN THE RESPONSE TO POLYMICROBIAL SEPSIS.

ABSTRACT: Background: Sepsis is marked by a dysregulated immune response to an infection. Invariant natural killer T cells ( i NKT cells) are a pluripotent lymphocyte subpopulation capable of affecting and coordinating the immune response to sepsis. The spleen is an important site of immune interactions in response to an infection. Splenic i NKT cells have emerged as important potential frontline mediators of chronic immune response. There are few data addressing the role splenic of i NKT cells in response to intra-abdominal polymicrobial sepsis. Methods: The cecal ligation and puncture model was used to create intra-abdominal sepsis in 8- to 12-week-old wild-type, i NKT -/- , or programmed cell death receptor-1 (PD-1) -/- mice. Twenty-four hours later, spleens were harvested. Flow cytometry was used for phenotyping using monoclonal antibodies. Cell sort was used to isolate i NKT cells. A macrophage cell line was used to assess i NKT cell-phagocyte interactions. Enzyme-linked immunosorbent assay was used for cytokine analysis. Results: Splenic i NKT-cell populations rapidly declined following induction of sepsis. Within i NKT-cell -/- mice, a distinct baseline hyperinflammatory environment was noted. Within wild type, sepsis induced an increase in splenic IL-6 and IL-10, whereas in i NKT -/- mice, there was no change in elevated IL-6 levels and a noted decrease in IL-10 expression. Further, following sepsis, PD-1 expression was increased upon spleen i NKT cells. With respect to PD-1 ligands upon phagocytes, PD-1 ligand expression was unaffected, whereas PD-L2 expression was significantly affected by the presence of PD-1. Conclusions: Invariant natural killer T cells play a distinct role in the spleen response to sepsis, an effect mediated by the checkpoint protein PD-1. Given that modulators are available in clinical trials, this offers a potential therapeutic target in the setting of sepsis-induced immune dysfunction.

Lymphocyte HVEM/BTLA co-expression after critical illness demonstrates severity indiscriminate upregulation, impacting critical illness-induced immunosuppression.

Introduction: The co-regulatory molecule, HVEM, can stimulate or inhibit immune function, but when co-expressed with BTLA, forms an inert complex preventing signaling. Altered HVEM or BTLA expression, separately have been associated with increased nosocomial infections in critical illness. Given that severe injury induces immunosuppression, we hypothesized that varying severity of shock and sepsis in murine models and critically ill patients would induce variable increases in HVEM/BTLA leukocyte co-expression. Methods: In this study, varying severities of murine models of critical illness were utilized to explore HVEM+BTLA+ co-expression in the thymic and splenic immune compartments, while circulating blood lymphocytes from critically ill patients were also assessed for HVEM+BTLA+ co-expression. Results: Higher severity murine models resulted in minimal change in HVEM+BTLA+ co-expression, while the lower severity model demonstrated increased HVEM+BTLA+ co-expression on thymic and splenic CD4+ lymphocytes and splenic B220+ lymphocytes at the 48-hour time point. Patients demonstrated increased co-expression of HVEM+BTLA+ on CD3+ lymphocytes compared to controls, as well as CD3+Ki67- lymphocytes. Both L-CLP 48hr mice and critically ill patients demonstrated significant increases in TNF-α. Discussion: While HVEM increased on leukocytes after critical illness in mice and patients, changes in co-expression did not relate to degree of injury severity of murine model. Rather, co-expression increases were seen at later time points in lower severity models, suggesting this mechanism evolves temporally. Increased co-expression on CD3+ lymphocytes in patients on non-proliferating cells, and associated TNF-α level increases, suggest post-critical illness co-expression does associate with developing immune suppression.

Bowel Obstruction from an Incidentally Ingested Foreign Body.

