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1.  Detection of enthesitis in children with Enthesitis-related arthritis: dolorimeter examination compared to ultrasonography 
To evaluate the distribution of enthesitis and accuracy of physical examination with a dolorimeter for the detection of enthesitis in children, using ultrasound (US) assessment as the reference standard.
We performed a prospective cross-sectional study of 30 enthesitis-related arthritis (ERA) and 30 controls subjects. The following tendon insertion sites were assessed by standardized physical examination with a dolorimeter and US: common extensor on the lateral humerus epicondyle, common flexor on the medial humerus epicondyle, quadriceps at the superior patella, patellar ligament at the inferior patella, Achilles, and plantar fascia at the calcaneus.
Abnormal US findings were detected most commonly at the insertions of the quadriceps (30% [18 of 60 sites]), common extensor (12% [7 of 60]), and Achilles (10% [6 of 60]) tendons. The intrarater reliability of US (kappa) was 0.78 (95% confidence interval [95% CI] 0.63–0.93) and the interrater reliability was 0.81 (95% CI 0.67–0.95). Tenderness as detected by standardized dolorimeter exam had poor positive predictive value for US-confirmed enthesitis. In comparison to controls, ERA patients reported more pain and had lower pain thresholds at every site, including control sites (P <0.01 for all comparisons). The interrater reliability of dolorimeter exam for detection of enthesitis was low (κ = 0.49 [95% CI 0.33–0.65]).
Compared to US, standardized dolorimeter examination for the detection of enthesitis in children has poor accuracy and reliability. The decreased pain threshold of ERA patients likely contributed to the limited accuracy of physical examination. Future research regarding the utility of US for identifying enthesitis at JIA diagnosis, accurately predicting disease progression, and guiding therapeutic decisions is warranted.
PMCID: PMC3964147  PMID: 24449586
2.  Prevalence of Diagnosed Chronic Hepatitis B Infection Among U.S. Medicaid Enrollees, 2000 – 2007 
Annals of epidemiology  2014;24(6):418-423.
Few population-based studies have estimated the number of persons diagnosed with chronic hepatitis B (CHB) infection in the United States. Our objective was to estimate the prevalence of diagnosed CHB infection among persons enrolled in the U.S. Medicaid programs of California, Florida, New York, Ohio, and Pennsylvania between 2000 and 2007. As part of our analyses, we confirmed the accuracy of CHB diagnoses within the Medicaid database.
CHB infection was defined by the presence of two outpatient CHB diagnoses recorded more than 6 months apart. Two clinicians reviewed the medical records of a random sample of patients who met this definition to confirm the diagnosis, which enabled calculation of the positive predictive value (PPV). The period prevalence of diagnosed CHB infection among Medicaid enrollees with at least 6 months of membership from 2000–2007 was then estimated, adjusting for both the PPV and estimated sensitivity of our definition of CHB infection.
The definition of CHB infection accurately identified clinician-confirmed cases (PPV, 96.3%; 95% confidence interval [CI], 87.3–99.5). Using this definition, 31,046 cases of CHB were diagnosed among 31,358,010 eligible Medicaid members from the five states (prevalence, 9.9 [95% CI, 9.8–10.0] per 10,000). Adjusting for the PPV and estimated sensitivity of our CHB definition, the prevalence of diagnosed CHB infection was 15.6 (95% CI, 15.4–15.7) per 10,000.
Two outpatient CHB diagnoses recorded more than 6 months apart validly identified clinician-confirmed CHB. The prevalence of diagnosed CHB infection among U.S. Medicaid enrollees was 15.6 per 10,000.
PMCID: PMC4262762  PMID: 24703196
Hepatitis B; viral hepatitis; prevalence
3.  Risk of Hip Fracture Associated with Untreated and Treated Chronic Hepatitis B Virus Infection 
Journal of hepatology  2014;61(2):210-218.
Background & Aims
Chronic hepatitis B (CHB) infection is associated with reduced bone mineral density, but its association with fractures is unknown. Our objectives were to determine whether untreated or treated CHB-infected persons are at increased risk for hip fracture compared to uninfected persons.
