Sarcopenia Best Predicts Complications in Free Flap Breast Reconstruction.

Breast reconstruction remains a major component of the plastic surgeon's repertoire, especially free-flap breast reconstruction (FFBR), though this is a high-risk surgery in which patient selection is paramount. Preoperative predictors of complication remain mixed in their utility. We sought to determine whether the sarcopenia score, a validated measure of physiologic health, outperforms the body mass index (BMI) and modified frailty index (mFI) in terms of predicting outcomes. Methods: All patients with at least 6-months follow-up and imaging of the abdomen who underwent FFBR from 2013 to 2022 were included in this study. Appropriate preoperative and postoperative data were included, and sarcopenia scores were extracted from imaging. Complications were defined as any unexpected outcome that required a return to the operating room or readmission. Statistical analysis and regression were performed. Results: In total, 299 patients were included. Patients were split into groups, based on sarcopenia scores. Patients with lower sarcopenia had significantly more complications than those with higher scores. BMI and mFI both did not correlate with complication rates. Sarcopenia was the only independent predictor of complication severity when other factors were controlled for in a multivariate regression model. Conclusions: Sarcopenia correlates with the presence of severe complications in patients who undergo FFBR in a stronger fashion to BMI and the mFI. Thus, sarcopenia should be considered in the preoperative evaluation in patients undergoing FFBR.

Comorbid status in patients with osteomyelitis is associated with long-term incidence of extremity amputation.

INTRODUCTION: Osteomyelitis is associated with significant morbidity, including amputation. There are limited data on long-term amputation rates following an osteomyelitis diagnosis. We sought to determine the incidence of amputation in patients with osteomyelitis over 2 years. RESEARCH DESIGN AND METHODS: Observational cohort study of 1186 inpatients with osteomyelitis between 2004 and 2015 and stratified by osteomyelitis location status to evaluate the impact on amputation, mortality rates, readmission data, and inpatient days. RESULTS: Persons with diabetes had 3.65 times greater probability of lower extremity amputation (p<0.001), readmission (p<0.001), and longer inpatient stay (p<0.001) and had higher 2-year mortality (relative risk (RR) 1.23, p=0.0027), adjusting for risk factors. Male gender (RR 1.57, p<0.001), black race (RR 1.41, p<0.05), former smoking status (RR 1.38, p<0.01), myocardial infarction (RR 1.72, p<0.001), congestive heart failure (RR 1.56, p<0.001), peripheral vascular disease (RR 2.25, p<0.001) and renal disease (RR 1.756, p<0.001) were independently associated with amputation. Male gender (RR 1.39, p<0.01), black race (RR 1.27, p<0.05), diabetes (RR 2.77, p<0.001) and peripheral vascular disease (RR 1.59, p<0.001) had increased risk of lower, not upper, extremity amputation. CONCLUSIONS: Patients with osteomyelitis have higher rates of amputation and hospitalization. Clinicians must incorporate demographic and comorbid risk factors to protect against amputation.

Requirement of Complement C6 for Intact Innate Immune Responses in Mice.

Over the first days of polymicrobial sepsis, there is robust activation of the innate immune system, causing the appearance of proinflammatory cytokines and chemokines, along with the appearance of extracellular histones, which are highly proinflammatory and prothrombotic. In the current study, we studied different innate immune responses in mice with knockout (KO) of complement protein 6 (C6). Polymorphonuclear neutrophils (PMNs) from these KO mice had defective innate immune responses, including defective expression of surface adhesion molecules, generation of superoxide anion, and appearance of reactive oxygen species and histone release after activation of PMNs, along with defective phagocytosis. In addition, in C6-/- mice, the NLRP3 inflammasome was defective both in PMNs and in macrophages. When these KO mice were subjected to polymicrobial sepsis, their survival was improved, associated with reduced levels in the plasma of proinflammatory cytokines and chemokines and lower levels of histones in plasma. In addition, sepsis-induced cardiac dysfunction was attenuated in these KO mice. In a model of acute lung injury induced by LPS, C6-/- mice showed reduced PMN buildup and less lung epithelial/endothelial cell dysfunction (edema and hemorrhage). These data indicate that C6-/- mice have reduced innate immune responses that result in less organ injury and improved survival after polymicrobial sepsis.

Short-term versus long-term trauma mortality: A systematic review.