Small bowel obstructions are common surgical presentations that are most often caused by adhesions following abdominopelvic surgeries. However, in patients with no history of abdominal surgical interventions, assessment of the cause of a small bowel obstruction is more complex, and such patients frequently require operative intervention. We present a case of a 65-year-old man who presented with a small bowel obstruction caused by an inadvertent ingestion of a bread tag that was not identified on preoperative imaging. The sharp end of the bread tag had eroded through the small bowel leading to a walled-off perforation of the small bowel. Surgical resection was required.

Management of Acute Appendicitis in HIV/AIDs Patients: A 19-year Review from the National In-Patient Sample.

BACKGROUND: Acute Appendicitis (AA), one of the most common surgical emergencies, is usually managed operatively. There is a paucity of data addressing how HIV/AIDS affects management of acute uncomplicated appendicitis. METHODS: A retrospective review of HIV/AIDS positive (HPos) versus negative (HNeg) patients with acute, uncomplicated appendicitis over a 19-year period. The primary outcome was undergoing appendectomy. RESULTS: Among 912,779 AA patients, 4,291 patients were HPos. HIV rates increased from 3.8/1,000 in 2000 to 6.3 per 1,000 appendicitis cases in 2019 (p<0.001). HPos patients were older, less likely to have private insurance, and more likely to have psychiatric illnesses, hypertension, and a history of prior malignancy. HPos AA patients underwent operative intervention less often than HNeg AA patients (90.7% versus 97.7%;p<0.001). Overall, comparing HPos to HNeg patients, there was no difference in post-operative infections or mortality. CONCLUSION: HIV-positive status should not deter surgeons from offering definitive care for acute uncomplicated appendicitis.

Disparities in Decompressive Cranial Surgery Utilization in Severe Traumatic Brain Injury Patients without a Primary Extra-Axial Hematoma: A U.S. Nationwide Study.

OBJECTIVE: Decompressive craniectomy is recommended to reduce mortality in severe traumatic brain injury (TBI). Disparities exist in TBI treatment outcomes; however, data on disparities pertaining to decompressive craniectomy utilization is lacking. We investigated these disparities, focusing on race, insurance, sex, and age. METHODS: Hospitalizations (2004-2014) were retrospectively extracted from the Nationwide Inpatient Sample. The criteria included are as follows: age ≥18 years and indicators of severe TBI diagnosis. Poor outcomes were defined as discharge to institutional care and death. Multivariable logistic regression models were used to assess the effects of race, insurance, age, and sex, on craniectomy utilization and outcomes. RESULTS: Of 349,164 hospitalized patients, 6.8% (n = 23,743) underwent craniectomy. White (odds ratio [OR] = 0.50, 95% confidence interval [CI] = 0.44-0.57; P < 0.001) and Black (OR = 0.45, 95% CI = 0.32-0.64; P = 0.003) Medicare beneficiaries were less likely to undergo craniectomy. Medicare (P < 0.0001) and Medicaid beneficiaries (P < 0.0001) of all race categories had poorer outcomes than privately insured White patients. Black (OR = 1.2, 95% CI = 1.08-2.34; P = 0.001) patients with private insurance and Black (OR = 1.39, 95% CI = 1.22-1.58; P < 0.0001) Medicaid beneficiaries had poorer outcomes than privately insured White patients (P < 0.0001). Older patients (OR = 0.74, 95%, CI = 0.71-0.76; P < 0.001) were less likely to undergo craniectomy and were more likely to have poorer outcomes. Females (OR = 0.82, 95% CI = 0.76-0.88; P < 0.001) were less likely to undergo craniectomy. CONCLUSIONS: There are disparities in race, insurance status, sex, and age in craniectomy utilization and outcome. This data highlights the necessity to appropriately address these disparities, especially race and sex, and actively incorporate these factors in clinical trial design and enrollment.

The Impact of Protective Devices Across the Spectrum of Trauma Care and Across Racial Groupings.