We conducted a cohort study among 18,796 untreated CHB-infected, 7,777 treated CHB-infected, and 979,751 randomly sampled uninfected persons within the U.S. Medicaid populations of California, Florida, New York, Ohio, and Pennsylvania (1999 – 2007). CHB infection was defined by two CHB diagnoses recorded >6 months apart and was classified as treated if a diagnosis was recorded and antiviral therapy was dispensed. After propensity score matching of CHB-infected and uninfected persons, Cox regression was used to estimate hazard ratios (HRs) with 95% confidence intervals (CIs) of incident hip fracture in: 1) untreated CHB-infected versus uninfected, and 2) treated CHB-infected versus uninfected patients.
Untreated CHB-infected patients of black race had a higher rate of hip fracture than uninfected black persons (HR, 2.55 [95% CI, 1.42 – 4.58]). Compared to uninfected persons, relative hazards of hip fracture were increased for untreated white (HR, 1.26 [95% CI, 0.98 – 1.62]) and Hispanic (HR, 1.36 [95% CI, 0.77 – 2.40]) CHB-infected patients, and treated black (HR, 3.09 [95% CI, 0.59 – 16.22) and white (HR, 1.90 [95% CI, 0.81 – 4.47]) CHB-infected patients, but these associations were not statistically significant.
Among U.S. Medicaid enrollees, untreated CHB-infected patients of black race had a higher risk of hip fracture than uninfected black persons.
PMCID: PMC4262153  PMID: 24713185
Hepatitis B; fracture; bone
4.  Hepatic Decompensation in Antiretroviral-Treated HIV/Hepatitis C-Coinfected Compared to Hepatitis C-Monoinfected Patients: A Cohort Study 
Annals of internal medicine  2014;160(6):369-379.
The incidence and determinants of hepatic decompensation have been incompletely examined among HIV/hepatitis C virus (HCV)-coinfected patients in the antiretroviral therapy (ART) era, and few studies have compared rates of outcomes to those of patients with chronic HCV alone.
To compare the incidence of hepatic decompensation between antiretroviral-treated HIV/HCV-coinfected and HCV-monoinfected patients, and evaluate factors associated with decompensation among coinfected patients on ART.
Retrospective cohort study.
Veterans Health Administration.
4,280 HIV/HCV-coinfected patients who initiated ART and 6,079 HCV-monoinfected patients receiving care between 1997 and 2010. All patients had detectable HCV RNA and were HCV treatment-naïve.
Incident hepatic decompensation, determined by diagnoses of ascites, spontaneous bacterial peritonitis, or esophageal variceal hemorrhage.
The incidence of hepatic decompensation was greater among coinfected than monoinfected patients (at 10 years: 7.4% versus 4.8%; p<0.001). Compared to HCV-monoinfected patients, antiretroviral-treated HIV/HCV-coinfected patients had a higher rate of hepatic decompensation (hazard ratio [HR] accounting for competing risks, 1.56 [95% confidence interval (CI), 1.31–1.86]). Coinfected patients who maintained HIV RNA levels <1,000 copies/mL still had higher rates of decompensation than HCV-monoinfected patients (HR, 1.44 [95% CI, 1.05–1.99]). Baseline advanced hepatic fibrosis (FIB-4 >3.25; HR, 5.45 [95% CI, 3.79–7.84]), baseline hemoglobin <10 g/dL (HR, 2.24 [CI, 1.20–4.20]), diabetes mellitus (HR, 1.88[95% CI, 1.38–2.56]), and non-black race (HR, 2.12 [95% CI, 1.65–2.72]) were each associated with higher rates of decompensation among coinfected patients on ART.
Observational study of predominantly male patients.
Despite ART, HIV/HCV-coinfected patients had higher rates of hepatic decompensation than HCV-monoinfected individuals. Rates of decompensation were higher for coinfected patients with advanced liver fibrosis, severe anemia, diabetes, and non-black race.
PMCID: PMC4254786  PMID: 24723077
hepatic decompensation; end-stage liver disease; HIV/HCV coinfection; HIV; hepatitis C
5.  The Relationship between Mental Health Diagnosis and Treatment with Second-Generation Antipsychotics over Time: A National Study of U.S. Medicaid-Enrolled Children 
Health Services Research  2012;47(5):1836-1860.
To describe the relationship between mental health diagnosis and treatment with antipsychotics among U.S. Medicaid-enrolled children over time.
