Functional Characterization of Neutrophils Allows Source Control Evaluation in a Murine Sepsis Model.

INTRODUCTION: Current surgical guidelines for the treatment of intra-abdominal sepsis recommend interventional source control as the key element of therapy, alongside resuscitation and antibiotic administration. Past trials attempted to predict the success of interventional source control to assess whether further interventional therapy is needed. However, no predictive score could be developed. MATERIALS AND METHODS: We utilized an established murine abdominal sepsis model, the cecal ligation and puncture (CLP), and performed a successful surgical source control intervention after full development of sepsis, the CLP-excision (CLP/E). We then sought to evaluate the success of the source control by characterizing circulating neutrophil phenotype and functionality 24 h postintervention. RESULTS: We showed a significant relative increase of neutrophils and a significant absolute and relative increase of activated neutrophils in septic mice. Source control with CLP/E restored these numbers back to baseline. Moreover, main neutrophil functions, the acidification of cell compartments, such as lysosomes, and the production of Tumor Necrosis Factor-alpha (TNF-α), were impaired in septic mice but restored after CLP/E intervention. CONCLUSIONS: Neutrophil characterization by phenotyping and evaluating their functionality indicates successful source control in septic mice and can serve as a prognostic tool. These findings provide a rationale for the phenotypic and functional characterization of neutrophils in human patients with infection. Further studies will be needed to determine whether a predictive score for the assessment of successful surgical source control can be established.

Surprising neutral effect of shorter staple cartridges in laparoscopic sleeve gastrectomy.

BACKGROUND: Consensus agreements regarding laparoscopic sleeve gastrectomy (LSG) advise against using staple loads less than 1.5 mm in closed staple height. However, few data exist to support this recommendation. We hypothesized that using staples with a shorter closed height would actually decrease incidence of intraoperative and postoperative bleeding during LSG, while not increasing the incidence of leak. METHODS: All LSG cases for a single institution from 1/1/2014 to 12/31/2019 were exported for analysis. Two cohorts were established: 1. 'Green/Blue' group was cases in which no white cartridges were used and 2. 'White' group was cases in which any white cartridges were used. Demographic variables, procedural characteristics, hospital length of stay, and postoperative outcomes were compared between groups. RESULTS: The study populations included 1710 patients, 974 in the green/blue group and 736 in the white cartridge group. There were no significant differences in postoperative leak, bleed, stricture, readmission, or death while using white staple loads as compared with the standard combination of blue and green loads. CONCLUSION: Using staples with a shorter closed height during LSG did not impact the postoperative bleeding or leak rate. The impact from selection of shorter staples to achieve more tissue compression may be limited.

Multisite study of Titan SGS stapler in longitudinal gastric resection.

BACKGROUND: Standardization of the laparoscopic sleeve gastrectomy procedure is needed to improve patient outcomes. A single-fire 23 cm stapler was developed to streamline the operation. Comparative testing conducted on excised human tissue has demonstrated the superiority of the novel Titan SGS stapler to two commonly utilized commercial devices in both staple line integrity and burst pressure. We hypothesized that the stapler would be safe and effective in creating longitudinal gastric resections in human patients. METHODS: 61 patients were enrolled to undergo gastric resection with the Titan SGS stapler. Perioperative interventions and post-operative adverse events were recorded. Upper GI study was completed on post-operative day 1, and patients were followed for 6 weeks post-operatively to determine any subacute device-related adverse events. RESULTS: Surgeon feedback for intraoperative device utilization and post-operative gastric pouch shape were positive. Adverse events were found to be mild, limited, and generally well-known effects of bariatric surgery. One episode of post-operative hemorrhage required surgical takeback, with no criminal bleeding vessel identified. CONCLUSION: The Titan SGS stapler is both safe and effective in sleeve gastrectomy pouch creation.

Impact of a Multimodal Analgesia Protocol on Inpatient and Outpatient Opioid Use in Acute Trauma.