INTRODUCTION: Protective devices such as seat belts and helmets save lives. Most studies only address one aspect of the injury profile - compliance or mortality - not the entire spectrum of trauma care, and little attention is paid to racial differences in the use or impact of protective devices. METHODS: Patients with blunt mechanisms where using protective devices would be expected were included and were divided into utilizing (P) vs not utilizing protection (Non-P). Chart review included demographics, injuries sustained, hemodynamics, and blood alcohol level. Outcomes included need for emergent operation, complications and death. RESULTS: Non-P patients were more likely male, presented at night and intoxicated. Highest risk behavior (intoxicated Non-P) presented at night (25.7% of nighttime presentations), and rarely during daytime (6.7% daytime presentations). Non-P were more likely hypotensive and sustain a traumatic brain injury. No race related differences were noted among young patients. Among older (>/=50 years) patients, White patients were least likely Non-P and least likely presented at night. Non-P required more emergent operative intervention, ICU admission, and longer hospital stay. Overall, Non-P was associated with increased risk of death (OR = 1.6 (95% CI = 1.28 - 2.11). CONCLUSION: Given unique age and racial differences, we advocate for culturally and age specific public service campaigns.

Machine learning models to prognose 30-Day Mortality in Postoperative Disseminated Cancer Patients.

Patients with disseminated cancer at higher risk for postoperative mortality see improved outcomes with altered clinical management. Being able to risk stratify patients immediately after their index surgery to flag high risk patients for healthcare providers is vital. The combination of physician uncertainty and a demonstrated optimism bias often lead to an overestimation of patient life expectancy which can precent proper end of life counseling and lead to inadequate postoperative follow up. In this cohort study of 167,474 postoperative patients with multiple types of disseminated cancer, patients at high risk of 30-day postoperative mortality were accurately identified using our machine learning models based solely on clinical features and preoperative lab values. Extreme Gradient Boosting, Random Forest, and Logistic Regression machine learning models were developed on the cohort. Among 167,474 disseminated cancer patients, 50,669 (30.3%) died within 30 days of their index surgery; After preprocessing, 28 features were included in the model development. The cohort was randomly divided into 133,979 patients (80%) for training the models and 33,495 patients (20%) for testing. The extreme gradient boosting model had an AUC of 0.93 (95% CI: 0.926-0.931), the random forest model had an AUC of 0.93 (95% CI: 0.930-0.934), and the logistic regression model had an AUC of 0.90 (95% CI: 0.900-0.906 the index operation. Ultimately, Machine learning models were able to accurately predict short-term postoperative mortality among a heterogenous population of disseminated cancer patients using commonly accessible medical features. These models can be included in electronic health systems to guide clinical judgements that affect direct patient care, particularly in low-resource settings.

The association between household and neighborhood characteristics and COVID-19 related ICU admissions.

Introduction: Approaches to COVID-19 mitigation can be more efficiently delivered with a more detailed understanding of where the severe cases occur. Our objective was to assess which demographic, housing and neighborhood characteristics were independently and collectively associated with differing rates of severe COVID-19. Methods: A cohort of patients with SARS-CoV-2 in a single health system from March 1, 2020 to February 15, 2021 was reviewed to determine whether demographic, housing, or neighborhood characteristics are associated with higher rates of severe COVID-19 infections and to create a novel scoring index. Characteristics included proportion of multifamily homes, essential workers, and ages of the homes within neighborhoods. Results: There were 735 COVID-19 ICU admissions in the study interval which accounted for 61 percent of the state's ICU admissions for COVID-19. Compared to the general population of the state those admitted to the ICU with COVID-19 were disproportionately older, male sex, and were more often Black, Indigenous, People of Color. Patients disproportionately resided in neighborhoods with three plus unit multifamily homes, homes built before 1940, homes with more than one person to a room, homes of lower average value, and in neighborhoods with a greater proportion of essential workers. From this our COVID-19 Neighborhood Index value was comparatively higher for the ICU patients (61.1) relative to the population of Rhode Island (49.4). Conclusion: COVID-19-related ICU admissions are highly related to demographic, housing and neighborhood-level factors. This may guide more nuanced and targeted vaccine distribution plans and public health measures for future pandemics.

