The effect of preexisting respiratory co-morbidities on burn outcomes.

INTRODUCTION: Burns cause physiologic changes in multiple organ systems in the body. Burn mortality is usually attributable to pulmonary complications, which can occur in up to 41% of patients admitted to the hospital after burn. Patients with preexisting comorbidities such as chronic lung diseases may be more susceptible. We therefore sought to examine the impact of preexisting respiratory disease on burn outcomes. METHODS: A retrospective analysis of patients admitted to a regional burn center from 2002-2012. Independent variables analyzed included basic demographics, burn mechanism, presence of inhalation injury, TBSA, pre-existing comorbidities, smoker status, length of hospital stay, and days of mechanical ventilation. Bivariate analysis was performed and Cox regression modeling using significant variables was utilized to estimate hazard of progression to mechanical ventilation and mortality. RESULTS: There were a total of 7640 patients over the study period. Overall survival rate was 96%. 8% (n=672) had a preexisting respiratory disease. Chronic lung disease patients had a higher mortality rate (7%) compared to those without lung disease (4%, p<0.01). The adjusted Cox regression model to estimate the hazard of progression to mechanical ventilation in patients with respiratory disease was 21% higher compared to those without respiratory disease (HR=1.21, 95% CI=1.01-1.44). The hazard of progression to mortality is 56% higher (HR=1.56, 95% CI=1.10-2.19) for patients with pre-existing respiratory disease compared to those without respiratory disease after controlling for patient demographics and injury characteristics. CONCLUSION: Preexisting chronic respiratory disease significantly increases the hazard of progression to mechanical ventilation and mortality in patients following burn. Given the increasing number of Americans with chronic respiratory diseases, there will likely be a greater number of individuals at risk for worse outcomes following burn.

The effect of smoking status on burn inhalation injury mortality.

INTRODUCTION: Three factors that effect burn mortality are age, total body surface of burn (TBSA), and inhalation injury. Of the three, inhalation injury is the strongest predictor of mortality thus its inclusion in the revised Baux score (age+TBSA+17* (inhalation injury, 1=yes, 0=no)). However, the weighted contribution of specific comorbidities such as smoker status on mortality has traditionally not been accounted for nor studied in this subset of burn patients. We therefore sought to examine the impact of current tobacco and/or marijuana smoking in patients with inhalation injury. METHODS: A retrospective analysis of patients admitted to a regional burn center from 2002 to 2012. Independent variables analyzed included basic demographics, burn mechanism, presence of inhalation injury, TBSA, pre-existing comorbidities, and smoker status. Bivariate analysis was performed and logistic regression modeling using significant variables was utilized to estimate odds of mortality. RESULTS: There were a total of 7640 patients over the study period. 7% (n=580) of the burn cohort with inhalation injury were included in this study. In-hospital burn mortality for inhalation injury patients was 23%. Current smokers (20%) included cigarette smokers and marijuana users, 19% and 3%, respectively. Preexisting respiratory disease (17%) was present in 36% of smokers compared to 13% of non-smokers (p<0.001). Smokers had significantly lower mortality rate (9%) compared to non-smokers (26%, p<0.01). The logistic regression model for mortality outcomes identified statistically four significant variables: age, TBSA, ethnicity, and smoker status (OR=0.41, 95% CI=0.18-0.93). Presence of comorbidities, including preexisting respiratory disease, was not significant. CONCLUSION: In the sub group of burn patients with inhalation injury, the odds of mortality significantly decreased in pre-existing smokers after adjusting for significant covariates. We postulate that an immune tolerance mechanism that modulates and diminishes the pro-inflammatory response confers a survival advantage in smokers after exposure to acute smoke inhalation injury. Future prospective studies in human and/or animal models are needed to confirm these findings.

Evolution of protein phosphorylation across 18 fungal species.

