Metabolomic Evaluation of N-Acetyl-p-Benzoquinone Imine Protein Adduct Formation with Therapeutic Acetaminophen Administration: Sex-based Physiologic Differences.

BACKGROUND: Acetaminophen (APAP)-associated transaminase elevation, induced by N-acetyl-p-benzoquinone imine (NAPQI) protein adduction, remains an area of research interest. Distinct from known genetic, physiologic, and dosage associations dictating severity of hepatic injury, no known factors predict an absence of protein adduct formation at therapeutic APAP dosing. HYPOTHESIS: Sex-based physiology is predictive of APAP-induced protein adduct formation and differential metabolite expression at therapeutic doses. METHODS: This retrospective study interrogated serum samples collected for a prior study investigating fluctuations of alanine aminotransferase (ALT) over time with 4G daily APAP dosing for ≥ 16 days in subjects from Denver, Colorado. Subjects were grouped by adduct formation (n = 184) vs no adducts (n = 20). Samples were run on ultra-high-performance liquid chromatography mass spectrometry from study days 0, 7, 16, and 31. Significant metabolite expressions were identified using t-tests with false discovery rate correction (FDR), partial least squares discriminant, and ANOVA simultaneous comparison analyses. Demographic and clinical data were explored using t-tests with FDR (age, weight, BMI, ALT) and Chi-square (sex, ethnicity, race) analyses. RESULTS: In pre-treatment samples, relative quantitation caprylic acid was expressed ninefold higher and 6-carboxyhexanoate was expressed threefold lower in subjects who did not develop adducts. Lactate had greater expression in the no adducts group (p = 0.001). Using absolute quantitation, glutathione was expressed 2.6-fold greater among no adduct subjects. Odds of males developing NAPQI protein adducts at therapeutic APAP dosing were 5.91 times lower than females (95% CI = 2.3-14.9; p = 0.0001). CONCLUSION: Multiple metabolites were differentially expressed based on adduct group and sex. Metabolites were identified unique to adduct development independent of sex. At therapeutic APAP dosing, males were less likely to develop APAP protein adducts. Further research into lipid biosynthesis and metabolism may provide further insight into physiology associated with adduct production.

Metabolomic markers predictive of hepatic adaptation to therapeutic dosing of acetaminophen.

BACKGROUND: Drug induced liver injury (DILI) remains a prominent global issue and acetaminophen (APAP) overdose represents a common cause of hepatic injury and DILI. Transient alanine aminotransferase (ALT) elevations have been documented while adhering to recommended daily dosing. However, no metabolites have been identified in pre-treatment samples predicting which patients will develop these transient increases. METHODS: This was a secondary analysis of samples collected from a parent study describing the course of ALT levels in subjects receiving therapeutic APAP dosing. Two hundred and four subjects recruited from Denver, Colorado received 4 g APAP/daily for at least 16 days. Subjects were grouped by ALT at any monitored time point above 60 units/L (n = 25) vs. no increase (n = 179). Serum samples from days 0, 7, 16, and 31 were run on ultra-high performance liquid chromatography mass spectrometry. We report the metabolomic results of samples analyzed prior to APAP administration and over time. Significant changes in metabolite and demographic variable expressions were explored using t-tests with false discovery rate correction, chi square, and partial least squares discriminant analyses. RESULTS: Within pre-treatment day 0 samples, allantoate and ornithine were significantly elevated in subjects of the ALT elevation group (p = .032). Baseline ALT (p = .011) and alkaline phosphatase (p = .006) were also significant. These metabolites were significant independent of race, ethnicity, gender, or BMI. CONCLUSIONS: Allantoate and ornithine are directly involved in pathways related to nitrogen release and urea production. Further investigation into alterations in the glutathione metabolism and urea cycle pathways may lead to a greater understanding of the mechanisms associated with hepatic adaptation for a variety of pharmaceuticals.

Risk Factors for Below-the-Knee Amputation in Diabetic Foot Osteomyelitis After Minor Amputation.

BACKGROUND: Below-the-knee amputation (BKA) can be a detrimental outcome of diabetic foot osteomyelitis (DFO). Ideal treatment of DFO is controversial, but studies suggest minor amputation reduces the risk of BKA. We evaluated risk factors for BKA after minor amputation for DFO. METHODS: This is a retrospective cohort of patients discharged from Denver Health Medical Center from February 1, 2012, through December 31, 2014. Patients who underwent minor amputation for diagnosis of DFO were eligible for inclusion. The outcome evaluated was BKA in the 6 months after minor amputation. RESULTS: Of 153 episodes with DFO that met the study criteria, 11 (7%) had BKA. Failure to heal surgical incision at 3 months (P < .001) and transmetatarsal amputation (P = .009) were associated with BKA in the 6 months after minor amputation. Peripheral vascular disease was associated with failure to heal but not with BKA (P = .009). Severe infection, bacteremia, hemoglobin A1c, and positive histopathologic margins of bone and soft tissue were not associated with BKA. The median antibiotic duration was 42 days for positive histopathologic bone resection margin (interquartile range, 32-47 days) and 16 days for negative margin (interquartile range, 8-29 days). Longer duration of antibiotics was not associated with lower risk of BKA. CONCLUSIONS: Patients who fail to heal amputation sites in 3 months or who have transmetatarsal amputation are at increased risk for BKA. Future studies should evaluate the impact of aggressive wound care or whether failure to heal is a marker of another variable.

How Do Preoperative Antibiotics Affect Culture Yield in Diabetic Foot Infections?

The impact of preoperative antibiotics on culture of diabetic foot infection samples has not been studied. We found that increasing exposure to preoperative antibiotics was associated with less frequent growth of streptococci and anaerobes and more culture-negative results. In contrast, the yield of Staphylococcus aureus and Gram-negative bacilli was unaffected.

Opioid prescription fill rates after emergency department discharge.

PURPOSE: Opioid prescription fill rates and the time to fill after emergency department (ED) discharge were studied. METHODS: Data were evaluated for all patients discharged from the ED between September 1, 2011, who were February 1, 2012, who were diagnosed with one of the following: dental pain, jaw pain, flank pain, abdominal pain, pelvic pain, back pain, neck pain, knee pain, headache, fracture, or sprain. Clinical information was abstracted via computer algorithm, and prescription filling within 100 days of prescription writing was determined by cross-referencing patient demographics with the state prescription drug monitoring program. Logistic regression analysis and a Cox proportional hazards model were used to determine if any clinical and demographic characteristics were associated with fill rates or the time to fill, respectively. RESULTS: Of the 2243 patients who received an opioid prescription at ED discharge, 1775 (79%) filled it, with a median time to fill of 0 days. On adjusted analysis, characteristics associated with filling the opioid prescriptions included Caucasian race, being insured by the federal government or through a state indigent assistance program, a chief complaint of back pain, and a history of filling an opioid prescription within the past year. No characteristics were predictive of a prolonged time to filling. CONCLUSION: One in five patients who received an opioid prescription at discharge from an urban academic ED did not fill it. Several factors may be associated with a greater likelihood of filling, such as insurance status and history of filling an opioid prescription within the past year.

Clinical Reasoning of Infectious Diseases Physicians Behind the Use or Nonuse of Transesophageal Echocardiography in Staphylococcus aureus Bacteremia.

In this prospective cohort with Staphylococcus aureus bacteremia, transesophageal echocardiography (TEE) was performed in 24% of cases. Consulting Infectious Diseases physicians most frequently cited low suspicion for endocarditis due to rapid clearance of blood cultures and the presence of a secondary focus requiring an extended treatment duration as reasons for foregoing TEE.