Comparison of Infectious Complications after Surgical Fixation versus Epidural Analgesia for Acute Rib Fractures.

Background: Surgical stabilization of rib fractures (SSRF) is associated with decreased mortality and respiratory complications. Patients who are not offered SSRF are often treated with epidural analgesia (EA) to reduce pain and improve pulmonary mechanics. We sought to compare infectious complications in patients undergoing either SSRF or EA. We hypothesized that infectious complications are equivalent between the two treatment groups. Patients and Methods: We performed a retrospective cohort study of adult trauma patients with acute rib fractures within the Trauma Quality Improvement Program (TQIP) 2017 dataset and used International Classification of Diseases, Tenth Revision, Clinical Modification (ICD-10-CM) codes to identify patients who underwent SSRF or EA. We excluded patients who received both treatments in the same admission. Our primary outcome was the development of sepsis. Secondary outcomes were specific infections including ventilator-associated pneumonia (VAP), catheter-associated urinary tract infection (CAUTI), and central line-associated blood stream infections (CLABSI). Multiple logistic regression analyses were used to adjust for age, injury severity score (ISS), chest Abbreviated Injury Scale (AIS), flail chest, traumatic brain injury (TBI), and comorbidities. Results: We identified 2,252 and 1,299 patients who underwent SSRF and EA, respectively. Patients with SSRF were younger with higher ISS and longer length of stay (LOS). There was no difference in mortality, however, SSRF had higher rate of sepsis (1.6% vs. 0.5%; p = 0.001), VAP (5.1% vs. 0.9%; p < 0.001), CAUTI (1.7% vs. 0.5%; p = 0.001), and CLABSI (0.2% vs. 0%; p = 0.05). On multiple regression, SSRF was associated with higher odds of sepsis (odds ratio [OR], 2.63; 95% confidence interval [CI], 1.04-6.63), CAUTI (OR, 2.96; 95% CI, 1.11-7.88), and VAP (OR, 3.24; 95% CI, 1.73-6.06). Among those who developed sepsis, there was no significant difference in mortality or LOS between groups. Conclusions: Despite no difference in mortality, SSRF was associated with increased risk of septic complications in patients with rib fractures compared to epidural analgesia. Identifying, and addressing, risk factors of sepsis in this patient population is a critical performance improvement process to optimize outcomes without increased adverse events.

Machine learning methods to predict presence of residual cancer following hysterectomy.

Surgical management for gynecologic malignancies often involves hysterectomy, often constituting the most common gynecologic surgery worldwide. Despite maximal surgical and medical care, gynecologic malignancies have a high rate of recurrence following surgery. Current machine learning models use advanced pathology data that is often inaccessible within low-resource settings and are specific to singular cancer types. There is currently a need for machine learning models to predict non-clinically evident residual disease using only clinically available health data. Here we developed and tested multiple machine learning models to assess the risk of residual disease post-hysterectomy based on clinical and operative parameters. Data from 3656 hysterectomy patients from the NSQIP dataset over 14 years were used to develop models with a training set of 2925 patients and a validation set of 731 patients. Our models revealed the top postoperative predictors of residual disease were the initial presence of gross abdominal disease on the diaphragm, disease located on the bowel mesentery, located on the bowel serosa, and disease located within the adjacent pelvis prior to resection. There were no statistically significant differences in performances of the top three models. Extreme gradient Boosting, Random Forest, and Logistic Regression models had comparable AUC ROC (0.90) and accuracy metrics (87-88%). Using these models, physicians can identify gynecologic cancer patients post-hysterectomy that may benefit from additional treatment. For patients at high risk for disease recurrence despite adequate surgical intervention, machine learning models may lay the basis for potential prospective trials with prophylactic/adjuvant therapy for non-clinically evident residual disease, particularly in under-resourced settings.

The Insurance Coverage Paradox - Characterizing Outcomes among Dual-Eligible Hemorrhagic Stroke Patients.