Living organisms have evolved protein phosphorylation, a rapid and versatile mechanism that drives signaling and regulates protein function. We report the phosphoproteomes of 18 fungal species and a phylogenetic-based approach to study phosphosite evolution. We observe rapid divergence, with only a small fraction of phosphosites conserved over hundreds of millions of years. Relative to recently acquired phosphosites, ancient sites are enriched at protein interfaces and are more likely to be functionally important, as we show for sites on H2A1 and eIF4E. We also observe a change in phosphorylation motif frequencies and kinase activities that coincides with the whole-genome duplication event. Our results provide an evolutionary history for phosphosites and suggest that rapid evolution of phosphorylation can contribute strongly to phenotypic diversity.

The measured effect magnitude of co-morbidities on burn injury mortality.

INTRODUCTION: The ability to better prognosticate burn injury outcome is challenging and historically, most center use the Baux or revised Baux score to help prognosticate burn outcome, however, the weighted contribution of comorbidity on burn mortality has traditionally not been accounted for nor adequately studied. We therefore sought to determine the effect of comorbidities, using the Charlson comorbidity index (CCI) on burn mortality. METHODS: The purpose of this study was to determine the effect of comorbidities on burn injury mortality as determined by the LA50 (lethal TBSA burn at which 50% of the cohort will succumb from the burn injury) in a retrospective analysis of patients admitted to a regional burn center from 2002 to 2012. Independent variables analyzed included basic demographics, burn mechanism, presence of inhalation injury, TBSA (total body surface area), length of hospital stay, and pre-existing comorbidities. Bivariate analysis was performed and logistic regression modeling using significant variables was utilized to estimate odds of death. RESULTS: 7640 patients were included in this study. Overall survival rate was 96%. 40% of our burn cohort had at least one comorbidity. There was a linear increase in the likelihood of death with an increase in CCI. The logistic regression model for mortality outcomes identified four statistically significant variables: age, TBSA, inhalational injury and the presence of comorbidities (OR=1.59 for each 1 point increase in CCI; 95% CI 1.44-1.77). The unadjusted LA50 was 53% for the entire cohort. Partial adjustment multivariate regression controlling for burn mechanism and inhalation injury only, produced a slight reduction in LA50 for the 0-18 and 19-64 age categories to 76% and 48% TBSA, respectively, but a significant decrease occurred in the ≥65 years age group with a reduced LA50 to 20% TBSA (p<0.001). After full adjustment for all significant covariates, including comorbidities, the independent magnitude of effect of comorbidities on the LA50 was evident in the <65 cohort. The full adjustment showed a LA50 decreased to 61% and 43% TBSA, respectively in the 0-18 and >18-65 age groups respectively (p<0.001), however, in the >65 years age cohort there was no change in the LA50. CONCLUSION: Preexisting comorbidities have a significant effect on burn injury mortality in all age groups, particularly the younger burn population. The measured effect of comorbidities in the >65 yr age cohort was mitigated by the co-linearity between age and comorbidities. The inclusion of CCI is imperative so as to better prognosticate burn outcome and help guide expectations and resource utilization, particularly in the younger burn cohort.

Detection and measurement of staphylococcal enterotoxin-like K (SEl-K) secretion by Staphylococcus aureus clinical isolates.

Staphylococcal enterotoxin-like K (SEl-K) is a potent mitogen that elicits T-cell proliferation and cytokine production at very low concentrations. However, unlike the classical enterotoxins SEB and toxic shock syndrome toxin 1 (TSST-1), the gene for SEl-K is commonly present in more than half of all Staphylococcus aureus clinical isolates and is present in almost all USA300 community-acquired methicillin-resistant S. aureus (CA-MRSA) isolates. Sequencing of the sel-k gene in over 20 clinical isolates and comparative analysis with all 14 published sel-k sequences indicate that there are at least 6 variants of the sel-k gene, including one that is conserved among all examined USA300 strains. Additionally, we have developed a highly sensitive enzyme-linked immunosorbent assay (ELISA) that specifically detects and measures SEl-K protein in culture supernatants and biological fluids. Quantification of in vitro SEl-K secretion by various S. aureus isolates using this novel capture ELISA revealed detectable amounts of SEl-K secretion by all isolates, with the highest secretion levels being exhibited by MRSA strains that coexpress SEB. In vivo secretion was measured in a murine thigh abscess model, where similar levels of SEl-K accumulation were noted regardless of whether the infecting strain exhibited high or low secretion of SEl-K in vitro. We conclude that SEl-K is commonly expressed in the setting of staphylococcal infection, in significant amounts. SEl-K should be further explored as a target for passive immunotherapy against complicated S. aureus infection.