BACKGROUND: Trauma is the leading cause of death in the United States for persons under 44 years and the fourth leading cause of death in the elderly. Advancements in clinical care and standardization of treatment protocols have reduced 30-day trauma mortality to less than 4%. However, these improvements do not seem to correlate with long-term outcomes. Some reports have shown a greater than 20% mortality rate when looking at long-term outcomes. The aim of this study was to systematically review the incongruence between short- and long-term mortality for trauma patients. METHODS: For this systematic review, we searched the Cochrane Library, EMBASE, Ovid Medline, Google Scholar, and Web of Science database to obtain relevant English, German, French, and Portuguese articles from 1965 to 2018. RESULTS: Trauma patients have decreased long-term survival when compared to the general population and when compared with age-matched cohorts. Postdischarge trauma mortality is significantly higher (mean, 4.6% at 3-6 months, 15.8% at 2-3 years, 26.3% at 5-25 years) compared with controls (mean, 1.3%, 2.2%, and 15.6%, respectively). Patient comorbidities likely contribute to long-term trauma deaths. Trauma patients discharged to a skilled nursing facility have worse mortality compared with those discharged either to home or a rehabilitation center. In contrast to data available which illustrate that short-term mortality has improved, quality of evidence was not sufficient to determine if any improvements in long-term trauma mortality outcomes have also occurred. CONCLUSIONS: The decreased short-term mortality observed in trauma patients does not appear correlated with decreased long-term mortality. The extent to which increased long-term trauma mortality is related to the initial traumatic insult-versus rising population age and comorbidity burden as well as suboptimal discharge location-requires further study. LEVEL OF EVIDENCE: Systematic Review, level IV.

Rectal cancer sub-clones respond differentially to neoadjuvant therapy.

Treatment of locally advanced rectal cancer includes chemotherapy, radiation, and surgery but patient responses to neoadjuvant treatment are variable. We have shown that rectal tumors are comprised of multiple genetically distinct sub-clones. Unique sub-clones within tumors may harbor mutations which contribute to inter-patient variation in response to neoadjuvant chemoradiotherapy (nCRT). Analysis of the influence of nCRT on the extent and nature of intra-tumoral genetic heterogeneity in rectal cancer may provide insights into mechanisms of resistance. Locally advanced rectal cancer patients underwent pre-treatment biopsies. At the time of surgery, tissue from the treated tumor was obtained and analyzed. Pre- and post-treatment specimens were subjected to whole exome and confirmatory deep sequencing for somatic mutations. Copy number variation was assessed using OncoScan SNP arrays. Genomic data were analyzed using PyClone to identify sub-clonal tumor population following nCRT. Alterations that persisted or were enriched in the post-treatment tumor specimen following nCRT were defined for each patient. Thirty-two samples were obtained from ten patients. PyClone identified 2 to 10 genetic sub-clones per tumor. Substantial changes in the proportions of individual sub-clones in pre- versus post-treatment tumor material were found in all patients. Resistant sub-clones recurrently contained mutations in TP53, APC, ABCA13, MUC16, and THSD4. Recurrent copy number variation was observed across multiple chromosome regions after nCRT. Pathway analysis including variant alleles and copy number changes associated with resistant sub-clones revealed significantly altered pathways, especially those linked to the APC and TP53 genes, which were the two most frequently mutated genes. Intra-tumoral heterogeneity is evident in pre-treatment rectal cancer. Following treatment, sub-clonal populations are selectively modified and enrichment of a subset of pre-treatment sub-clones is seen. Further studies are needed to define recurrent alterations at diagnosis that may contribute to resistance to nCRT.

Complications and resource utilization in trauma patients with diabetes.

Diabetes is associated with poor outcomes in critically ill populations. The goal of this study was to determine if diabetic patients suffer poorer outcomes following trauma. Collaborative trauma patient data from 2012-2018 was analyzed. Patients with no signs-of-life, Injury Severity Score (ISS) <5, age <16 years, and hospitalization <1 day were excluded. Multivariable logistic and linear regression were used to compare patients with and without diabetes for selected outcomes. Risk-adjustment variables included demographics, physiology, comorbidities, and injury scoring. Of 106,141 trauma patients, 14,150 (13%) had diabetes. On admission, diabetes was associated with significantly increased risk of any, serious, infectious, urinary tract, sepsis, pneumonia, and cardiac complications. Diabetes was also associated with increased ventilator days (7.5 vs. 6.6 days, p = 0.003), intensive care unit days (5.8 vs. 5.3 days, p<0.001), and hospital length of stay (5.7 vs. 5.3 days, p<0.001). Subgroup analysis revealed the least injured diabetic category (ISS 5-15) suffered higher odds of hospital mortality and any, serious, infectious and cardiac complications. The association between diabetes, hospital mortality and complication rates in mild traumatic injury is independent of age. Trauma patients with diabetes experience higher rates of complications and resource utilization. The largest cohort of diabetics experience the least severe injuries and suffer the greatest in hospital mortality and complication rates. A better understanding of the physiologic derangements associated with diabetes is necessary to develop novel approaches to reduce excess trauma morbidity, mortality and resource consumption.

GM-CSF Administration Improves Defects in Innate Immunity and Sepsis Survival in Obese Diabetic Mice.