BACKGROUND: Socioeconomic factors, such as insurance status, have been shown to affect outcomes for patients following emergency injuries. Dual-eligible beneficiaries, receiving both Medicare and Medicaid, constitute an especially vulnerable population. There is limited data addressing whether dual-eligible beneficiaries with hemorrhagic stroke display unique characteristics and outcomes compared to patients with Medicare, Medicaid, or private insurance. STUDY DESIGN: We conducted a retrospective analysis of 10-years of National Inpatient Sample data. Using ICD-9-CM codes, we identified adult patients with known insurance status who were emergently hospitalized for intracranial hemorrhage; epidural, subdural, subarachnoid, and intracerebral hemorrhages were included. Patient characteristics including whether they underwent surgical intervention were collected. Multivariable logistic regression was used to adjust for confounders. Primary clinical outcomes of interest included mortality (in-hospital), complications (any), and favorable discharge (home/home with services). RESULTS: Among 410,621 patients, dual-eligible (6.8%) patients were on average older (mean age = 73yrs) compared to Medicaid (46yrs), private insurance (67yrs), or no-charge (47yrs) patients. Caucasian race was highest among Medicare patients (83%) while African-American race was highest among Medicaid (22%). Among all patients, 5.3% underwent operative intervention. Dual-eligibles had significantly higher odds of in-hospital mortality compared to no-charge (adjusted odds ratio (aOR) = 1.61, 95% CI = [1.04 - 2.49]), but no significant difference between Medicare and Medicaid although dual-eligibles. Dual-eligibles had significantly increased odds of complications compared to Medicaid (aOR = 1.23, 95% CI = [1.11 - 1.37]) and privately insured patients (aOR = 1.19, 95% CI = [1.11 - 1.28]), both p < 0.001, and lower odds of favorable discharge compared to all other groups, all p < 0.001. Dual-eligibles underwent a shorter length of stay, an 18% decrease, compared to Medicaid patients (ß-Coefficient = 0.82, 95% CI = [0.78 - 0.86], p < 0.001), and inflation adjusted admission costs that were 24% lower compared to Medicaid patients (ß-Coefficient = 0.76, 95% CI = [0.73 - 0.80], p < 0.001), amounting to a $3,684 decrease in cost. CONCLUSIONS: Dual-eligible beneficiaries experience unique health disparities from lower odds of favorable discharge to increased odds of complications and in-hospital mortality compared to other insured and uninsured groups. Adverse outcomes among dual-eligible beneficiaries highlight the need to uncover and address unknown sources of disparities to improve emergency treatment of hemorrhagic stroke in this population.

A Case of Recurrent Malignant Melanoma of the Left Foot with In-Transit Metastases.

We report a 73-year-old male with recurrent amelanotic malignant melanoma of the left foot with in-transit metastases to the left thigh. In-transit metastatic melanoma can often represent a diagnostic and therapeutic challenge for physicians. This patient was treated with talimogene laherparepvec injections (T-VEC; Imlygic) in the left inguinal and the left plantar region every two weeks for one year as oncolytic viral therapy for advanced non- operable malignant melanoma. He then received consistent follow-up including blood work and PET scans every four months, and he also required further lymph node surgical dissection. To date, our patient has survived 3 years and 11 months, which is 27 months longer than the esti- mated median survival of 1 year 8 months for patients diagnosed with in-transit metastatic melanoma.

Adding Infectious Insult to Traumatic Injury: The Impact of Infectious Complications in End-of-Life Decision Making.

