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1.  Heart rate and blood pressure variability in children with chronic kidney disease: a report from the CKiD study 
Autonomic nervous system dysfunction and sympathetic nervous system over-activity play important roles in the development of hypertension associated with chronic kidney disease (CKD). In adults, increased blood pressure variability (BPV) appears to be directly related to sympathetic over-activity with increased risk of end-organ damage and cardiovascular events. Decreased heart rate variability (HRV) has been observed in adults with CKD, and is an independent predictor of mortality.
The purpose of this study was to evaluate BPV and HRV in pediatric patients enrolled in the Chronic Kidney Disease in Children Study. Ambulatory blood pressure monitoring data were available for analysis of 215 person-visits from 144 children that were not receiving antihypertensive medications.
BPV and HRV were determined by standard deviation and coefficient of variation for heart rate and systolic and diastolic blood pressure for each patient averaged for wake/sleep periods during 24-h monitoring. Uniformly lower values were displayed during sleep versus wake periods: BPV was 20 % lower during sleep (p<0.001) and HRV was 30 % lower during sleep (p<0.001). A significant increase in systolic BPV was observed in hypertensive children compared to children with normal blood pressure (6.9 %, p=0.009). Increased diastolic BPV was detected among hypertensive children during sleep period compared to children with normal blood pressure (11.5 %, p=0.008). There was a significant decrease in HRV in hypertensive compared to normotensive children (−8.2 %, p=0.006).
These findings are similar to those in adult patients and may underscore childhood origin and natural progression of adverse cardiovascular outcomes in adults with CKD.
PMCID: PMC4072494  PMID: 24488505
Heart rate variability; Blood pressure variability; Chronic kidney disease; Hypertension; Pediatrics
2.  Intellectual Impairment in Children with Blood Lead Concentrations below 10 µg per Deciliter 
The New England journal of medicine  2003;348(16):1517-1526.
Despite dramatic declines in children’s blood lead concentrations and a lowering of the Centers for Disease Control and Prevention’s level of concern to 10 µg per deciliter (0.483 µmol per liter), little is known about children’s neurobehavioral functioning at lead concentrations below this level.
We measured blood lead concentrations in 172 children at 6, 12, 18, 24, 36, 48, and 60 months of age and administered the Stanford–Binet Intelligence Scale at the ages of 3 and 5 years. The relation between IQ and blood lead concentration was estimated with the use of linear and nonlinear mixed models, with adjustment for maternal IQ, quality of the home environment, and other potential confounders.
The blood lead concentration was inversely and significantly associated with IQ. In the linear model, each increase of 10 µg per deciliter in the lifetime average blood lead concentration was associated with a 4.6-point decrease in IQ (P=0.004), whereas for the subsample of 101 children whose maximal lead concentrations remained below 10 µg per deciliter, the change in IQ associated with a given change in lead concentration was greater. When estimated in a nonlinear model with the full sample, IQ declined by 7.4 points as lifetime average blood lead concentrations increased from 1 to 10 µg per deciliter.
Blood lead concentrations, even those below 10 µg per deciliter, are inversely associated with children’s IQ scores at three and five years of age, and associated declines in IQ are greater at these concentrations than at higher concentrations. These findings suggest that more U.S. children may be adversely affected by environmental lead than previously estimated.
PMCID: PMC4046839  PMID: 12700371
3.  Suture button suspension following trapeziectomy in a cadaver model 
Hand (New York, N.Y.)  2012;8(2):195-200.
The safety and the effects of different trajectories on thumb motion of suture-button suspensionplasty post-trapeziectomy are not known.
In a cadaveric model, thumb range of motion, trapeziectomy space height, and distance between the device and nerve to the first dorsal interosseous muscle (first DI) were measured for proximal and distal trajectory groups. Proximal trajectory was defined as a suture button angle directed from the thumb metacarpal to the second metacarpal at a trajectory less than 60° from the horizontal; distal trajectory was defined as a suture button angle directed from the thumb metacarpal to the second metacarpal at a trajectory of greater than 60° from the horizontal (Fig. 1).
There were no significant differences in range of motion and trapeziectomy space height between both groups. The device was significantly further away from the nerve to the first DI in the proximal trajectory group compared to the distal trajectory group, but was still safely away from the nerve in both groups (greater than 1 cm).
These results suggest that the device placement in either a proximal or distal location on the second metacarpal will yield similar results regarding safety and thumb range of motion.
PMCID: PMC3652989  PMID: 24426918
Safety; Suture button suspensionplasty; Thumb carpometacarpal arthritis; Trajectory; Trapeziectomy
4.  Rapid Burkholderia pseudomallei identification and antibiotic resistance determination by bacteriophage amplification and MALDI-TOF MS 
Bacteriophage  2014;4:e29011.
