Comparison of Cox and Gray's survival models in severe sepsis

BACKGROUND: Although survival is traditionally modeled using Cox proportional hazards modeling, this approach may be inappropriate in sepsis, in which the proportional hazards assumption does not hold. Newer, more flexible models, such as Gray's model, may be more appropriate. OBJECTIVES: To construct and compare Gray's model and two different Cox models in a large sepsis cohort. To determine whether hazards for death after sepsis were nonproportional. To explore how well the different survival modeling approaches describe these data. DESIGN: Analysis of combined data from the treatment and placebo arms of a large, negative, sepsis trial. SETTING: Intensive care units at 136 U.S. medical centers. SUBJECTS: A total of 1090 adults aged 18 yrs or older with signs and symptoms of severe sepsis and documented or probable Gram-negative infection. MEASUREMENTS: We considered 27 potential baseline risk factors and modeled survival over the 28 days after the onset of sepsis. We tested proportionality in single-variable Cox analysis using Schoenfeld residuals and log-log plots. We constructed a traditional multivariable Cox model, a multivariable Cox model with time-varying covariates, and a multivariable Gray's model. RESULTS: In single-variable analyses, 20 of the 27 potential factors were significantly associated with mortality, and 10 of 20 had nonproportional hazards. In multivariate analysis, all three models retained a very similar set of significant covariates (two models retained the identical set of nine variables, and the third differed only in that it retained the same nine plus a tenth variable). Four of the nine common covariates had nonproportional hazards. Of the three models, Gray's model best captured these changing hazard ratios over time. CONCLUSION: We confirm that many of the important predictors of mortality in severe sepsis are nonproportional and find that Gray's model seems best suited for modeling survival in this condition.     

Impact of the Combination of Daptomycin and Trimethoprim-Sulfamethoxazole on Clinical Outcomes in Methicillin-Resistant Staphylococcus aureus Infections

Complicated Staphylococcus aureus infections, including bacteremia, are often associated with treatment failures, prolonged hospital stays, and the emergence of resistance to primary and even secondary therapies. Daptomycin is commonly used as salvage therapy after vancomycin failure for the treatment of methicillin-resistant S. aureus (MRSA) infections. Unfortunately, the emergence of daptomycin resistance, especially in deep-seated infections, has been reported, prompting the need for alternative or combination therapy. Numerous antibiotic combinations with daptomycin have been investigated clinically and in vitro. Of interest, the combination of daptomycin and trimethoprim-sulfamethoxazole (TMP-SMX) has proved to be rapidly bactericidal in vitro to strains that are both susceptible and nonsusceptible to daptomycin. However, to date, there is limited clinical evidence supporting the use of this combination. This was a multicenter, retrospective case series of patients treated with the combination of daptomycin and TMP-SMX for at least 72 h. The objective of this study was to describe the safety and effectiveness of this regimen in clinical practice. The most commonly stated reason that TMP-SMX was added to daptomycin was persistent bacteremia and/or progressive signs and symptoms of infection. After the initiation of combination therapy, the median time to clearance of bacteremia was 2.5 days. Microbiological eradication was demonstrated in 24 out of 28 patients, and in vitro synergy was demonstrated in 17 of the 17 recovered isolates. Further research with this combination is necessary to describe the optimal role and its impact on patient outcomes.     

Relative risks for comorbidities associated with myotonic dystrophy: A population‐based analysis

Introduction: A population‐level relative risk assessment for comorbidities associated with myotonic dystrophy has not been performed. Methods: In this study we utilized the Utah Population Database to identify patients with myotonic dystrophy in Utah according to ICD‐9 coding. Comorbidity cases listed in the medical record were compared with those of the Utah population. Results: Individuals with myotonic dystrophy were found to possess an increased risk of central and obstructive sleep apnea, hypothyroidism, and intellectual disability. The risk of cardiac conduction disorder is 60 times the population risk. Conclusions: This study provides a population‐level relative risk assessment of comorbidities in myotonic dystrophy. This allows for improved counseling of patients regarding these increased risks. Muscle Nerve 52: 659–661, 2015     

Effects of aerobic exercise training on the protein kinase B (PKB)/mammalian target of rapamycin (mTOR) signaling pathway in aged skeletal muscle

The protein kinase B (PKB)/mammalian target of rapamycin (mTOR) signaling pathway is thought to play a critical role in the regulation of protein synthesis and skeletal muscle mass. The purpose of the present study was to determine the effects of voluntary wheel running on the PKB/mTOR signaling pathway in muscles from aged mice (20-22 months). The total levels of mTOR were 65% higher in gastrocnemius muscles from aged mice subjected to wheel running compared to aged sedentary mice (p-0.002) PKB phosphorlation on Ser473 was 45% higher in gastrocnemius muscles from aged mice subjected to wheel running compared to aged sedentary mice (p=0.01) The total abundance of PKB was 50% higher in gastrocnemius muscles from wheel running mice compared to aged controls (p=0.005). Three months of wheel running did not alter the total amount of p70 S6K in gastrocnemius muscle. Protein synthesis, as assessed by [(14)C]phenylalanine incorporation into protein was significantly higher in soleus muscles from aged mice subjected to wheel running compared to aged sedentary mice (p-0.001) These findings indicate the aerobic exercise training may attenuate the age-related decline in protein synthesis, a process that appears to be due, in part, to increases in mTOR and PKB.     

Discovery of Benzimidazole Oxazolidinediones as Novel and Selective Nonsteroidal Mineralocorticoid Receptor Antagonists

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