Background: Trauma increases the risk for infection, but it is unknown how infection affects goals-of-care (GOC) decision making. We sought to determine how infections impact transition to comfort measures only (CMO), hypothesizing that infectious complications would expedite withdrawal of life-sustaining treatment (WOLST). Patients and Methods: We performed a retrospective review at a level-one trauma center over two years for adult patients without pre-existing advance directives who were made CMO with length of stay longer than one day. Demographics, injuries, and hospital course including infections and the GOC timeline were collected. Patients were divided on the basis of infection development, defined as an infectious complication requiring antibiotics or more invasive intervention, with subgroup analysis comparing those with single versus multiple infections. The primary end point was time to death or discharge. Results: Two hundred thirty-two patients met inclusion criteria and 72 developed an infection. Pneumonia was the most common infection (53.8%). Although those in the infection group had no substantial difference in demographics or comorbidities, they had higher emergency department Glasgow Coma Scale (GCS; 14 vs. 13), lower rate of head injury (28.6 vs. 49%), and higher time to death or discharge (12 vs. 2 days). Goals-of-care discussions were initiated later based on time to first family meeting (7 vs. 1 days), most occurring after the first infection. Subsequent analysis showed that versus those with a single infection (n = 38), those with multiple infections (n = 34) had a higher time to death or discharge (16.5 vs. 10.5 days) despite no difference in demographics, comorbidities, or trauma severity. Time to first family meeting was longer (8.5 vs. 4.5 days) with most occurring after the first infection. Conclusions: We did not find that development of an infection shortens time to WOLST. The increased time to death or discharge in the setting of multiple infections and similar patient populations may be a marker of provider approach to GOC plus family beliefs. Infectious complications play an uncertain role in end-of-life discussions after trauma.

Survival and Pulmonary Injury After Neonatal Sepsis: PD1/PDL1's Contributions to Mouse and Human Immunopathology.

Morbidity and mortality associated with neonatal sepsis remains a healthcare crisis. PD1-/- neonatal mice endured experimental sepsis, in the form of cecal slurry (CS), and showed improved rates of survival compared to wildtype (WT) counterparts. End-organ injury, particularly of the lung, contributes to the devastation set forth by neonatal sepsis. PDL1-/- neonatal mice, in contrast to PD1-/- neonatal mice did not have a significant improvement in survival after CS. Because of this, we focused subsequent studies on the impact of PD1 gene deficiency on lung injury. Here, we observed that at 24 h post-CS (but not at 4 or 12 h) there was a marked increase in pulmonary edema (PE), neutrophil influx, myeloperoxidase (MPO) levels, and cytokine expression sham (Sh) WT mice. Regarding pulmonary endothelial cell (EC) adhesion molecule expression, we observed that Zona occludens-1 (ZO-1) within the cell shifted from a membranous location to a peri-nuclear location after CS in WT murine cultured ECs at 24hrs, but remained membranous among PD1-/- lungs. To expand the scope of this inquiry, we investigated human neonatal lung tissue. We observed that the lungs of human newborns exposed to intrauterine infection had significantly higher numbers of PD1+ cells compared to specimens who died from non-infectious causes. Together, these data suggest that PD1/PDL1, a pathway typically thought to govern adaptive immune processes in adult animals, can modulate the largely innate neonatal pulmonary immune response to experimental septic insult. The potential future significance of this area of study includes that PD1/PDL1 checkpoint proteins may be viable therapeutic targets in the septic neonate.

Emerging therapeutic targets for sepsis.

Introduction: Sepsis is characterized by a dysregulated host response to infection. Sepsis-associated morbidity/mortality demands concerted research efforts toward therapeutic interventions which are reliable, broadly effective, and etiologically based. More intensive and extensive investigations on alterations in cellular signaling pathways, gene targeting as a means of modifying the characteristic hyper and/or hypo-immune responses, prevention through optimization of the microbiome, and the molecular pathways underlying the septic immune response could improve outcomes.] Areas covered: The authors discuss key experimental mammalian models and clinical trials. They provide an evaluation of evolving therapeutics in sepsis and how they have built upon past and current treatments. Relevant literature was derived from a PubMed search spanning 1987-2020.Expert opinion: Given the complex nature of sepsis and the elicited immune response, it is not surprising that a single cure-all therapeutic intervention, which is capable of effectively and reliably improving patient outcomes has failed to emerge. Innovative approaches seek to address not only the disease process but modify underlying patient factors. A true improvement in sepsis-associated morbidity/mortality will require a combination of unique therapeutic modalities.