Phage amplification detected by MALDI-TOF MS was investigated for rapid and simultaneous Burkholderia pseudomallei identification and ceftazidime resistance determination. B. pseudomallei ceftazidime susceptible and resistant ΔpurM mutant strains Bp82 and Bp82.3 were infected with broadly targeting B. pseudomallei phage ϕX216 and production of the m/z 37.6 kDa phage capsid protein observed by MALDI-TOF MS over the course of 3 h infections. This allowed for repoducible phage-based bacterial ID within 2 h of the onset of infection. MALDI-TOF MS-measured time to detection correlated with in silico modeling, which predicted an approximate 2 h detection time. Ceftazidime susceptible strain Bp82, while detectable in the absence of the drug, owing to the reliance of phage amplification on a viable host, was not detectable when 10 μg/mL ceftazidime was added at the onset of infection. In contrast, resistant strain Bp82.3 was detected in the same 2 h timeframe both with and without the addition of ceftazidime.
PMCID: PMC4090906  PMID: 25050191
phage amplification; bacterial identification; antibiotic resistance; Burkholderia; MALDI-TOF MS
5.  Neuropsychological Test Performance Before and After HIV-1 Seroconversion: The Multicenter AIDS Cohort Study 
Journal of neurovirology  2012;19(1):24-31.
To compare neuropsychological test performance before and after HIV-1 seroconversion in order to identify possible acute changes in psychomotor speed, memory, attention, and concentration secondary to seroconversion.
Mixed effects models to examine longitudinal neuropsychological test data.
We conducted a nested cohort study of 362 male HIV-1 seroconverters enrolled in the Multicenter AIDS Cohort Study. We used linear mixed models with random subject effects to compare repeated neuropsychological test outcomes from 5 years before seroconversion to 2 years after seroconversion on the Trail Making Test (Parts A & B), Symbol-Digit Test, Grooved Pegboard (dominant and non-dominant hands), Stroop Color-Interference Test, Rey Auditory Verbal Learning Test, and the CalCAP Reaction Time Test.
We found no significant changes in the time-dependent score after seroconversion for the majority of neuropsychological tests used in the Multicenter AIDS Cohort Study. There was a significant change in time trend after seroconversion on part B of the Trail Making Test (p=0.042) but the difference only represented a 2% decrease in performance. We found the following characteristics to be associated with worse neuropsychological test performance: lower education levels, history of depression, older age, and no previous neurocognitive testing (p<.05).
Our results suggest that despite a 50% decrease in CD4 cell count immediately following infection, HIV-1 does not appear to have a measurable effect on psychomotor or complex cognitive processing for up to 2 years following infection, using this set of neurocognitive measures.
PMCID: PMC3568242  PMID: 23229349
HIV; neuropsychological test; seroconversion; CD4; neurocognition
6.  Shaping suvorexant: application of experimental and theoretical methods for driving synthetic designs 
Dual Orexin Receptor Antagonists (DORA) bind to both the Orexin 1 and 2 receptors. High resolution crystal structures of the Orexin 1 and 2 receptors, both class A GPCRs, were not available at the time of this study, and thus, ligand-based analyses were invoked and successfully applied to the design of DORAs. Computational analysis, ligand based superposition, unbound small-molecule X-ray crystal structures and NMR analysis were utilized to understand the conformational preferences of key DORAs and excellent agreement between these orthogonal approaches was seen in the majority of compounds examined. The predominantly face-to-face (F2F) interaction observed between the distal aromatic rings was the core 3D shape motif in our design principle and was used in the development of compounds. A notable exception, however, was seen between computation and experiment for suvorexant where the molecule exhibits an extended conformation in the unbound small-molecule X-ray structure. Even taking into account solvation effects explicitly in our calculations, we nevertheless find support that the F2F conformation is the bioactive conformation. Using a dominant states approximation for the partition function, we made a comprehensive assessment of the free energies required to adopt both an extended and a F2F conformation of a number of DORAs. Interestingly, we find that only a F2F conformation is consistent with the activities reported.
Electronic supplementary material
The online version of this article (doi:10.1007/s10822-014-9710-x) contains supplementary material, which is available to authorized users.
PMCID: PMC3927067  PMID: 24488306
Suvorexant; Conformational analysis; Free energy; ROCS
7.  Cochlear Function among HIV-Seropositive and HIV-Seronegative Men and Women 
Ear and hearing  2014;35(1):10.1097/AUD.0b013e3182a021c8.
There is limited research about cochlear function in adults who are human immunodeficiency virus (HIV) positive (+). The aim of the present study was to collect measures of cochlear function in a large sample of adults with, or at risk for, HIV infection, to evaluate associations between HIV status, HIV treatment, and cochlear function.
Distortion product otoacoustic emissions (DPOAEs) were used to evaluate cochlear function in 506 participants; 329 men, 150 of whom were HIV+, and 177 women, 136 of whom were HIV+. DPOAEs were measured at frequencies 1000, 2000, 3000, 4000, and 6000 Hz. A DPOAE nonresponse (NR) was defined as an absolute DPOAE level less than −15 dB SPL or a difference between the absolute DPOAE level and the background noise level less than 6 dB. The total number of NRs was calculated for each ear. The associations of demographic variables, HIV status, and HIV treatment with number of NRs were evaluated with univariate and multivariate ordinal regression models.
There was a statistically significant increase in the odds of higher numbers of NRs with age, being male, and being non-Black, but not with HIV status. Among HIV+ participants, there were no statistically significant associations of the HIV disease status or treatment variables with higher number of NRs.