BACKGROUND: Multimodal analgesia protocols have been implemented after elective surgery to reduce opioid use, however there is limited data on utility after polytrauma. Therefore, we investigated the impact of a multimodal analgesia protocol on inpatient and post-discharge outpatient opioid use after polytrauma. METHODS: A retrospective review of patients admitted to a Level I trauma center between September 2017-February 2018 (prior to multimodal protocol; "pre-cohort") and October 2018-April 2019 (after multimodal protocol; "post-cohort") was performed. An outpatient controlled substance registry was utilized to capture morphine milligram equivalents (MME) and gabapentin dispensed in the 6 mo after injury. RESULTS: 620 patients were included (295 pre-cohort, 325 post-cohort). Total inpatient MME decreased from 177.5 mg-130 mg (P= 0.01) between the cohorts. Daily inpatient MME decreased from 70.8 mg-44.7 mg (P< 0.01). Intravenous hydromorphone decreased from 2 mg in the pre-cohort to 1 mg in the post-cohort (P= 0.02). Inpatient oxycodone decreased from 45 mg-30 mg (P= 0.01). Concurrently, gabapentin increased from 0 mg-400 mg in the post-cohort (P< 0.01). Patients in the post-cohort were prescribed fewer MMEs than the pre-cohort at discharge (P< 0.05). However, the number of patients prescribed gabapentin increased from 6.1%-16% (P< 0.01). CONCLUSION: Implementation of an updated multimodal analgesia protocol decreased total MME, daily MME, hydromorphone, and oxycodone consumed while increasing gabapentin use. This suggests that while reducing opioid usage in-hospital is critical to reducing outpatient usage, multimodal pain protocols may lead to an increase in gabapentin prescriptions and utilization after discharge.

Intraperitoneal Neutrophil IL-10 production is promoted by interferon γ in a murine model of sepsis model in the acute phase of sepsis.

The disease burden of sepsis continues to increase, with intraabdominal contamination being a significant source of infection. Sepsis is a syndrome involving both an increase in systemic inflammation as well as a regulatory component. We have previously demonstrated that neutrophils are significant IL-10 producers in the abdomen during sepsis. Here, we sought to further characterize these neutrophils and elucidate potential underlying mechanisms resulting in IL-10 generation. Using transcriptional reporter mice, we observed that IL-10 producing neutrophils were activated, non-apoptotic, and expressed C-X-C chemokine receptor type 4-expressing. Further, we observed that active Signal Transducer and Activator of Transcription 1 expression was significantly increased in IL-10 producing versus non-IL-10 producing neutrophils. During sepsis, IFN-γ blockade lead to a decrease of neutrophil IL-10 production, while peritoneal CD4 T cells were found to be the most numerous acute producers of IFN-γ. Altogether, this report demonstrates that during sepsis, mature neutrophils can potentially dampen local inflammation by IL-10 production and this can be orchestrated by CD4 T cells through an IFN-γ dependent manner.

H1N1 influenza vaccination in HIV-infected women on effective antiretroviral treatment did not induce measurable antigen-driven proliferation of the HIV-1 proviral reservoir.

OBJECTIVES: Antigen-induced activation and proliferation of HIV-1-infected cells is hypothesized to be a mechanism of HIV persistence during antiretroviral therapy. The objective of this study was to determine if proliferation of H1N1-specific HIV-infected cells could be detected following H1N1 vaccination. METHODS: This study utilized cryopreserved PBMC from a previously conducted trial of H1N1 vaccination in HIV-infected pregnant women. HIV-1 DNA concentrations and 437 HIV-1 C2V5 env DNA sequences were analyzed from ten pregnant women on effective antiretroviral therapy, before and 21 days after H1N1 influenza vaccination. RESULTS: HIV-1 DNA concentration did not change after vaccination (median pre- vs. post-vaccination: 95.77 vs. 41.28 copies/million PBMC, p = .37). Analyses of sequences did not detect evidence of HIV replication or proliferation of infected cells. CONCLUSIONS: Antigenic stimulation during effective ART did not have a detectable effect on the genetic makeup of the HIV-1 DNA reservoir. Longitudinal comparison of the amount and integration sites of HIV-1 in antigen-specific cells to chronic infections (such as herpesviruses) may be needed to definitively evaluate whether antigenic stimulation induces proliferation of HIV-1 infected cells.

Experience of surgical subspecialty residents on general surgery rotations.

BACKGROUND: Surgical subspecialty residents complete 5-6 years of training which includes general surgery rotations. A lack of data exists evaluating these rotations. This study aims to identify discrepancies in subspecialty training and improve the quality of surgical education. METHODS: Case logs for surgical subspecialty residents and general surgery residents at our institution were analyzed and queried for cases performed on general surgery rotations. A survey was distributed to subspecialty residents regarding their perceptions of these rotations. RESULTS: 50 residents were included in the study and the majority were male (n = 27, 54%). Subspecialty residents perform fewer cases per month compared to general surgery residents (13 vs 21, p < 0.001). 75% of subspecialty residents were satisfied with their experience on general surgery rotations. CONCLUSIONS: Subspecialty residents perform fewer operations on general surgery rotations. Despite this, most are satisfied with off-service rotations and believe they are an important part of their education.

Do General Surgery Residents Begin Specializing Before Fellowship? A Multi-Institutional Study from the US ROPE Consortium.

BACKGROUND: Single-center data suggest that general surgery residents perform more cases related to their future fellowship compared with their peers. This study aimed to determine whether this experience was true for residents across multiple programs. STUDY DESIGN: Data from graduates of 18 Accreditation Council for Graduate Medical Education (ACGME)-accredited general surgery residency programs in the US Resident OPerative Experience (ROPE) Consortium were analyzed. Residents were categorized as entering 1 of 12 fellowships or entering directly into general surgery practice. Case log operative domains were mapped to each fellowship, and analyses were performed between groups. RESULTS: Of 1,192 graduated general surgery residents, 955 (80%) pursued fellowship training whereas 235 (20%) went directly into general surgery practice. The top 3 fellowships pursued were trauma/surgical critical care (18%), vascular surgery (13%), and minimally invasive surgery (12%). Residents entering minimally invasive surgery performed the most total cases, whereas residents pursuing breast performed the least (1,209 [1,056-1,325] vs 1,091 [1,006-1,171], p < 0.01). For each fellowship type, graduates completed more total fellowship-specific cases in their future specialty compared with their peers (all p < 0.05). This association was observed for all 12 fellowships at the surgeon chief level (all p < 0.05) and for 10 of 12 fellowships at the surgeon junior level (all p < 0.05). CONCLUSIONS: General surgery residents perform more cases related to their future specialty choice compared with their peers. These data suggest that the specialization process begins during residency. This tendency among residents should be considered as general surgery residency undergoes structural redesign in the future.

A multi-institutional study from the US ROPE Consortium examining factors associated with directly entering practice upon residency graduation.

BACKGROUND: There is concern regarding the competency of today's general surgery graduates as a large proportion defer independent practice in favor of additional fellowship training. Little is known about the graduates who directly enter general surgery practice and if their operative experiences during residency differ from graduates who pursue fellowship. METHODS: Nineteen Accreditation Council for Graduate Medical Education-accredited general surgery programs from the US Resident OPerative Experience Consortium were included. Demographics, career choice, and case logs from graduates between 2010 to 2020 were analyzed. RESULTS: There were 1,264 general surgery residents who graduated over the 11-year period. A total of 248 (19.6%) went directly into practice and 1,016 (80.4%) pursued fellowship. Graduates directly entering practice were more likely to be a high-volume resident (43.1% vs 30.5%, P < .01) and graduate from a high-volume program (49.2% vs 33.0%, P < .01). Direct-to-practice graduates performed 53 more cases compared with fellowship-bound graduates (1,203 vs 1,150, P < .01). On multivariable analysis, entering directly into practice was positively associated with total surgeon chief case volume (odds ratio = 1.47, 95% confidence interval 1.18-1.84, P < .01) and graduating from a US medical school (odds ratio = 2.54, 95% confidence interval 1.45-4.44, P < .01) while negatively associated with completing a dedicated research experience (odds ratio = 0.31, 95% confidence interval 0.22-0.45, P < .01). CONCLUSION: This is the first multi-institutional study exploring resident operative experience and career choice. These data suggest residents who desire immediate practice can tailor their experience with less research time and increased operative volume. These data may be helpful for programs when designing their experience for residents with different career goals.

Potential Targets to Mitigate Trauma- or Sepsis-Induced Immune Suppression.

In sepsis and trauma, pathogens and injured tissue provoke a systemic inflammatory reaction which can lead to overwhelming inflammation. Concurrent with the innate hyperinflammatory response is adaptive immune suppression that can become chronic. A current key issue today is that patients who undergo intensive medical care after sepsis or trauma have a high mortality rate after being discharged. This high mortality is thought to be associated with persistent immunosuppression. Knowledge about the pathophysiology leading to this state remains fragmented. Immunosuppressive cytokines play an essential role in mediating and upholding immunosuppression in these patients. Specifically, the cytokines Interleukin-10 (IL-10), Transforming Growth Factor-ß (TGF-ß) and Thymic stromal lymphopoietin (TSLP) are reported to have potent immunosuppressive capacities. Here, we review their ability to suppress inflammation, their dynamics in sepsis and trauma and what drives the pathologic release of these cytokines. They do exert paradoxical effects under certain conditions, which makes it necessary to evaluate their functions in the context of dynamic changes post-sepsis and trauma. Several drugs modulating their functions are currently in clinical trials in the treatment of other pathologies. We provide an overview of the current literature on the effects of IL-10, TGF-ß and TSLP in sepsis and trauma and suggest therapeutic approaches for their modulation.