Data Sources/Study Setting
Medicaid Analytic Extract (MAX) files for 50 states and the District of Columbia from 2002 to 2007.
Study Design
Repeated cross-sectional design. Using logistic regression, outcomes of mental health diagnosis and filled prescriptions for antipsychotics were standardized across demographic and service use characteristics and reported as probabilities across age groups over time.
Data Collection
Center for Medicaid Services data extracted by means of age, ICD-9 codes, service use intensity, and National Drug Classification codes.
Principal Findings
Antipsychotic use increased by 62 percent, reaching 354,000 youth by 2007 (2.4 percent). Although youth with bipolar disorder, schizophrenia, and autism proportionally were more likely to receive antipsychotics, youth with attention deficit hyperactivity disorder (ADHD) and those with three or more mental health diagnoses were the largest consumers of antipsychotics over time; by 2007, youth with ADHD accounted for 50 percent of total antipsychotic use; 1 in 7 antipsychotic users were youth with ADHD as their only diagnosis.
In the context of safety concerns, disproportionate antipsychotic use among youth with nonapproved indications illustrates the need for more generalized efficacy data in pediatric populations.
PMCID: PMC3513608  PMID: 22946905
Antipsychotics; mental health; pediatrics; Medicaid
6.  National Trends in Pelvic Inflammatory Disease among Adolescents in the Emergency Department 
In 2002 the CDC broadened the pelvic inflammatory disease (PID) diagnostic criteria to increase detection and prevent serious sequelae of untreated PID. The impact of this change on PID detection is unknown. Our objective was to estimate trends in PID diagnosis among adolescent emergency department (ED) patients before and after the revised CDC definition and identify factors associated with PID diagnoses.
We performed a retrospective repeated cross-sectional study using the National Hospital Ambulatory Medical Care Survey from 2000–2009 of ED visits by 14 to 21 year old females. National estimates of PID rates were calculated. Multivariable logistic regression analyses and tests of trends were performed.
During 2000–2009, of the 77 million female adolescent ED visits, there were an estimated 704,882 (95% CI 571,807, 837,957) cases of PID. Following the revised criteria, PID diagnosis declined from 5.4 cases per 1000 U.S. adolescent females to 3.9 cases per 1000 (p=0.03). In a multivariable model, age ≥17 years (OR 2.14, 95% CI 1.25, 3.64) and Black race (OR 2.04, 95% CI 1.36, 3.07) were associated with PID diagnosis
Despite broadened CDC diagnostic criteria, PID diagnoses did not increase over time. This raises concern about awareness and incorporation of the new guidelines into clinical practice.
PMCID: PMC3725218  PMID: 23743002
Pelvic inflammatory disease; Adolescents; Trends
7.  Prevalence of abuse among young children with femur fractures: a systematic review 
BMC Pediatrics  2014;14:169.
Clinical factors that affect the likelihood of abuse in children with femur fractures have not been well elucidated. Consequently, specifying which children with femur fractures warrant an abuse evaluation is difficult. Therefore the purpose of this study is to estimate the proportion of femur fractures in young children attributable to abuse and to identify demographic, injury and presentation characteristics that affect the probability that femur fractures are secondary to abuse.
We conducted a systematic review of published articles written in English between January 1990 and July 2013 on femur fracture etiology in children less than or equal to 5 years old based on searches in PubMed/MEDLINE and CINAHL databases. Data extraction was based on pre-defined data elements and included study quality indicators. A meta-analysis was not performed due to study population heterogeneity.
Across the 24 studies reviewed, there were a total of 10,717 children less than or equal to 60 months old with femur fractures. Among children less than 12 months old with all types of femur fractures, investigators found abuse rates ranging from 16.7% to 35.2%. Among children 12 months old or greater with femur fractures, abuse rates were lower: from 1.5% - 6.0%. In multiple studies, age less than 12 months, non-ambulatory status, a suspicious history, and the presence of additional injuries were associated with findings of abuse. Diaphyseal fractures were associated with a lower abuse incidence in multiple studies. Fracture side and spiral fracture type, however, were not associated with abuse.
Studies commonly find a high proportion of abuse among children less than 12 months old with femur fractures. The reported trauma history, physical examination findings and radiologic results must be examined for characteristics that increase or decrease the likelihood of abuse determination.