Effects of polymer type and storage relative humidity on the kinetics of felodipine crystallization from amorphous solid dispersions.

PURPOSE: The objective of this study was to investigate the effects of polymer type and storage relative humidity (RH) on the crystallization kinetics of felodipine from amorphous solid dispersions. METHODS: Crystallization of the model drug felodipine from amorphous solid dispersion samples containing poly(vinyl pyrrolidone) (PVP) and hypromellose acetate succinate (HPMCAS) were evaluated. Samples at three different drug-polymer weight ratios (10, 25, and 50 wt. % polymer) were prepared and stored at six different RHs (0%, 32%, 52% or 66%, 75%, 86%, and 93%). Periodically, the fraction of the drug that had crystallized from the samples was quantified using powder X-ray diffractometry (PXRD). RESULTS: Felodipine crystallization rates from PVP-containing dispersions were found to be very sensitive to changes in storage RH, while crystallization rates from HPMCAS-containing dispersions were not. PVP and HPMCAS were similar in terms of their ability to inhibit crystallization at low RH, but when the storage RH was increased to 75% or above, felodipine crystallization from PVP-containing solid dispersions proceeded much faster. It is hypothesized that this trend was caused by moisture-induced drug-polymer immiscibility in PVP-felodipine system. For PVP-containing solid dispersion samples stored at 75% RH and above, crystallization of the model drug felodipine seemed to approach a kinetic plateau, whereby a fraction of the drug still remained amorphous even after storage for 500 days or more. CONCLUSIONS: The physical stability of solid dispersions as a function of RH is highly dependent on the polymer used to form the solid dispersion, with PVP-containing dispersions being much less physically stable at high RH than HPMCAS-containing dispersions.

Phase behavior of poly(vinylpyrrolidone) containing amorphous solid dispersions in the presence of moisture.

The objective of this study was to investigate the phase behavior of amorphous solid dispersions composed of a hydrophobic drug and a hydrophilic polymer following exposure to elevated relative humidity. Infrared (IR) spectroscopy, differential scanning calorimetry (DSC) and moisture sorption analysis were performed on five model systems (nifedipine-poly(vinylpyrrolidone) (PVP), indomethacin-PVP, ketoprofen-PVP, droperidol-PVP, and pimozide-PVP) immediately after production of the amorphous solid dispersions and following storage at room temperature and elevated relative humidity. Complete miscibility between the drug and the polymer immediately after solid dispersion formation was confirmed by the presence of specific drug-polymer interactions and a single glass transition (T(g)) event. Following storage at elevated relative humidity (75-94% RH), nifedipine-PVP, droperidol-PVP, and pimozide-PVP dispersions formed drug-rich and polymer-rich amorphous phases prior to crystallization of the drug, while indomethacin-PVP and ketoprofen-PVP dispersions did not. Drug crystallization in systems exhibiting amorphous-amorphous phase separation initiated earlier (<6 days at 94% RH) when compared to systems that remained miscible (>or=46 days at 94% RH). Evidence of moisture-induced amorphous-amorphous phase separation was observed following storage at as low as 54% RH for the pimozide-PVP system. It was concluded that, when an amorphous molecular level solid dispersion containing a hydrophobic drug and hydrophilic polymer is subjected to moisture, drug crystallization can occur via one of two routes: crystallization from the plasticized one-phase solid dispersion, or crystallization from a plasticized drug-rich amorphous phase in a two-phase solid dispersion. In the former case, the polymer is still present in the same phase as the drug, and can inhibit crystallization to a greater extent than the latter scenario, where the polymer concentration in the drug phase is reduced as a result of the amorphous-amorphous phase separation. The strength of drug-polymer interactions appears to be important in influencing the phase behavior.