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BACKGROUND - Prior retrospective cross-sectional work has associated antimicrobials with a non-specific phrase: encephalopathy without seizures. The purpose of this study is to determine whether different classes of antimicrobials have differential associations with the daily risk of delirium after critical illness is adjusted for.
METHODS - Our study was a nested cohort that enrolled non-neurological critically ill adults from a medical or surgical intensive care unit (ICU) with daily follow-up to 30 days. Our independent variable was exposure to previous-day antimicrobial class: beta-lactams (subclasses: penicillins, first- to third-generation cephalosporins, fourth-generation cephalosporins, and carbapenems), macrolides, fluoroquinolones, and other. We adjusted for baseline covariates (age, comorbidities, cognition scores, sepsis, and mechanical ventilation), previous-day covariates (delirium, doses of analgesics/sedatives, and antipsychotic use), and same-day covariates (illness severity). Our primary outcome of delirium was measured by using the Confusion Assessment Method for the ICU. A daily delirium logistic regression model was used with an ICU time-restricted sensitivity analysis including daily adjustment for sepsis and mechanical ventilation.
RESULTS - Of 418 ICU patients, delirium occurred in 308 (74%) with a median of 3 days (interquartile range 2-6) among those affected and 318 (76%) were exposed to antimicrobials. When covariates and ICU type were adjusted for, only first- to third-generation cephalosporins were associated with delirium (logistic regression model odds ratio (OR) = 2.2, 95% confidence interval (CI) 1.28-3.79, P = 0.004; sensitivity analysis OR = 2.13, 95% CI 1.10-4.10, P = 0.024).
CONCLUSIONS - First-, second-, and third-generation cephalosporins doubled the odds of delirium after baseline co-morbidities, ICU type, the course of critical care, and other competing antimicrobial and psychotropic medication risks were adjusted for. We did not find an association between delirium and cefepime, penicillins, carbapenems, fluoroquinolones, or macrolides.

Dysregulated iron transport and a compromised blood-brain barrier are implicated in HIV-associated neurocognitive disorders (HAND). We quantified the levels of proteins involved in iron transport and/or angiogenesis-ceruloplasmin, haptoglobin, and vascular endothelial growth factor (VEGF)-as well as biomarkers of neuroinflammation, in cerebrospinal fluid (CSF) from 405 individuals with HIV infection and comprehensive neuropsychiatric assessments. Associations with HAND [defined by a Global Deficit Score (GDS) ≥ 0.5, GDS as a continuous measure (cGDS), or by Frascati criteria] were evaluated for the highest versus lowest tertile of each biomarker, adjusting for potential confounders. Higher CSF VEGF was associated with GDS-defined impairment [odds ratio (OR) 2.17, p = 0.006] and cGDS in unadjusted analyses and remained associated with GDS impairment after adjustment (p = 0.018). GDS impairment was also associated with higher CSF ceruloplasmin (p = 0.047) and with higher ceruloplasmin and haptoglobin in persons with minimal comorbidities (ORs 2.37 and 2.13, respectively; both p = 0.043). In persons with minimal comorbidities, higher ceruloplasmin and haptoglobin were associated with HAND by Frascati criteria (both p < 0.05), and higher ceruloplasmin predicted worse impairment (higher cGDS values, p < 0.01). In the subgroup with undetectable viral load and minimal comorbidity, CSF ceruloplasmin and haptoglobin were strongly associated with GDS impairment (ORs 5.57 and 2.96, respectively; both p < 0.01) and HAND (both p < 0.01). Concurrently measured CSF IL-6 and TNF-α were only weakly correlated to these three biomarkers. Higher CSF ceruloplasmin, haptoglobin, and VEGF are associated with a significantly greater likelihood of HAND, suggesting that interventions aimed at disordered iron transport and angiogenesis may be beneficial in this disorder.