The authors found no evidence of impaired cochlear function by HIV disease status or highly active antiretroviral therapy–treated HIV infection in this cross-sectional study.
PMCID: PMC3872496  PMID: 24080949
8.  Model-Based Estimation of the Attributable Risk: A Loglinear Approach 
This paper considers model-based methods for estimation of the adjusted attributable risk (AR) in both case-control and cohort studies. An earlier review discussed approaches for both types of studies, using the standard logistic regression model for case-control studies, and for cohort studies proposing the equivalent Poisson model in order to account for the additional variability in estimating the distribution of exposures and covariates from the data. In this paper we revisit case-control studies, arguing for the equivalent Poisson model in this case as well. Using the delta method with the Poisson model, we provide general expressions for the asymptotic variance of the AR for both types of studies. This includes the generalized AR, which extends the original idea of attributable risk to the case where the exposure is not completely eliminated. These variance expressions can be easily programmed in any statistical package that includes Poisson regression and has capabilities for simple matrix algebra. In addition, we discuss computation of standard errors and confidence limits using bootstrap resampling. For cohort studies, use of the bootstrap allows binary regression models with link functions other than the logit.
PMCID: PMC3462467  PMID: 23049150
adjusted attributable risk; case-control study; cohort study; Poisson regression; delta method; model-based estimate; bootstrap methods
9.  Diagnostic Performance of Combined Non-invasive Coronary Angiography and Myocardial Perfusion Imaging Using 320 Row Detector Computed Tomography: Design and Implementation of the CORE320 Multicenter, Multinational Diagnostic Study 
Journal of cardiovascular computed tomography  2011;5(6):10.1016/j.jcct.2011.11.001.
Multi-detector coronary computed tomography angiography (CTA) is a promising modality for widespread clinical application because of its non-invasive nature and high diagnostic accuracy as found in previous studies using 64 to 320 simultaneous detector rows. It is, however, limited in its ability to detect myocardial ischemia. In this manuscript we describe the design of the CORE320 study (“Combined Coronary Atherosclerosis and Myocardial Perfusion Evaluation Using 320 Detector Row Computed Tomography”). This prospective, multicenter, multinational study is unique in that it is designed to assess the diagnostic performance of combined 320-row CTA and myocardial CT perfusion imaging (CTP) in comparison to the combination of invasive coronary angiography and single photon emission computed tomography myocardial perfusion imaging (SPECT-MPI). The trial is being performed at 16 medical centers located in 8 countries worldwide. Computed tomography has the potential to assess both anatomy and physiology in a single imaging session. The co-primary aims of the CORE320 study is to define the per-patient diagnostic accuracy of the combination of coronary CTA and myocardial CTP to detect physiologically significant coronary artery disease compared to 1) the combination of conventional coronary angiography and SPECT-MPI and 2) conventional coronary angiography alone. If successful, the technology could revolutionize the management of patients with symptomatic CAD.
PMCID: PMC3828643  PMID: 22146496
computed tomography; coronary angiography; myocardial perfusion imaging; study design and implementation; multicenter study
10.  Development and pilot testing of a decision aid for surrogates of patients with prolonged mechanical ventilation 
Critical care medicine  2012;40(8):10.1097/CCM.0b013e3182536a63.
Shared decision making is inadequate in intensive care units (ICUs). Decision aids can improve decision making quality, though their role in an ICU setting is unclear. We aimed to develop and pilot test a decision aid for shared decision makers of patients undergoing prolonged mechanical ventilation.
ICUs at three medical centers.
53 surrogate decision makers and 58 physicians.
Design and interventions
We developed the decision aid using defined methodological guidelines. After an iterative revision process, formative cognitive testing was performed among surrogate-physician dyads. Next, we compared the decision aid to usual care control in a prospective, before/after design study.
Measurements and main results
Primary outcomes were physician-surrogate discordance for expected patient survival, comprehension of relevant medical information, and the quality of communication. Compared to control, the intervention group had lower surrogate-physician discordance (7 [10] vs 43 [21]), greater comprehension (11.4 [0.7] vs 6.1 [3.7]), and improved quality of communication (8.7 [1.3] vs 8.4 [1.3]) (all p<0.05) post-intervention. Hospital costs were lower in the intervention group ($110,609 vs $178,618; p=0.044); mortality did not differ by group (38% vs 50%, p=0.95). 94% of surrogates and 100% of physicians reported that the decision aid was useful in decision making.
We developed a prolonged mechanical ventilation decision aid that is feasible, acceptable, and associated with both improved decision making quality and less resource utilization. Further evaluation using a randomized controlled trial design is needed to evaluate the decision aid's effect on long-term patient and surrogate outcomes.
PMCID: PMC3826165  PMID: 22635048
decision aid; decision making; respiration; artificial; critical illness; prolonged mechanical ventilation
11.  Association of HIV infection with Incident Diabetes Mellitus: Impact of using Hemoglobin A1C as a Criterion for Diabetes 
Data regarding the association between HIV and DM are conflicting, with little known regarding the impact of including hemoglobin A1C (A1C) as a criterion for DM.