Lymphocyte Immunosuppression and Dysfunction Contributing to Persistent Inflammation, Immunosuppression, and Catabolism Syndrome (PICS).

ABSTRACT: Persistent Inflammation, Immune Suppression, and Catabolism Syndrome (PICS) is a disease state affecting patients who have a prolonged recovery after the acute phase of a large inflammatory insult. Trauma and sepsis are two pathologies after which such an insult evolves. In this review, we will focus on the key clinical determinants of PICS: Immunosuppression and cellular dysfunction. Currently, relevant immunosuppressive functions have been attributed to both innate and adaptive immune cells. However, there are significant gaps in our knowledge, as for trauma and sepsis the immunosuppressive functions of these cells have mostly been described in acute phase of inflammation so far, and their clinical relevance for the development of prolonged immunosuppression is mostly unknown. It is suggested that the initial immune imbalance determines the development of PCIS. Additionally, it remains unclear what distinguishes the onset of immune dysfunction in trauma and sepsis and how this drives immunosuppression in these cells. In this review, we will discuss how regulatory T cells (Tregs), innate lymphoid cells, natural killer T cells (NKT cells), TCR-a CD4- CD8- double-negative T cells (DN T cells), and B cells can contribute to the development of post-traumatic and septic immunosuppression. Altogether, we seek to fill a gap in the understanding of the contribution of lymphocyte immunosuppression and dysfunction to the development of chronic immune disbalance. Further, we will provide an overview of promising diagnostic and therapeutic interventions, whose potential to overcome the detrimental immunosuppression after trauma and sepsis is currently being tested.

Novel Therapeutics for the Treatment of Burn Infection.

Background: Burn injury continues to be a significant cause of morbidity and death, with infectious complications being the primary cause of death. Patients are susceptible to overwhelming infection secondary to both the physical breakdown of the skin and mucosal barrier and the immune dysfunction that accompanies the inflammatory response to a major burn. With resistance to traditional antibiosis looming as a serious threat to patient outcome, advancement in the treatment of burn infections is imperative. Methods: Between February 15 and March 15, 2020, a search of Pubmed and clinicaltrials.gov was performed using search terms such as "burn immunotherapy," "therapeutic microorganisms in burn," "burn infection clinical trials," and applicable variations. Results: Topical antimicrobial drugs continue to be standard of care for burn wound injuries, but personalized and molecular treatments that rely on immune manipulation of the host show great promise. We discuss novel therapeutics for the treatment of burn infection: Probiotics and therapeutic microorganisms, immune modulators, tailored monoclonal antibodies, and extracellular vesicles and proteins. Conclusions: The treatment strategies discussed employ manipulation of structure and function in host immune cells and pathogen virulence for improved outcomes in burn infection.

Staging and Personalized Intervention for Infection and Sepsis.

Background: Sepsis is defined as a dysregulated host response to infection, resulting in life-threatening organ dysfunction. It is now understood that this dysregulation not only constitutes excessive inflammation, but also sustained immune suppression. Immune-modulatory therapies thus have great potential for novel sepsis therapies. Here, we provide a review of biomarkers and functional assays designed to immunologically stage patients with sepsis as well as therapies designed to alter the innate and adaptive immune systems of patients with sepsis beneficially. Methods: A search of PubMed/MEDLINE and clinicaltrials.gov was performed between October 1, 2019 and December 22, 2019 using search terms such as "sepsis immunotherapy," "sepsis biomarkers," "sepsis clinical trials," and variations thereof. Results: Despite more than 30 years of research, there is still no Food and Drug Administration (FDA)-cleared biomarker that has proven to be effective in either identifying patients with sepsis who are at an increased risk of adverse outcomes or responsive to specific interventions. Similarly, past clinical trials investigating new treatment strategies have rarely stratified patients with sepsis. Overall, the results of these trials have been disappointing. Novel efforts to properly gauge an individual patient's immune response and choose an appropriate immunomodulatory agent based on the results are underway. Conclusion: Our evolving understanding of the different mechanisms perturbing immune homeostasis during sepsis strongly suggests that future successes will depend on finding the right therapy for the right patient and administering it at the right time. For such a personalized medicine approach, novel biomarkers and functional assays to properly stage the patient with sepsis will be crucial. The growing repertoire of immunomodulatory agents at our disposal, as well as re-appraisal of agents that have already been tested in unstratified cohorts of patients with sepsis, may finally translate into successful treatment strategies for sepsis.