Diastolic dysfunction (DD), an abnormality in cardiac left ventricular (LV) chamber compliance, is associated with increased morbidity and mortality. Although DD has been extensively studied in older populations, co-morbidity patterns are less well characterized in middle-aged subjects. We screened 156,434 subjects with transthoracic echocardiogram reports available through Vanderbilt's electronic heath record and identified 6,612 subjects 40 to 55 years old with an LV ejection fraction ≥50% and diastolic function staging. We tested 452 incident and prevalent clinical diagnoses for associations with early-stage DD (n = 1,676) versus normal function. There were 44 co-morbid diagnoses associated with grade 1 DD including hypertension (odds ratio [OR] = 2.02, 95% confidence interval [CI] 1.78 to 2.28, p <5.3 × 10-29), type 2 diabetes (OR 1.96, 95% CI 1.68 to 2.29, p = 2.1 × 10-17), tachycardia (OR 1.38, 95% CI 0.53 to 2.19, p = 2.9 × 10-6), obesity (OR 1.76, 95% CI 1.51 to 2.06, p = 1.7 × 10-12), and clinical end points, including end-stage renal disease (OR 3.29, 95% CI 2.19 to 4.96, p = 1.2 × 10-8) and stroke (OR 1.5, 95% CI 1.12 to 2.02, p = 6.9 × 10-3). Among the 60 incident diagnoses associated with DD, heart failure with preserved ejection fraction (OR 4.63, 95% CI 3.39 to 6.32, p = 6.3 × 10-22) had the most significant association. Among subjects with normal diastolic function and blood pressure at baseline, a blood pressure measurement in the hypertensive range at the time of the second echocardiogram was associated with progression to stage 1 DD (p = 0.04). In conclusion, DD was common among subjects 40 to 55 years old and was associated with a heavy burden of co-morbid disease.
Copyright © 2018 Elsevier Inc. All rights reserved.

BACKGROUND & AIMS - Insulin resistance is a risk marker for non-alcoholic fatty liver disease, and a risk factor for liver disease progression. We assessed temporal trajectories of insulin resistance and β-cell response to serum glucose concentration throughout adulthood and their association with diabetes risk in non-alcoholic fatty liver disease.
METHODS - Three thousand and sixty participants from Coronary Artery Risk Development in Young Adults, a prospective bi-racial cohort of adults age 18-30 years at baseline (1985-1986; Y0) who completed up to 5 exams over 25 years and had fasting insulin and glucose measurement were included. At Y25 (2010-2011), non-alcoholic fatty liver disease was assessed by noncontrast computed tomography after exclusion of other liver fat causes. Latent mixture modelling identified 25-year trajectories in homeostatic model assessment insulin resistance and β-cell response homeostatic model assessment-β.
RESULTS - Three distinct trajectories were identified, separately, for homeostatic model assessment insulin resistance (low-stable [47%]; moderate-increasing [42%]; and high-increasing [12%]) and homeostatic model assessment-β (low-decreasing [16%]; moderate-decreasing [63%]; and high-decreasing [21%]). Y25 non-alcoholic fatty liver disease prevalence was 24.5%. Among non-alcoholic fatty liver disease, high-increasing homeostatic model assessment insulin resistance (referent: low-stable) was associated with greater prevalent (OR 95% CI = 8.0, 2.0-31.9) and incident (OR = 10.5, 2.6-32.8) diabetes after multivariable adjustment including Y0 or Y25 homeostatic model assessment insulin resistance. In contrast, non-alcoholic fatty liver disease participants with low-decreasing homeostatic model assessment-β (referent: high-decreasing) had the highest odds of prevalent (OR = 14.1, 3.9-50.9) and incident (OR = 10.3, 2.7-39.3) diabetes.
CONCLUSION - Trajectories of insulin resistance and β-cell response during young and middle adulthood are robustly associated with diabetes risk in non-alcoholic fatty liver disease. Thus, how persons with non-alcoholic fatty liver disease develop resistance to insulin provides important information about risk of diabetes in midlife above and beyond degree of insulin resistance at the time of non-alcoholic fatty liver disease assessment.
© 2018 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

BACKGROUND - Recent studies in adults have found an incidence of acute kidney injury (AKI) in patients treated with a combination of vancomycin and piperacillin-tazobactam (TZP) that is greater than that expected with either medication alone. The purpose of this study was to determine whether combination therapy with vancomycin and TZP is associated with an incidence of AKI in pediatric patients higher than that in those on combination therapy with vancomycin and cefepime.
METHODS - We performed a retrospective single-center matched-cohort study of pediatric patients who received vancomycin in combination with TZP or cefepime between January 2015 and June 2016. The patients were matched according to chronic disease, age, sex, and number of concomitant nephrotoxic medications at the time of combination antibiotic therapy. The primary outcome was incidence of AKI. Secondary outcomes included differences between groups in time to AKI, resolution of AKI, and effect of vancomycin trough levels on the incidence of nephrotoxicity. Conditional logistic regression was used to compare categorical and continuous variables between treatment groups. Conditional Poisson regression was used to assess the association between AKI and treatment groups. Stratified log-rank tests and Cox proportional hazards models with shared frailty were used to compare the times to AKI according to treatment group.
RESULTS - Two hundred twenty-eight matched patients were included. AKI developed in 9 (7.9%) of 114 and 33 (28.9%) of 114 patients in the cefepime and TZP groups, respectively (P < .001). Type of combination therapy remained a significant predictor for AKI in multivariate conditional Poisson analysis in which adjustments were made for age, sex, use of concomitant nephrotoxins, and vancomycin dose (relative risk, 2.5 [95% confidence interval, 1.1-5.8]; P = .03). AKI developed almost 3 times sooner in the TZP group than in the cefepime group (hazard ratio, 2.9 [95% confidence interval, 1.3-6.1]; P = .006). Sensitivity analyses in which adjustment was made for antibiotic indication in addition to the aforementioned variables and excluding those with gastrointestinal infection revealed similar results.
CONCLUSION - Among hospitalized children at our institution, combination therapy with vancomycin and TZP was associated with an incidence of AKI higher than that associated with vancomycin and cefepime.
© The Author(s) 2018. Published by Oxford University Press on behalf of The Journal of the Pediatric Infectious Diseases Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

BACKGROUND - Time to tumor recurrence may be associated with outcomes following resection of hepatobiliary cancers. The objective of the current study was to investigate risk factors and prognosis among patients with early versus late recurrence of hilar cholangiocarcinoma (HCCA) after curative-intent resection.
METHODS - A total of 225 patients who underwent curative-intent resection for HCCA were identified from 10 academic centers in the USA. Data on clinicopathologic characteristics, pre-, intra-, and postoperative details and overall survival (OS) were analyzed. The slope of the curves identified by linear regression was used to categorize recurrences as early versus late.
RESULTS - With a median follow-up of 18.0 months, 99 (44.0%) patients experienced a tumor recurrence. According to the slope of the curves identified by linear regression, the functions of the two straight lines were y = -0.465x + 16.99 and y = -0.12x + 7.16. The intercept value of the two lines was 28.5 months, and therefore, 30 months (2.5 years) was defined as the cutoff to differentiate early from late recurrence. Among 99 patients who experienced recurrence, the majority (n = 80, 80.8%) occurred within the first 2.5 years (early recurrence), while 19.2% of recurrences occurred beyond 2.5 years (late recurrence). Early recurrence was more likely present as distant disease (75.1% vs. 31.6%, p = 0.001) and was associated with a worse OS (Median OS, early 21.5 vs. late 50.4 months, p < 0.001). On multivariable analysis, poor tumor differentiation (HR 10.3, p = 0.021), microvascular invasion (HR 3.3, p = 0.037), perineural invasion (HR 3.9, p = 0.029), lymph node metastases (HR 5.0, p = 0.004), and microscopic positive margin (HR 3.5, p = 0.046) were independent risk factors associated with early recurrence.
CONCLUSIONS - Early recurrence of HCCA after curative resection was common (~35.6%). Early recurrence was strongly associated with aggressive tumor characteristics, increased risk of distant metastatic recurrence and a worse long-term survival.

BACKGROUND - Systemic inflammation and muscle wasting are highly prevalent and coexist in patients on maintenance hemodialysis (MHD). We aimed to determine the effects of systemic inflammation on skeletal muscle protein metabolism in MHD patients.
METHODS - Whole body and skeletal muscle protein turnover were assessed by stable isotope kinetic studies. We incorporated expressions of E1, E214K, E3αI, E3αII, MuRF-1, and atrogin-1 in skeletal muscle tissue from integrin β1 gene KO CKD mice models.
RESULTS - Among 129 patients with mean (± SD) age 47 ± 12 years, 74% were African American, 73% were male, and 22% had diabetes mellitus. Median high-sensitivity C-reactive protein (hs-CRP) concentration was 13 (interquartile range 0.8, 33) mg/l. There were statistically significant associations between hs-CRP and forearm skeletal muscle protein synthesis, degradation, and net forearm skeletal muscle protein balance (P < 0.001 for all). The associations remained statistically significant after adjustment for clinical and demographic confounders, as well as in sensitivity analysis, excluding patients with diabetes mellitus. In attempting to identify potential mechanisms involved in this correlation, we show increased expressions of E1, E214K, E3αI, E3αII, MuRF-1, and atrogin-1 in skeletal muscle tissue obtained from an animal model of chronic kidney disease.
CONCLUSION - These data suggest that systemic inflammation is a strong and independent determinant of skeletal muscle protein homeostasis in MHD patients, providing rationale for further studies using anticytokine therapies in patients with underlying systemic inflammation.
FUNDING - This study was in part supported by NIH grants R01 DK45604 and 1K24 DK62849, the Clinical Translational Science Award UL1-TR000445 from the National Center for Advancing Translational Sciences, the Veterans Administration Merit Award I01 CX000414, the SatelliteHealth Normon Coplon Extramural Grant Program, and the FDA grant 000943.

BACKGROUND - Among women aged 50 to 59 years at baseline in the Women's Health Initiative (WHI) Estrogen-Alone (E-Alone) trial, randomization to conjugated equine estrogen-alone versus placebo was associated with lower risk of myocardial infarction and mortality, and, in an ancillary study, the WHI-CACS (WHI Coronary Artery Calcification Study) with lower CAC, measured by cardiac computed tomography ≈8.7 years after baseline randomization. We hypothesized that higher CAC would be related to post-trial coronary heart disease (CHD), cardiovascular disease (CVD), and total mortality, independent of baseline randomization or risk factors.
METHODS AND RESULTS - WHI-CACS participants (n=1020) were followed ≈8 years from computed tomography scan in 2005 (mean age=64.4) through 2013 for incident CHD (myocardial infarction and fatal CHD, n=17), CVD (n=69), and total mortality (n=55). Incident CHD and CVD analyses excluded women with CVD before scan (n=89). Women with CAC=0 (n=54%) had very low age-adjusted rates/1000 person-years of CHD (0.91), CVD (5.56), and mortality (3.45). In comparison, rates were ≈2-fold higher for women with any CAC (>0). Associations were not modified by baseline randomization to conjugated equine estrogen-alone versus placebo. Adjusted for baseline randomization and risk factors, the hazard ratio (95% confidence interval) for CAC >100 (19%) was 4.06 (2.11, 7.80) for CVD and 2.70 (1.26, 5.79) for mortality.
CONCLUSIONS - Among a subset of postmenopausal women aged 50 to 59 years at baseline in the WHI E-Alone Trial, CAC at mean age of 64 years was strongly related to incident CHD, CVD, and to total mortality over ≈8 years, independent of baseline randomization to conjugated equine estrogen-alone versus placebo or CVD risk factors.
CLINICAL TRIAL REGISTRATION - URL: https://www.clinicaltrials.gov. Unique identifier: NCT00000611.
© 2017 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley.

BACKGROUND - Orthostatic hypotension causes ≈80 000 hospitalizations per year in the United States. Treatments for orthostatic hypotension include fludrocortisone, a mineralocorticoid analog that promotes sodium reabsorption; and midodrine, an α-1 adrenergic agonist that is a direct vasoconstrictor. Although both medications are used to treat orthostatic hypotension, few studies have compared their relative safety.
METHODS AND RESULTS - We compared incidence rates of hospitalizations for all causes, and for congestive heart failure between users of fludrocortisone and users of midodrine in a retrospective cohort study of Tennessee Medicaid adult enrollees (1995-2009). Adjusted incidence rate ratios were calculated using negative binomial regression models. Subgroup analyses based on history of congestive heart failure were conducted. We studied 1324 patients initiating fludrocortisone and 797 patients initiating midodrine. Compared with fludrocortisone users, midodrine users had higher prevalence of cardiovascular conditions. Incidence rates of all-cause hospitalizations for fludrocortisone and midodrine users were 1489 and 1330 per 1000 person-years, respectively (adjusted incidence-rate ratio 1.20, 95% confidence interval, 1.02-1.40). The respective rates of heart failure-related hospitalization were 76 and 84 per 1000 person-years (adjusted incidence-rate ratio: 1.33, 95% confidence interval, 0.79-2.56). Among patients with a history of congestive heart failure, the rates of all-cause hospitalization for fludrocortisone and midodrine were 2448 and 1820 per 1000 person-years (adjusted incidence-rate ratio: 1.42, 95% confidence interval, 1.07-1.90), and the respective rates of heart failure exacerbation-related hospitalizations were 297 and 263 per 1000 person-years (adjusted incidence-rate ratio: 1.48, 95% confidence interval, 0.69-3.16).
CONCLUSIONS - Compared with users of midodrine, users of fludrocortisone had higher rates of all-cause hospitalizations, especially among patients with congestive heart failure.
© 2017 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley.

OBJECTIVE - Excess deposition of fat within and around vital organs and nonadipose tissues is hypothesized to contribute to cardiovascular disease (CVD) risk. We evaluated the association of abdominal intermuscular adipose tissue (IMAT) volume with coronary artery calcification in the CARDIA study (Coronary Artery Risk Development in Young Adults) participants.
APPROACH AND RESULTS - We measured IMAT in the abdominal muscles, visceral adipose tissue and pericardial adipose tissue, and coronary artery calcification using computed tomography in 3051 CARDIA participants (56% women) at the CARDIA year 25 examination (2010-2011). Mean IMAT volume and mean IMAT/total muscle volume (IMAT normalized for muscle size) were calculated in a 10-mm block of slices centered at L3-L4. Multivariable analyses included potential confounders and traditional cardiovascular disease risk factors. Compared with the lowest quartile, the upper quartile of abdominal IMAT volume was associated with higher coronary artery calcification prevalence (odds ratio [95% confidence interval], 1.6 [1.2-2.1]) after adjusting for cardiovascular disease risk factors. Results were similar for highest versus lowest quartile of IMAT normalized to total muscle volume (odds ratio [95% confidence interval], 1.5 [1.1-2.0]). Significant associations of higher IMAT and normalized IMAT with coronary artery calcification prevalence persisted when body mass index, visceral adipose tissue, or pericardial adipose tissue were added to the models.
CONCLUSIONS - In a large, community-based, cross-sectional study, we found that higher abdominal skeletal muscle adipose tissue volume was associated with subclinical atherosclerosis independent of traditional cardiovascular disease risk factors and other adipose depots.
© 2017 American Heart Association, Inc.