Pooled logistic regression was used to quantify the association between HIV and DM in 1501 HIV-infected and 550 HIV-uninfected participants from the Women’s Interagency HIV Study. Incident DM was defined using three DM definitions: (I) fasting glucose (FG) ≥126mg/dl, anti-DM medication, or reporting DM diagnosis (with confirmation by FG≥126mg/dl or anti-DM medication); (II) confirmation with a second FG≥126mg/dl; and (III) addition of A1C≥6.5% confirmed by FG≥126mg/dl or anti-DM medication.
DM incidence per 100 person-years was 2.44, 1.55, and 1.70 for HIV-infected women; 1.89, 0.85, and 1.13 for HIV-uninfected women, using definition I, II, and III, respectively. After adjustment for traditional DM risk factors, HIV infection was associated with 1.23, 1.90, and 1.38-fold higher risk of incident DM, respectively; the association reached statistical significance only when confirmation with a second FG≥126mg/dl was required. Older age, obesity, and a family history of DM were each consistently and strongly associated with increased DM risk.
HIV infection is consistently associated with greater risk of DM. Inclusion of an elevated A1C to define DM increases the accuracy of the diagnosis and only slightly attenuates the magnitude of the association otherwise observed between HIV and DM. By contrast, a DM diagnosis made without any confirmatory criteria for FG ≥126mg/dl overestimates the incidence, while also underestimating the effects of HIV on DM risk, and should be avoided.
PMCID: PMC3480977  PMID: 22878421
Diabetes mellitus; HIV; Women; Hemoglobin A1C
12.  Papillomavirus-Like Particles Are an Effective Platform for Amyloid-β Immunization in Rabbits and Transgenic Mice1 
Immunization with amyloid-β (Aβ) prevents the deposition of Aβ in the brain and memory deficits in transgenic mouse models of Alzheimer’s disease (AD), opening the possibility for immunotherapy of AD in humans. Unfortunately, the first human trial of Aβ vaccination was complicated, in a small number of vaccinees, by cell-mediated meningoencephalitis. To develop an Aβ vaccine that lacks the potential to induce autoimmune encephalitis, we have generated papillomavirus-like particles (VLP) that display 1–9 aa of Aβ protein repetitively on the viral capsid surface (Aβ-VLP). This Aβ peptide was chosen because it contains a functional B cell epitope, but lacks known T cell epitopes. Rabbit and mouse vaccinations with Aβ-VLP were well tolerated and induced high-titer autoAb against Aβ, that inhibited effectively assembly of Aβ1–42 peptides into neurotoxic fibrils in vitro. Following Aβ-VLP immunizations of APP/presenilin 1 transgenic mice, a model for human AD, we observed trends for reduced Aβ deposits in the brain and increased numbers of activated microglia. Furthermore, Aβ-VLP vaccinated mice also showed increased levels of Aβ in plasma, suggesting efflux from the brain into the vascular compartment. These results indicate that the Aβ-VLP vaccine induces an effective humoral immune response to Aβ and may thus form a basis to develop a safe and efficient immunotherapy for human AD.
PMCID: PMC3792340  PMID: 16888028
13.  Assessing mortality in women with hepatitis C virus and HIV using indirect markers of fibrosis 
AIDS (London, England)  2012;26(5):599-607.
Co-infection with hepatitis C virus (HCV) is a major cause of morbidity and mortality in HIV-infected individuals. However, predictors of mortality are poorly defined and most studies have focused predominantly on co-infection in men. We evaluated whether two indirect markers of hepatic fibrosis, aspartate aminotransferase-to-platelet ratio index (APRI) and FIB-4 scores, were predictive of mortality in a well defined longitudinal cohort of HCV/HIV-co-infected women on HAART.
HCV/HIV-co-infected women on antiretroviral therapy enrolled in Women’s Interagency HIV Study (WIHS), a National Institutes of Health-funded prospective, multicenter, cohort study of women with and at risk for HIV infection were included. Using Cox regression analysis, associations between APRI and FIB-4 with all-cause mortality were assessed.
Four hundred and fifty HCV/HIV-co-infected women, of whom 191 women died, had a median follow-up of 6.6 years and 5739 WIHS visits. Compared with women with low APRI or FIB-4 levels, severe fibrosis was significantly associated with an increased risk of all-cause mortality {APRI: hazard ratio 2.78 [95% confidence interval (CI) 1.87, 4.12]; FIB-4: hazard ratio 2.58 (95% CI 1.68, 3.95)}. Crude death rates per 1000 patient-years increased with increasing liver fibrosis: 34.8 for mild, 51.3 for moderate and 167.9 for severe fibrosis as measured by FIB-4. Importantly, both APRI and FIB-4 increased during the 5 years prior to death for all women: the slope of increase was greater for women dying a liver-related death compared with nonliver-related death.
Both APRI and FIB-4 are independently associated with all-cause mortality in HCV/HIV-co-infected women and may have clinical prognostic utility among women with HIV and HCV.
PMCID: PMC3698040  PMID: 22156972
fibrosis markers; hepatitis C virus; HIV; longitudinal study; mortality
14.  RNA Expression Profiles from Blood for the Diagnosis of Stroke and its Causes 
Journal of child neurology  2011;26(9):1131-1136.
A blood test to detect stroke and its causes would be particularly useful in babies, young children, and patients in intensive care units, and for emergencies when imaging is difficult to obtain or unavailable. Using whole genome microarrays, we first showed specific gene expression profiles in rats 24 hours after ischemic and hemorrhagic stroke, hypoxia, and hypoglycemia. These proof-of-principle studies revealed that groups of genes (called gene profiles) can distinguish ischemic stroke patients from controls 3 hours to 24 hours after the strokes. In addition, gene expression profiles have been developed that distinguish stroke due to large-vessel atherosclerosis from cardioembolic stroke. These profiles will be useful for predicting the causes of cryptogenic stroke. Our results in adults suggest similar diagnostic tools could be developed for children.
PMCID: PMC3674558  PMID: 21636778
Gene expression profiling; blood; RNA; stroke; brain ischemia
15.  The Cumulative Effects of Medication Use, Drug Use, and Smoking on Erectile Dysfunction Among Men Who Have Sex With Men 
The Journal of Sexual Medicine  2012;9(4):1106-1113.
Erectile dysfunction (ED) is highly prevalent among Human Immunodeficiency Virus-seropositive (HIV+) men who have sex with men (MSM). There is a need for additional research to determine the correlates of HIV+ and HIV-seronegative (HIV−) MSM, especially regarding non-antiretroviral medication use.
This study examined the prevalence of ED and the socio-demographic, medical conditions, medication use, and substance use correlates of ED among HIV+ and HIV− MSM.
A modified version of the International Index of Erectile Function (IIEF) for MSM was self-administered by participants enrolled in the Multicenter AIDS Cohort Study (MACS), an ongoing prospective study of the natural and treated histories of HIV infection among MSM in the United States. The study sample included 1,340 participants, including 612 HIV+ and 728 HIV− men. Poisson regression with robust error variance was used to estimate prevalence ratios of ED in multivariable models in combined (HIV+/−) and separate analyses.
Main outcome measure
ED was determined by the summed scores of a modified version of the IIEF validated among MSM.
Twenty-one percent of HIV+ MSM and 16% of HIV− MSM reported ED. Being >55 years of age, Black race, cumulative pack-years of smoking, cumulative antihypertensive use, and cumulative antidepressant use had significant positive associations with the prevalence of ED in the total sample. Among HIV+ men, duration of antihypertensive use and antidepressant use were significantly associated with increasing prevalence of ED. Among HIV− men, being >55 years of age, Black race, and cigarette smoking duration were associated with increased prevalence of ED.
Predictors of ED may differ by HIV status.. Although smoking cessation and effective medication management may be important as possible treatment strategies for ED among all MSM, there may be a burden on sexual functioning produced by non-HIV medications for HIV+ men.
PMCID: PMC3319271  PMID: 22321450
16.  Cumulative exposure to stimulants and immune function outcomes among HIV-positive and HIV-negative men in the Multicenter AIDS Cohort Study 
We examined associations between stimulant use (methamphetamine and cocaine) and other substances (nicotine, marijuana, alcohol, inhaled nitrites) with immune function biomarkers among HIV-seropositive (HIV+) men using highly active antiretroviral therapy (ART) and -seronegative (HIV−) men in the Multicenter AIDS Cohort Study (MACS). Among HIV+ men, cumulative adherence to ART (4.07, 95% CI: 3.52, 4.71, per 10 years of adherent HAART use), and recent cohort enrollment (1.38; 95% CI: 1.24, 1.55) were multiplicatively associated with increases in CD4+/CD8+ ratios. Cumulative use of methamphetamine (0.93; 95% CI: 0.88, 0.98, per 10 use years), cocaine (0.93; 95% CI: 0.89, 0.96, per 10 use years), and cumulative medical visits (0.99; 95% CI: 0.98, 0.99, per 10 visit years), each showed small negative associations with CD4+/CD8+ ratios. Among HIV- men, cumulative medical visits (0.996; 95% CI: 0.993, 0.999), cumulative number of male sexual partners (0.999; 95% CI: 0.998, 0.9998, per 10 partner years) and cigarette pack years (1.10; 95% CI: 1.02, 1.18, per 10 pack years) were associated with CD4+/CD8+ ratios over the same period. ART adherence is associated with a positive immune function independent of stimulant use, underscoring the influence of ART on immune health for HIV+ men who engage in stimulant use.
PMCID: PMC3576843  PMID: 22930295
HIV; men; methamphetamine; cocaine; CD4+/CD8+ ratio; antiretroviral therapy; adherence; Multicenter AIDS Cohort Study
17.  Diagnostic Accuracy of CT Coronary Angiography According to Pretest Probability of Coronary Artery Disease and Severity of Coronary Arterial Calcification: The CorE-64 International, Multicenter Study 
Assess the impact of patient population characteristics on accuracy by CT angiography (CTA) to detect obstructive coronary artery disease (CAD).
The ability of CTA to exclude obstructive CAD in patients of different pretest probabilities and in presence of coronary calcification remains uncertain.
For the CorE-64 study 371 patients underwent CTA and cardiac catheterization for the detection of obstructive CAD defined as 50% or greater luminal stenosis by quantitative coronary angiography (QCA). This analysis includes 80 initially excluded patients with a calcium score ≥ 600. Area under the receiver-operating-characteristics curve (AUC) was used to evaluate CTA diagnostic accuracy compared to QCA in patients according to calcium score and pretest probability of CAD.
Analysis of patient-based quantitative CTA accuracy revealed an AUC of 0.93 (95% confidence interval [CI] 0.90-0.95). AUC remained 0.93 (0.90-0.96) after excluding patients with known CAD but decreased to 0.81 (0.71-0.89) in patients with calcium score ≥ 600 (p=0.077). While AUC were similar (0.93, 0.92, and 0.93, respectively) for patients with intermediate, high pretest probability for CAD, and known CAD, negative predictive values were different: 0.90, 0.83, and 0.50, respectively. Negative predictive values decreased from 0.93 to 0.75 for patients with calcium score < or ≥ 100, respectively (p= 0.053).
Both pretest probability for CAD and coronary calcium scoring should be considered before using CTA for excluding obstructive CAD. CTA is less effective for this purpose in patients with calcium score ≥ 600 and in patients with a high pretest probability for obstructive CAD.
PMCID: PMC3348589  PMID: 22261160
Coronary Disease; Imaging; Angiography
18.  Development and preliminary evaluation of a telephone-based coping skills training intervention for survivors of acute lung injury and their informal caregivers 
Intensive care medicine  2012;38(8):1289-1297.
Survivors of acute lung injury (ALI) and their informal caregivers have difficulty coping with the physical and emotional challenges of recovery from critical illness. We aimed to develop and pilot test a telephone-based coping skills training intervention for this population.
58 participants were enrolled overall. 21 patients and 23 caregivers participated in a cross-sectional study to assess coping and its association with psychological distress. This also informed the development of an ALI coping skills training intervention in an iterative process involving content and methodological experts. The intervention was then evaluated in 7 patients and 7 caregivers in an uncontrolled, prospective, pre-post study. Outcomes included acceptability, feasibility, and symptoms of psychological distress measured with the Hospital Anxiety and Depression Scale (HADS) and Post-Traumatic Symptom Scale (PTSS).
Survivors and their caregivers used adaptive coping infrequently, a pattern that was strongly associated with psychological distress. These findings informed the development of a 12-session intervention for acquiring, applying, and maintaining coping skills. In the evaluation phase, participants completed 77 (92%) of a possible 84 telephone sessions and all (100%) reported that the intervention’s usefulness in their daily routine. Mean change scores reflecting improvements in the HADS (7.8 units) and PTSS (10.3 units) were associated with adaptive coping (r=0.50–0.70) and high self-efficacy (r=0.67–0.79).
A novel telephone-based coping skills training intervention was acceptable, feasible, and may have been associated with a reduction in psychological distress among survivors of ALI and their informal caregivers. A randomized trial is needed to evaluate the intervention.
PMCID: PMC3535183  PMID: 22527082
coping; acute lung injury; behavioral therapy; quality of life
19.  Development and Validation of a Printed Information Brochure for Families of Chronically Critically Ill Patients 
Critical Care Medicine  2012;40(1):73-78.
Families and other surrogate decision-makers for chronically critically ill patients often lack information about patient prognosis or options for care. This study describes an approach to develop and validate a printed information brochure about chronic critical illness aimed at improving comprehension of the disease process and outcomes for patients’ families and other surrogate decision-makers.
Investigators reviewed existing literature to identify key domains of informational needs. Content of these domains was incorporated in a draft brochure that included graphics and a glossary of terms. Clinical sensibility, balance, and emotional sensitivity of the draft brochure were tested in a series of evaluations by cohorts of experienced clinicians (n=49) and clinical content experts (n=8), with revisions after each review. Cognitive testing of the brochure was performed through interviews of 10 representative family members of chronically critically ill patients with quantitative and qualitative analysis of responses.
Measurements and Main Results
Clinical sensibility and balance were rated in the two most favorable categories on a 5-point scale by more than two thirds of clinicians and content experts. After review, family members described the brochure as clear and readable and recommended that the brochure be delivered to family members by clinicians, followed by a discussion of its contents. They indicated that the glossary was useful and recommended supplementation by additional lists of local resources. After reading the brochure, their prognostic estimates became more consistent with actual outcomes.
We have developed and validated a printed information brochure that may improve family comprehension of chronic critical illness and its outcomes. The structured process that is described can serve as a template for the development of other information aids for use with seriously ill populations.
PMCID: PMC3339568  PMID: 21926610
critically ill; mechanical ventilation; communication; information sharing; tracheostomies; validation studies
20.  φX216, a P2-like bacteriophage with broad Burkholderia pseudomallei and B. mallei strain infectivity 
BMC Microbiology  2012;12:289.
Burkholderia pseudomallei and B. mallei are closely related Category B Select Agents of bioterrorism and the causative agents of the diseases melioidosis and glanders, respectively. Rapid phage-based diagnostic tools would greatly benefit early recognition and treatment of these diseases. There is extensive strain-to-strain variation in B. pseudomallei genome content due in part to the presence or absence of integrated prophages. Several phages have previously been isolated from B. pseudomallei lysogens, for example φK96243, φ1026b and φ52237.
We have isolated a P2-like bacteriophage, φX216, which infects 78% of all B. pseudomallei strains tested. φX216 also infects B. mallei, but not other Burkholderia species, including the closely related B. thailandensis and B. oklahomensis. The nature of the φX216 host receptor remains unclear but evidence indicates that in B. mallei φX216 uses lipopolysaccharide O-antigen but a different receptor in B. pseudomallei. The 37,637 bp genome of φX216 encodes 47 predicted open reading frames and shares 99.8% pairwise identity and an identical strain host range with bacteriophage φ52237. Closely related P2-like prophages appear to be widely distributed among B. pseudomallei strains but both φX216 and φ52237 readily infect prophage carrying strains.
The broad strain infectivity and high specificity for B. pseudomallei and B. mallei indicate that φX216 will provide a good platform for the development of phage-based diagnostics for these bacteria.
PMCID: PMC3548686  PMID: 23217012
Bacteriophage; Burkholderia pseudomallei; B. mallei; P2; Prophage distribution; Phage-based diagnostics
21.  The relationship between methamphetamine and popper use and risk of HIV seroconversion in the multicenter AIDS cohort study 
The association between methamphetamine use and HIV seroconversion for men who have sex with men (MSM) was examined using longitudinal data from the Multicenter AIDS Cohort Study.
Seronegative (n=4003) men enrolled in 1984–85, 1987–1991 and 2001–2003 were identified. Recent methamphetamine and popper use were determined at either the current or the previous visit. Time to HIV-seroconversion was the outcome of interest. Covariates included race/ethnicity, cohort, study site, educational level, number of sexual partners, number of unprotected insertive anal sexual partners (UIAS), number of unprotected receptive anal sexual partners (URAS), insertive rimming, cocaine use at either the current or last visit, ecstasy use at either the current or last visit, any needle use since last visit, CES-D depression score > 16 since last visit, and alcohol consumption.
After adjusting for covariates, there was an approximately 1.46-fold independent increased relative hazard (HR) of HIV seroconversion for methamphetamine use. The HR associated with popper use was 2.1 [95% CI 1.63, 2.70]. The HR of HIV seroconversion increased with URAS ranging from 1.87 [95% CI 1.40, 2.51] for 1 partner to 9.32 [95% CI 6.20, 13.98] for 5+ partners. The joint HR for methamphetamine and popper use was 3.05 [95% CI 2.12, 4.37]. Most notably, there was a significant joint HR for methamphetamine use and URAS of 2.71 [95% CI 1.81, 4.04] for men with 1 unprotected receptive anal sex partner, which increased in a dose-dependent manner for >1 partners.
Further examination of the synergism of patterns of drug use and sexual risk behaviors on rates of HIV seroconversion will be necessary in order to develop new HIV prevention strategies for drug-using MSM.
PMCID: PMC3486782  PMID: 17325605
Multicenter AIDS cohort study; methamphetamine; HIV seroconversion; MSM
22.  A multicenter mortality prediction model for patients receiving prolonged mechanical ventilation 
Critical Care Medicine  2012;40(4):1171-1176.
Significant deficiencies exist in the communication of prognosis for patients requiring prolonged mechanical ventilation after acute illness, in part because of clinician uncertainty about long-term outcomes. We sought to refine a mortality prediction model for patients requiring prolonged ventilation using a multicentered study design.
Cohort study.
Five geographically diverse tertiary care medical centers in the United States (California, Colorado, North Carolina, Pennsylvania, Washington).
Two hundred sixty adult patients who received at least 21 days of mechanical ventilation after acute illness.
Measurements and Main Results
For the probability model, we included age, platelet count, and requirement for vasopressors and/or hemodialysis, each measured on day 21 of mechanical ventilation, in a logistic regression model with 1-yr mortality as the outcome variable. We subsequently modified a simplified prognostic scoring rule (ProVent score) by categorizing the risk variables (age 18–49, 50–64, and >65 yrs; platelet count 0–150 and >150; vasopressors; hemodialysis) in another logistic regression model and assigning points to variables according to β coefficient values. Overall mortality at 1 yr was 48%. The area under the curve of the receiver operator characteristic curve for the primary ProVent probability model was 0.79 (95% confidence interval, 0.75–0.81), and the p value for the Hosmer-Lemeshow goodness-of-fit statistic was .89. The area under the curve for the categorical model was 0.77, and the p value for the goodness-of-fit statistic was .34. The area under the curve for the ProVent score was 0.76, and the p value for the Hosmer-Lemeshow goodness-of-fit statistic was .60. For the 50 patients with a ProVent score >2, only one patient was able to be discharged directly home, and 1-yr mortality was 86%.
The ProVent probability model is a simple and reproducible model that can accurately identify patients requiring prolonged mechanical ventilation who are at high risk of 1-yr mortality.