PMCID: PMC4085378  PMID: 24989500
Child abuse; Child maltreatment; Femur fracture; Accident; Trauma
8.  Clostridium difficile Infection Is Associated With Increased Risk of Death and Prolonged Hospitalization in Children 
Clostridium difficile infection (CDI) is associated with increased mortality, prolonged hospitalization, and higher costs among a multicenter cohort of hospitalized children matched by important demographic and clinical characteristics. The impact of CDI is most significant among children with hospital-onset disease.
Background Clostridium difficile infection (CDI) is associated with significant morbidity and mortality among adults. However, outcomes are poorly defined among children.
Methods A retrospective cohort study was performed among hospitalized children at 41 children's hospitals between January 2006 and August 2011. Patients with CDI (exposed) were matched 1:2 to patients without CDI (unexposed) based on the probability of developing CDI (propensity score derived from patient characteristics). Exposed subjects were stratified by C. difficile test date, suggestive of community-onset (CO) versus hospital-onset (HO) CDI. Outcomes were analyzed for matched subjects.
Results We identified 5107 exposed and 693 409 unexposed subjects. Median age was 6 years (interquartile range [IQR], 2–13 years) for exposed and 8 years (IQR, 3–14 years) for unexposed subjects. Of these, 4474 exposed were successfully matched to 8821 unexposed by propensity score. In-hospital mortality differed significantly (CDI, 1.43% vs matched unexposed, 0.66%; P < .001). Mortality rates were similar between CO-CDI and matched subjects. However, mortality rates were significantly greater among HO-CDI compared with matched unexposed (odds ratio, 6.73 [95% confidence interval {CI}, 3.77–12.02]). Mean differences in length of stay (LOS) and total cost were significant: 5.55 days (95% CI, 4.54–6.56 days) and $18 900 (95% CI, $15 100–$22 700) for CO-CDI, and 21.60 days (95% CI, 19.29–23.90 days) and $93 600 (95% CI, $80 000–$107 200) for HO-CDI.
Conclusions Pediatric CDI is associated with increased mortality, longer LOS, and higher costs. These findings underscore the importance of antibiotic stewardship and infection control programs to prevent this disease in children.
PMCID: PMC3669523  PMID: 23532470
C. difficile infection; pediatrics; outcomes; epidemiology
9.  Effectiveness of Decision Support for Families, Clinicians, or Both on HPV Vaccine Receipt 
Pediatrics  2013;131(6):1114-1124.
To improve human papillomavirus (HPV) vaccination rates, we studied the effectiveness of targeting automated decision support to families, clinicians, or both.
Twenty-two primary care practices were cluster-randomized to receive a 3-part clinician-focused intervention (education, electronic health record-based alerts, and audit and feedback) or none. Overall, 22 486 girls aged 11 to 17 years due for HPV vaccine dose 1, 2, or 3 were randomly assigned within each practice to receive family-focused decision support with educational telephone calls. Randomization established 4 groups: family-focused, clinician-focused, combined, and no intervention. We measured decision support effectiveness by final vaccination rates and time to vaccine receipt, standardized for covariates and limited to those having received the previous dose for HPV #2 and 3. The 1-year study began in May 2010.
Final vaccination rates for HPV #1, 2, and 3 were 16%, 65%, and 63% among controls. The combined intervention increased vaccination rates by 9, 8, and 13 percentage points, respectively. The control group achieved 15% vaccination for HPV #1 and 50% vaccination for HPV #2 and 3 after 318, 178, and 215 days. The combined intervention significantly accelerated vaccination by 151, 68, and 93 days. The clinician-focused intervention was more effective than the family-focused intervention for HPV #1, but less effective for HPV #2 and 3.
A clinician-focused intervention was most effective for initiating the HPV vaccination series, whereas a family-focused intervention promoted completion. Decision support directed at both clinicians and families most effectively promotes HPV vaccine series receipt.
PMCID: PMC3666111  PMID: 23650297
decision support systems; electronic records; immunizations
10.  Clinical Risk Factors for Primary Graft Dysfunction after Lung Transplantation 
Rationale: Primary graft dysfunction (PGD) is the main cause of early morbidity and mortality after lung transplantation. Previous studies have yielded conflicting results for PGD risk factors.
Objectives: We sought to identify donor, recipient, and perioperative risk factors for PGD.
Methods: We performed a 10-center prospective cohort study enrolled between March 2002 and December 2010 (the Lung Transplant Outcomes Group). The primary outcome was International Society for Heart and Lung Transplantation grade 3 PGD at 48 or 72 hours post-transplant. The association of potential risk factors with PGD was analyzed using multivariable conditional logistic regression.
Measurements and Main Results: A total of 1,255 patients from 10 centers were enrolled; 211 subjects (16.8%) developed grade 3 PGD. In multivariable models, independent risk factors for PGD were any history of donor smoking (odds ratio [OR], 1.8; 95% confidence interval [CI], 1.2–2.6; P = 0.002); FiO2 during allograft reperfusion (OR, 1.1 per 10% increase in FiO2; 95% CI, 1.0–1.2; P = 0.01); single lung transplant (OR, 2; 95% CI, 1.2–3.3; P = 0.008); use of cardiopulmonary bypass (OR, 3.4; 95% CI, 2.2–5.3; P < 0.001); overweight (OR, 1.8; 95% CI, 1.2–2.7; P = 0.01) and obese (OR, 2.3; 95% CI, 1.3–3.9; P = 0.004) recipient body mass index; preoperative sarcoidosis (OR, 2.5; 95% CI, 1.1–5.6; P = 0.03) or pulmonary arterial hypertension (OR, 3.5; 95% CI, 1.6–7.7; P = 0.002); and mean pulmonary artery pressure (OR, 1.3 per 10 mm Hg increase; 95% CI, 1.1–1.5; P < 0.001). PGD was significantly associated with 90-day (relative risk, 4.8; absolute risk increase, 18%; P < 0.001) and 1-year (relative risk, 3; absolute risk increase, 23%; P < 0.001) mortality.
Conclusions: We identified grade 3 PGD risk factors, several of which are potentially modifiable and should be prioritized for future research aimed at preventative strategies.
Clinical trial registered with (NCT 00552357).
PMCID: PMC3733407  PMID: 23306540
lung transplantation; clinical risk factors; primary graft dysfunction
11.  Women of Child-Bearing Age Have Better In-Hospital Cardiac Arrest Survival Outcomes than Equal Aged Men 
Critical care medicine  2010;38(5):1254-1260.
Estrogen and progesterone improve neurologic outcomes in experimental models of cardiac arrest and stroke. Our objective was to determine whether women of child-bearing age are more likely than men to survive to hospital discharge following in-hospital cardiac arrest.
Prospective, observational study
519 hospitals in the National Registry of CPR database
95,852 men and women 15-44 years and ≥56 years with pulseless cardiac arrests from 01/01/00 through 07/31/08
Measurements and Main Results
Patients were stratified a priori by sex and age groups (15-44 years and ≥56 years). Fixed effects regression conditioning on hospital was used to examine the relationship between age, sex and survival outcomes. The unadjusted survival to discharge rate for younger women of child bearing age (15-44 years of age) was 19% (940/4887) versus 17% (1203/7025) for younger men (p=.013). The adjusted hospital discharge difference between these younger women and men was 2.8% (95% CI, 1.0%-4.6%; p=.002) and these younger women also had a 2.6% (95% CI, 0.9% - 4.3%; p=.002) absolute increase in favorable neurologic outcome. For older women compared with men (≥56 years), there were no demonstrable differences in discharge rates (18% versus 18%, adjusted difference -0.1%; 95% CI, -0.9% - +0.6%; p=.68) or favorable neurologic outcome (14% versus 14%, adjusted difference -0.1%; 95% CI, -0.7% - +0.5%; p=.74).
Women of child-bearing age were more likely than comparably aged men to survive to hospital discharge following in-hospital cardiac arrest, even after controlling for etiology of arrest and other important variables.
PMCID: PMC3934212  PMID: 20228684
heart arrest; cardiopulmonary resuscitation; sex; women; outcome
12.  Risk Factors for Renal Failure in Pediatric Patients With Acute Myeloid Leukemia: A Retrospective Cohort Study 
Pediatric blood & cancer  2010;55(4):655-661.
In children receiving treatment for acute myeloid leukemia (AML) there is often concern for the development of acute renal failure (ARF). Despite this, data are limited to define the incidence of ARF in this population. This study aims to evaluate the rate of ARF in AML patients and to delineate the impact of age, race, various co-morbid conditions and antimicrobial agents on the development of ARF.
A cohort of newly diagnosed AML patients from children's hospitals across the United States was identified using the Pediatric Health Information Systems database. Information regarding demographics, discharge diagnoses, pharmaceutical exposures, and hospital resource utilization were collected for each hospitalization for up to 1 year from AML diagnosis. Cox regression analysis was used to define the hazard ratios for development of ARF by demographic variables, co-morbid conditions, and exposure to various antimicrobial agents.
Within 1 year of AML diagnosis, 135 (16.2%) patients were diagnosed with ARF. After adjustment for the presence of co-morbid conditions, the risk for ARF was greater in older patients and in black patients. Vancomycin exposure duration of greater than 48 hr and carbapenem exposure duration greater than 10 days were associated with an increased risk for ARF.
ARF is a relatively common problem in children with AML. Future studies should address the different risks of ARF by age and race. Empiric therapy with potentially nephrotoxic agents did not increase the risk of nephrotoxicity. Patients on prolonged vancomycin therapy should be monitored closely for development of ARF.
PMCID: PMC3909928  PMID: 20533519
antimicrobials; epidemiology; leukemia; pediatrics; renal failure
13.  Effectiveness of Interventions in Reducing Antibiotic Use for Upper Respiratory Infections in Ambulatory Care Practices 
Population Health Management  2013;16(1):22-27.
The objective was to evaluate the effect of separate interventions on antimicrobial prescribing for uncomplicated upper respiratory tract infections. The authors conducted a quasi-experimental pre-post study with concurrent control groups for each intervention. Academic detailing led to a significant reduction in unnecessary antibiotic prescribing. However, there was no significant change in antibiotic prescribing in response to educational mailings to providers or to provider involvement in patient mailings. Organizations that seek to reduce inappropriate use of antibiotics should use proven approaches, even when they are more expensive. (Population Health Management 2013;16:22–27)
PMCID: PMC3595097  PMID: 23113630
14.  Adherence to Hepatitis C Virus Therapy in HIV/Hepatitis C-Coinfected Patients 
AIDS and behavior  2013;17(1):94-103.
Adherence to hepatitis C virus (HCV) therapy has been incompletely examined among HIV-infected patients. We assessed changes in interferon and ribavirin adherence and evaluated the relationship between adherence and early (EVR) and sustained virologic response (SVR). We performed a cohort study among 333 HIV/HCV-coinfected patients who received pegylated interferon and ribavirin between 2001 and 2006 and had HCV RNA before and after treatment. Adherence was calculated over 12-week intervals using pharmacy refills. Mean interferon and ribavirin adherence declined 2.5 and 4.1 percentage points per 12-week interval, respectively. Among genotype 1/4 patients, EVR increased with higher ribavirin adherence, but this association was less strong for interferon. SVR among these patients was higher with increasing interferon and ribavirin adherence over the first, second, and third, but not fourth, 12-week intervals. Among HIV/HCV patients, EVR and SVR increased with higher interferon and ribavirin adherence. Adherence to both antivirals declined over time, but more so for ribavirin.
PMCID: PMC3514597  PMID: 22907288
Adherence; hepatitis C virus; HIV; antiviral therapy; pegylated interferon; ribavirin
15.  Risk of Hip Fracture Associated with Hepatitis C Virus Infection and Hepatitis C/HIV Coinfection 
Hepatology (Baltimore, Md.)  2012;56(5):1688-1698.
Hepatitis C virus (HCV) infection has been associated with reduced bone mineral density, but its association with fracture rates is unknown, particularly in the setting of human immunodeficiency virus (HIV) coinfection. Our objectives were to determine whether persons with HCV infection alone are at increased risk for hip fracture compared to uninfected individuals and to examine if the risk of hip fracture is higher among HCV/HIV-coinfected persons compared to those with HCV alone, those with HIV alone, and those uninfected with either virus. We conducted a cohort study in 36,950 HCV/HIV-coinfected, 276,901HCV-monoinfected, 95,827 HIV-monoinfected, and 3,110,904 HCV/HIV-uninfected persons within the U.S. Medicaid populations of California, Florida, New York, Ohio, and Pennsylvania (1999–2005). Incidence rates of hip fracture were lowest among uninfected persons (1.29 events/1000 person-years), increased with the presence of either HIV infection (1.95 events/1000 person-years) or HCV infection (2.69 events/1000 person-years), and were highest among HCV/HIV-coinfected individuals (3.06 events/1000 person-years). HCV/HIV coinfection was associated with an increased relative hazard (adjusted hazard ratio [95% confidence interval]) of hip fracture compared to HCV-monoinfected (1.38 [1.25–1.53]), HIV-monoinfected (females: 1.76 [1.44–2.16]; males: 1.36 [1.20–1.55]), and uninfected persons (females: 2.65 [2.21–3.17]; males: 2.20 [1.97–2.47]). HCV monoinfection was associated with an increased risk of hip fracture compared to uninfected individuals, and the relative increase was highest in the youngest age groups (females, 18–39 years: 3.56 [2.93–4.32]; males, 18–39 years: 2.40 [2.02–2.84]).
Among Medicaid enrollees, HCV/HIV coinfection was associated with increased rates of hip fracture compared to HCV-monoinfected, HIV-monoinfected, and HCV/HIV-uninfected persons. HCV-monoinfected patients had an increased risk of hip fracture compared to uninfected individuals.
PMCID: PMC3433632  PMID: 22619086
Hepatitis C virus; HCV; HIV; fracture; coinfection
16.  Variation in Occult Injury Screening for Children With Suspected Abuse in Selected US Children’s Hospitals 
Pediatrics  2012;130(5):853-860.
To describe variation across selected US children’s hospitals in screening for occult fractures in children <2 years old diagnosed with physical abuse and in infants <1 year old who have injuries associated with a high likelihood of physical abuse.
We performed a retrospective study of children <2 years old with a diagnosis of physical abuse and infants <1 year old with non-motor vehicle crash–associated traumatic brain injuries or femur fractures admitted to 40 hospitals within the Pediatric Hospital Information System database from January 1, 1999, to December 31, 2009. We examined variation among the hospitals in the performance of screening for occult fractures as defined by receipt of skeletal survey or radionuclide bone scan. Marginal standardization implemented with logistic regression analysis was used to examine hospital variation after adjusting for patient demographic characteristics, injury severity, and year of admission.
Screening for occult fractures was performed in 83% of the 10 170 children <2 years old with a diagnosis of physical abuse, 68% of the 9942 infants who had a traumatic brain injury, and 77% of the 2975 infants who had femur fractures. After adjustment for patient characteristics, injury severity, and year of admission, hospitals varied significantly in use of screening for occult fractures in all 3 groups of children.
The observed variation in screening for occult fractures in young victims of physical abuse and infants who have injuries associated with a high likelihood of abuse underscores opportunities to improve the quality of care provided to this vulnerable population.
PMCID: PMC4074645  PMID: 23071208
child abuse; child maltreatment; femur fracture; traumatic brain injury
Journal of critical care  2011;27(5):522.e11-522.e17.
Endocan is a proteoglycan expressed by endothelial cells in the lung which may inhibit leukocyte recruitment and thus prevent the development of acute lung injury (ALI). We tested the association of serum endocan levels with subsequent development of ALI after major trauma.
Materials and Methods
Single-center nested case control study within a prospective cohort study of major trauma patients. Using an ELISA test, we measured endocan levels from admission serum in 24 controls (no ALI) and 24 cases (ALI within 5 days of trauma). Multivariable logistic regression was used to test the association of admission serum endocan levels with subsequent ALI.
Patients who developed ALI had lower levels of endocan on admission (mean 3.5 ± 1.4 ng/mL vs. 4.9 ± 2.6 ng/mL in controls, p=0.02). For each 1-unit increase in serum endocan level, the odds ratio for ALI development decreased (0.69, 95% confidence interval (CI): 0.49, 0.97, p=0.03). Lower endocan levels remained associated with a higher incidence of ALI after adjustment for age and illness severity.
Lower levels of serum endocan on admission are associated with subsequent development of ALI in trauma patients. These observations may be explained by endocan-mediated blockade of leukocyte recruitment in the lung.
PMCID: PMC3790584  PMID: 21958978
Trauma; acute respiratory distress syndrome; acute lung injury; biomarkers; endothelium
18.  African American race, obesity, and blood product transfusion are risk factors for acute kidney injury in critically ill trauma patients 
Journal of critical care  2012;27(5):496-504.
Acute kidney injury (AKI) is a common source of morbidity after trauma. We sought to determine novel risk factors for AKI, by Acute Kidney Injury Network (AKIN) criteria, in critically ill trauma patients.
Materials and Methods
Prospective cohort study of 400 patients admitted to the ICU of a level one trauma center, followed for development of AKI over five days.
AKI developed in 147/400 (36.8%) patients. In multivariable regression analysis, independent risk factors for AKI included African American race (OR 1.86; 95% CI 1.08,3.18; p=0.024), body mass index ≥30 (OR 4.72 versus normal BMI, 95% CI 2.59, 8.61, p<0.001), diabetes mellitus (OR 3.26; 95% CI 1.30,8.20; p=0.012), abdominal Abbreviated Injury Scale score ≥4 (OR 3.78; 95% CI 1.79,7.96; p<0.001), and unmatched packed red blood cells administered during resuscitation (OR 1.13 per unit; 95% CI 1.04,1.23; p=0.004). AKIN stages 1, 2, and 3 were associated with hospital mortality rates of 9.8%, 13.7%, and 30.4%, respectively, compared with 3.8% for those without AKI (p<0.001).
AKI in critically ill trauma patients is associated with substantial mortality. The findings of African American race, obesity, and blood product administration as independent risk factors for AKI deserve further study to elucidate underlying mechanisms.
PMCID: PMC3472045  PMID: 22591570
acute kidney injury; trauma; critical illness; race; obesity; transfusion; epidemiology; risk factors
19.  The Association of Early Transfusion with Acute Lung Injury in Severely Injured Patients 
Packed Red Blood Cell (PRBC) transfusion is associated with Acute Lung Injury (ALI) development after trauma, but this risk may not be constant through time after trauma. We hypothesized the relationship between PRBC delivery and ALI risk varies through time after injury.
Data were collected prospectively from 1999–2006. Inclusion criteria: age > 13 years, SICU admission, and injury severity score (ISS) ≥ 16. Exclusion criteria included discharge/death within 24 hours of admission. Patients were followed prospectively for ALI development for 5 days after trauma. Discrete time models were fit to test the association of timing of PRBC delivery with development of ALI while controlling for patient demographics, resuscitation variables, ISS, and APACHE III scores.
At total of 602 patients were included. Median age was 33 years, 77% were male, and 50% were African American. Using a discrete time-survival model, the relation between transfusion and ALI development was found to vary by transfusion time-window (p<0.0001). The major effect of PRBC delivery on ALI risk occurred in the first 24 hours after trauma; this finding persisted in multivariable modeling (adjusted OR = 1.07 per unit; 95%CI 1.02–1.11, p<0.001). Cumulative incidence of ALI approached 50% in patients receiving ≥ 6u PRBC in the first 24 hours.
The association between PRBC transfusion and ALI development in trauma patients is time-dependent, with PRBC delivery in the first 24 hours after injury driving the overall relation. Each PRBC unit during this time period increases odds of subsequent ALI development by 7%.
PMCID: PMC3541013  PMID: 23034528
Pediatrics  2009;123(2):636-642.
Early transition from intravenous to oral antimicrobial therapy for acute osteomyelitis in children has been suggested as a safe and effective alternative to traditional prolonged intravenous therapy via central venous catheter, but no studies have directly compared these two treatment modalities. We sought to compare the effectiveness of early transition from intravenous to oral antimicrobial therapy vs. prolonged intravenous antimicrobial therapy for the treatment of children with acute osteomyelitis.
We conducted a retrospective cohort study of children ages 2 months to 17 years diagnosed with acute osteomyelitis between 2000 and 2005 at 29 free-standing children’s hospitals in the United States to confirm the extent of variation in use of early transition to oral therapy. We used a propensity scores to adjust for potential differences between children treated with prolonged intravenous therapy, and logistic regression to model the association of outcome (treatment failure rates within 6 months of diagnosis and difference in the mode of therapy within hospitals and across hospitals.
Of the 1969 children who met inclusion criteria, 1021 received prolonged intravenous therapy and 948 received oral therapy. