Early detection of soluble CD27, BTLA, and TIM-3 predicts the development of nosocomial infection in pediatric burn patients

Thermal injury induces concurrent inflammatory and immune dysfunction, which is associated with adverse clinical outcomes. However, these effects in the pediatric population are less studied and there is no standard method to identify those at risk for developing infections. Our goal was to better understand immune dysfunction and identify soluble protein markers following pediatric thermal injury. Further we wanted to determine which early inflammatory, soluble, or immune function markers are most predictive of the development of nosocomial infections (NI) after burn injury. We performed a prospective observational study at a single American Burn Association-verified Pediatric Burn Center. A total of 94 pediatric burn subjects were enrolled and twenty-three of those subjects developed a NI with a median time to diagnosis of 8 days. Whole blood samples, collected within the first 72 hours after injury, were used to compare various markers of inflammation, immune function, and soluble proteins between those who recovered without developing an infection and those who developed a NI after burn injury. Within the first three days of burn injury, innate and adaptive immune function markers (ex vivo lipopolysaccharide-induced tumor necrosis factor alpha production capacity, and ex vivo phytohemagglutinin-induced interleukin-10 production capacity, respectively) were decreased for those subjects who developed a subsequent NI. Further analysis of soluble protein targets associated with these pathways displayed significant increases in soluble CD27, BTLA, and TIM-3 for those who developed a NI. Our findings indicate that suppression of both the innate and adaptive immune function occurs concurrently within the first 72 hours following pediatric thermal injury. At the same time, subjects who developed NI have increased soluble protein biomarkers. Soluble CD27, BTLA, and TIM-3 were highly predictive of the development of subsequent infectious complications. This study identifies early soluble protein makers that are predictive of infection in pediatric burn subjects. These findings should inform future immunomodulatory therapeutic studies

Failure to normalize lymphopenia following trauma is associated with increased mortality, independent of the leukocytosis pattern

INTRODUCTION: Following trauma and systemic inflammatory response syndrome (SIRS), the typical response is an elevation of the total complete blood count (CBC) and a reduction of the lymphocyte count. This leukocytosis typically returns to normal within 48 hours. The persistence of a leukocytosis following trauma is associated with adverse outcomes. Although lymphocyte anergy and dysfunction following trauma is associated with increased risk for infection and sepsis, there is a paucity of data regarding the impact of a persistence of a low lymphocyte count in trauma patients. METHODS: This is a retrospective review of prospectively collected data from trauma patients collected over the 5 years of September 2003 to September 2008. Patients were included if the injury severity score (ISS) was >/=15, and they survived at least 3 days. Demographic data, mechanism and injury severity score, mortality, and length of stay were collected from the medical record. Laboratory values for the first 4 hospital days were collected. Leukocyte, neutrophil and lymphocyte counts were extracted from the daily complete blood count (CBC). Patients were then grouped based on response (elevation/depression) of each component of the CBC, and their return, or failure thereof, to normal. Proportional hazards regression with time-varying covariates as well as Kaplan-Meier curves were used to predict risk of death, time to death and time to healthy discharge based on fluctuations of the individual components of the CBC. RESULTS: There were 2448 patients admitted over the 5 years included in the analysis. When adjusting for age, gender and ISS the relative risk of death was elevated with a persistent leukocytosis (2.501 (95% CI = 1.477-4.235)) or failure to normalize lymphopenia (1.639 (95% CI = 10.17-2.643)) within the first 4 days following admission. Similar results were seen when Kaplan-Meier curves were created. Persistent lymphopenia was associated with shortest time to death. Paradoxically in survivors persistent lymphopenia was associated with the shortest time to discharge. CONCLUSIONS: Persistently abnormal CBC responses are associated with a higher mortality following trauma. This is the first report noting that a failure to normalize lymphopenia in severely injured patients is associated with significantly higher mortality

Antiinflammatory Therapy with Canakinumab for Atherosclerotic Disease

Background: Experimental and clinical data suggest that reducing inflammation without affecting lipid levels may reduce the risk of cardiovascular disease. Yet, the inflammatory hypothesis of atherothrombosis has remained unproved. Methods: We conducted a randomized, double-blind trial of canakinumab, a therapeutic monoclonal antibody targeting interleukin-1β, involving 10,061 patients with previous myocardial infarction and a high-sensitivity C-reactive protein level of 2 mg or more per liter. The trial compared three doses of canakinumab (50 mg, 150 mg, and 300 mg, administered subcutaneously every 3 months) with placebo. The primary efficacy end point was nonfatal myocardial infarction, nonfatal stroke, or cardiovascular death. RESULTS: At 48 months, the median reduction from baseline in the high-sensitivity C-reactive protein level was 26 percentage points greater in the group that received the 50-mg dose of canakinumab, 37 percentage points greater in the 150-mg group, and 41 percentage points greater in the 300-mg group than in the placebo group. Canakinumab did not reduce lipid levels from baseline. At a median follow-up of 3.7 years, the incidence rate for the primary end point was 4.50 events per 100 person-years in the placebo group, 4.11 events per 100 person-years in the 50-mg group, 3.86 events per 100 person-years in the 150-mg group, and 3.90 events per 100 person-years in the 300-mg group. The hazard ratios as compared with placebo were as follows: in the 50-mg group, 0.93 (95% confidence interval [CI], 0.80 to 1.07; P = 0.30); in the 150-mg group, 0.85 (95% CI, 0.74 to 0.98; P = 0.021); and in the 300-mg group, 0.86 (95% CI, 0.75 to 0.99; P = 0.031). The 150-mg dose, but not the other doses, met the prespecified multiplicity-adjusted threshold for statistical significance for the primary end point and the secondary end point that additionally included hospitalization for unstable angina that led to urgent revascularization (hazard ratio vs. placebo, 0.83; 95% CI, 0.73 to 0.95; P = 0.005). Canakinumab was associated with a higher incidence of fatal infection than was placebo. There was no significant difference in all-cause mortality (hazard ratio for all canakinumab doses vs. placebo, 0.94; 95% CI, 0.83 to 1.06; P = 0.31). Conclusions: Antiinflammatory therapy targeting the interleukin-1β innate immunity pathway with canakinumab at a dose of 150 mg every 3 months led to a significantly lower rate of recurrent cardiovascular events than placebo, independent of lipid-level lowering. (Funded by Novartis; CANTOS ClinicalTrials.gov number, NCT01327846.

Mitochondrial physiology

As the knowledge base and importance of mitochondrial physiology to evolution, health and disease expands, the necessity for harmonizing the terminology concerning mitochondrial respiratory states and rates has become increasingly apparent. The chemiosmotic theory establishes the mechanism of energy transformation and coupling in oxidative phosphorylation. The unifying concept of the protonmotive force provides the framework for developing a consistent theoretical foundation of mitochondrial physiology and bioenergetics. We follow the latest SI guidelines and those of the International Union of Pure and Applied Chemistry (IUPAC) on terminology in physical chemistry, extended by considerations of open systems and thermodynamics of irreversible processes. The concept-driven constructive terminology incorporates the meaning of each quantity and aligns concepts and symbols with the nomenclature of classical bioenergetics. We endeavour to provide a balanced view of mitochondrial respiratory control and a critical discussion on reporting data of mitochondrial respiration in terms of metabolic flows and fluxes. Uniform standards for evaluation of respiratory states and rates will ultimately contribute to reproducibility between laboratories and thus support the development of data repositories of mitochondrial respiratory function in species, tissues, and cells. Clarity of concept and consistency of nomenclature facilitate effective transdisciplinary communication, education, and ultimately further discovery

Mitochondrial physiology

As the knowledge base and importance of mitochondrial physiology to evolution, health and disease expands, the necessity for harmonizing the terminology concerning mitochondrial respiratory states and rates has become increasingly apparent. The chemiosmotic theory establishes the mechanism of energy transformation and coupling in oxidative phosphorylation. The unifying concept of the protonmotive force provides the framework for developing a consistent theoretical foundation of mitochondrial physiology and bioenergetics. We follow the latest SI guidelines and those of the International Union of Pure and Applied Chemistry (IUPAC) on terminology in physical chemistry, extended by considerations of open systems and thermodynamics of irreversible processes. The concept-driven constructive terminology incorporates the meaning of each quantity and aligns concepts and symbols with the nomenclature of classical bioenergetics. We endeavour to provide a balanced view of mitochondrial respiratory control and a critical discussion on reporting data of mitochondrial respiration in terms of metabolic flows and fluxes. Uniform standards for evaluation of respiratory states and rates will ultimately contribute to reproducibility between laboratories and thus support the development of data repositories of mitochondrial respiratory function in species, tissues, and cells. Clarity of concept and consistency of nomenclature facilitate effective transdisciplinary communication, education, and ultimately further discovery

Update on bariatric surgery in adolescence

Recent evidence highlighting the prevalence of severe obesity in the pediatric population, coupled with disappointing outcomes related to medical weight loss interventions, has led to increased interest in bariatric surgery. This article focuses on recent additions to the literature regarding the current indications and outcomes of adolescent bariatric surgery, emerging guidelines on the development of surgical weight loss programs and the status of access to bariatric surgical care for adolescents in the United States. Current data have shown a steady rise in the use of bariatric surgery among adolescents and serve to highlight the prevalence of several important obesity-related comorbidities. In addition to reports showing the safety and efficacy of adolescent bariatric surgery, a number of investigators have demonstrated significant improvement in key physiological and metabolic parameters (i.e., glucose metabolism, elevated blood pressure, dyslipidemia, etc.), offering updated consensus-driven guidelines for the indications for surgical intervention, as well as the development of multidisciplinary adolescent-specific care. Despite favorable outcomes, a disparity exists between the pediatric and adult populations related to access to such care. In contrast to previous small and mostly retrospective series, contemporary studies have shown that adolescent bariatric surgery is well tolerated and effective. Despite these findings and the emergence of a national consensus regarding multidisciplinary care, skepticism among primary care providers, as well as significant challenges related to healthcare access, remain. Longitudinal studies and open dialogue within the medical community are needed

Pediatric burn care: new techniques and outcomes

Thermal injury is a leading cause of morbidity and mortality in children. This review highlights the current management of thermal injury and its complications. Many recent advances in burn care have improved the outcomes of patients with thermal injury; however, variability does exist, and there are many opportunities for improvement. This review will highlight the complexity of issues encountered along the continuum of care for thermal injury patients. Accurate estimation of total burn surface area (TBSA) of a burn continues to be a challenge in pediatric patients. Variability continues to exist surrounding the management of burn resuscitation and complex wounds. Children with extensive burns have profound immune and metabolic changes that can lead to multiple complications, including infections, growth arrest, and loss of lean body mass. Standardization in measurements related to quality of life and psychological stress following pediatric thermal injury is much needed. The care of pediatric patients with thermal injury is complex and multifaceted. This review highlights the most recent advances in pediatric burn care

Secondary overtriage in a pediatric level one trauma center

Previous studies have explored under- and overtriage, and the means by which to optimize these rates. Few have examined secondary overtriage (SO), or the unnecessary transfer of minimally injured patients to higher level trauma centers. We sought to determine the incidence and impact of SO in our pediatric level one trauma center. We performed a retrospective analysis of all trauma activations at our institution from 2015 through 2017. SO was defined as transferred patients who required neither PICU admission nor an operation, with ISS ≤ 9 and LOS ≤ 24 h. We compared SO patients against all trauma activation transfers, and against similar non-transferred patients. We identified 1789 trauma activations, including 766 (42.8%) transfers. Of the transfers, 335 (43.7%) met criteria for SO. Compared to other transfers, SO patients had a shorter mean travel distance (52.9 v 58.1 mi; p = 0.02). Compared to similar patients transported from the trauma scene, SO patients were more likely to be admitted (52.2% v 29.2%; p < 0.001), with longer inpatient stay and greater hospital charges. SO represents an underrecognized burden to trauma centers which could be minimized to improve resource allocation. Future research should evaluate trauma activation criteria for transferred pediatric patients

US pediatric trauma patient unplanned 30-day readmissions

We sought to determine readmission rates and risk factors for acutely injured pediatric trauma patients. We produced 30-day unplanned readmission rates for pediatric trauma patients using the 2013 National Readmission Database (NRD). In US pediatric trauma patients, 1.7% had unplanned readmissions within 30days. The readmission rate for patients with index operating room procedures was no higher at 1.8%. Higher readmission rates were seen in patients with injury severity scores (ISS)=16–24 (3.4%) and ISS ≥25 (4.9%). Higher rates were also seen in patients with LOS beyond a week, severe abdominal and pelvic region injuries (3.0%), crushing (2.8%) and firearm injuries (4.5%), and in patients with fluid and electrolyte disorders (3.9%). The most common readmission principal diagnoses were injury, musculoskeletal/integumentary diagnoses and infection. Nearly 39% of readmitted patients required readmission operative procedures. Most common were operations on the musculoskeletal system (23.9% of all readmitted patients), the integumentary system (8.6%), the nervous system (6.6%), and digestive system (2.5%). Overall, the readmission rate for pediatric trauma patients was low. Measures of injury severity, specifically length of stay, were most useful in identifying those who would benefit from targeted care coordination resources. This is a Level III retrospective comparative study