PMCID: PMC3395423  PMID: 22080643
communication; critical care; mechanical ventilation; multiple organ failure; outcomes; prognosis
23.  Methods for Characterizing Differences in Longitudinal Glomerular Filtration Rate Changes Between Children With Glomerular Chronic Kidney Disease and Those With Nonglomerular Chronic Kidney Disease 
American Journal of Epidemiology  2011;174(5):604-612.
The rate of decline of glomerular filtration rate (GFR) in children with chronic kidney disease (CKD) can vary, even among those with similar diagnoses. Classic regression methods applied to the log-transformed GFR (i.e., lognormal) quantify only rigid shifts in a given outcome. The generalized gamma distribution offers an alternative approach for characterizing the heterogeneity of effect of an exposure on a positive, continuous outcome. Using directly measured GFR longitudinally assessed between 2005 and 2010 in 529 children enrolled in the Chronic Kidney Disease in Children Study, the authors characterized the effect of glomerular CKD versus nonglomerular CKD diagnoses on the outcome, measured as the annualized GFR ratio. Relative percentiles were used to characterize the heterogeneity of effect of CKD diagnosis across the distribution of the outcome. The rigid shift assumed by the classic mixed models failed to capture the fact that the greatest difference between the glomerular and nonglomerular diagnosis’ annualized GFR ratios was in children who exhibited the fastest GFR declines. Although this difference was enhanced in children with an initial GFR level of 45 mL/minute/1.73 m2 or less, the effect of diagnosis on outcome was not significantly modified by level. Generalized gamma models captured heterogeneity of effect more richly and provided a better fit to the data than did conventional lognormal models.
PMCID: PMC3202151  PMID: 21828368
epidemiologic methods; glomerular filtration rate; pediatrics; prospective studies; regression analysis; renal insufficiency, chronic; statistical distributions
24.  Characterization of Peri-Infarct Zone Heterogeneity by Contrast Enhanced Multi-detector Computed Tomography: Comparison with Magnetic Resonance Imaging 
We examined whether MDCT improves the ability to define peri-infarct zone (PIZ) heterogeneity relative to MRI.
The PIZ as characterized by delayed enhanced (de) MRI identifies patients susceptible to ventricular arrhythmias and predicts outcome after myocardial infarction (MI).
Fifteen mini-pigs underwent coronary artery occlusion followed by reperfusion. MDCT and MRI were performed on the same day approximately 6 months after MI induction followed by animal sacrifice and ex-vivo MRI (n=5). Signal density threshold algorithms were applied to MRI and MDCT data sets reconstructed at various slice thicknesses (1–8mm) to define the PIZ and quantify partial volume effects.
De-MDCT reconstructed at 8mm slice thickness demonstrated excellent correlation of infarct size with post mortem pathology (r2=0.97; p<0.0001) and MRI (r2=0.92; p<0.0001). De-MDCT and de-MRI were able to detect a PIZ in all animals, which correlates to a mixture of viable and non-viable myocytes at the PIZ by histology. The ex-vivo de-MRI PIZ volume decreased with slice thickness from 0.9±0.2cc at 8mm to 0.2±0.1cc at 1mm (p=0.01). PIZ volume/mass by de-MDCT increased with decreasing slice thickness due to declining partial volume averaging in the PIZ, but was susceptible to increased image noise.
De-MDCT provides a more detailed assessment of the PIZ in chronic MI and is less susceptible to partial volume effects than MRI. This increased resolution best reflects the extent of tissue mixture by histopathology and has the potential to further enhance the ability to define the substrate of malignant arrhythmia in ischemic heart disease non-invasively.
PMCID: PMC3381611  PMID: 19406346
MDCT; delayed enhancement; peri-infarct zone; MRI
25.  Prevalence of Abnormalities in Vestibular Function and Balance among HIV-Seropositive and HIV-Seronegative Women and Men 
PLoS ONE  2012;7(5):e38419.
Most HIV-seropositive subjects in western countries receive highly active antiretroviral therapy (HAART). Although many aspects of their health have been studied, little is known about their vestibular and balance function. The goals of this study were to determine the prevalences of vestibular and balance impairments among HIV-seropositive and comparable seronegative men and women and to determine if those groups differed.
Standard screening tests of vestibular and balance function, including head thrusts, Dix-Hallpike maneuvers, and Romberg balance tests on compliant foam were performed during semiannual study visits of participants who were enrolled in the Baltimore and Washington, D. C. sites of the Multicenter AIDS Cohort Study and the Women's Interagency HIV Study.
No significant differences by HIV status were found on most tests, but HIV-seropositive subjects who were using HAART had a lower frequency of abnormal Dix-Hallpike nystagmus than HIV-seronegative subjects. A significant number of nonclassical Dix-Hallpike responses were found. Age was associated with Romberg scores on foam with eyes closed. Sex was not associated with any of the test scores.
These findings suggest that HAART-treated HIV infection has no harmful association with vestibular function in community-dwelling, ambulatory men and women. The association with age was expected, but the lack of association with sex was unexpected. The presence of nonclassical Dix-Hallpike responses might be consistent with central nervous system lesions.
PMCID: PMC3364989  PMID: 22675462

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