Sepsis is the leading cause of death in the intensive care unit with an overall mortality rate of 20%. Individuals who are obese and have type 2 diabetes have increased recurrent, chronic, nosocomial infections that worsen the long-term morbidity and mortality from sepsis. Additionally, animal models of sepsis have shown that obese, diabetic mice have lower survival rates compared with nondiabetic mice. Neutrophils are essential for eradication of bacteria, prevention of infectious complications, and sepsis survival. In diabetic states, there is a reduction in neutrophil chemotaxis, phagocytosis, and reactive oxygen species (ROS) generation; however, few studies have investigated the extent to which these deficits compromise infection eradication and mortality. Using a cecal ligation and puncture model of sepsis in lean and in diet-induced obese mice, we demonstrate that obese diabetic mice have decreased "emergency hematopoiesis" after an acute infection. Additionally, both neutrophils and monocytes in obese, diabetic mice have functional defects, with decreased phagocytic ability and a decreased capacity to generate ROS. Neutrophils isolated from obese diabetic mice have decreased transcripts of Axl and Mertk, which partially explains the phagocytic dysfunction. Furthermore, we found that exogenous GM-CSF administration improves sepsis survival through enhanced neutrophil and monocytes phagocytosis and ROS generation abilities in obese, diabetic mice with sepsis.

Obesity and type 2 diabetes mellitus drive immune dysfunction, infection development, and sepsis mortality.

Obesity and type 2 diabetes mellitus (T2D) are global pandemics. Worldwide, the prevalence of obesity has nearly tripled since 1975 and the prevalence of T2D has almost doubled since 1980. Both obesity and T2D are indolent and chronic diseases that develop gradually, with cellular physiologic changes occurring before the clinical signs and symptoms of the diseases become apparent. Individuals with obesity and T2D are physiologically frail and have an increased risk of infections and mortality from sepsis. Improvement in the morbidity and mortality of these at-risk populations would provide a great societal benefit. We believe that the worsened outcomes observed in these patient populations is due to immune system dysfunction that is triggered by the chronic low-grade inflammation present in both diseases. As immune modulatory therapies have been utilized in other chronic inflammatory diseases, there is an emerging role for immune modulatory therapies that target the chronically affected immune pathways in obese and T2D patients. Additionally, bariatric surgery is currently the most successful treatment for obesity and is the only weight loss method that also causes a sustained, substantial improvement of T2D. Consequently, bariatric surgery may also have a role in improving immunity in these patient populations.

Role of complement C5a and histones in septic cardiomyopathy.

Polymicrobial sepsis (after cecal ligation and puncture, CLP) causes robust complement activation with release of C5a. Many adverse events develop thereafter and will be discussed in this review article. Activation of complement system results in generation of C5a which interacts with its receptors (C5aR1, C5aR2). This leads to a series of harmful events, some of which are connected to the cardiomyopathy of sepsis, resulting in defective action potentials in cardiomyocytes (CMs), activation of the NLRP3 inflammasome in CMs and the appearance of extracellular histones, likely arising from activated neutrophils which form neutrophil extracellular traps (NETs). These events are associated with activation of mitogen-activated protein kinases (MAPKs) in CMs. The ensuing release of histones results in defective action potentials in CMs and reduced levels of [Ca2+]i-regulatory enzymes including sarco/endoplasmic reticulum Ca2+-ATPase (SERCA2) and Na+/Ca2+ exchanger (NCX) as well as Na+/K+-ATPase in CMs. There is also evidence that CLP causes release of IL-1ß via activation of the NLRP3 inflammasome in CMs of septic hearts or in CMs incubated in vitro with C5a. Many of these events occur after in vivo or in vitro contact of CMs with histones. Together, these data emphasize the role of complement (C5a) and C5a receptors (C5aR1, C5aR2), as well as extracellular histones in events that lead to cardiac dysfunction of sepsis (septic cardiomyopathy).

Diabetes and Sepsis: Risk, Recurrence, and Ruination.

Sepsis develops when an infection surpasses local tissue containment. A series of dysregulated physiological responses are generated, leading to organ dysfunction and a 10% mortality risk. When patients with sepsis demonstrate elevated serum lactates and require vasopressor therapy to maintain adequate blood pressure in the absence of hypovolemia, they are in septic shock with an in-hospital mortality rate >40%. With improvements in intensive care treatment strategies, overall sepsis mortality has diminished to ~20% at 30 days; however, mortality continues to steadily climb after recovery from the acute event. Traditionally, it was thought that the complex interplay between inflammatory and anti-inflammatory responses led to sepsis-induced organ dysfunction and mortality. However, a closer examination of those who die long after sepsis subsides reveals that many initial survivors succumb to recurrent, nosocomial, and secondary infections. The comorbidly challenged, physiologically frail diabetic individuals suffer the highest infection rates. Recent reports suggest that even after clinical "recovery" from sepsis, persistent alterations in innate and adaptive immune responses exists resulting in chronic inflammation, immune suppression, and bacterial persistence. As sepsis-associated immune defects are associated with increased mortality long-term, a potential exists for immune modulatory therapy to improve patient outcomes. We propose that diabetes causes a functional immune deficiency that directly reduces immune cell function. As a result, patients display diminished bactericidal clearance, increased infectious complications, and protracted sepsis mortality. Considering the substantial expansion of the elderly and obese population, global adoption of a Western diet and lifestyle, and multidrug resistant bacterial emergence and persistence, diabetic mortality from sepsis is predicted to rise dramatically over the next two decades. A better understanding of the underlying diabetic-induced immune cell defects that persist following sepsis are crucial to identify potential therapeutic targets to bolster innate and adaptive immune function, prevent infectious complications, and provide more durable diabetic survival.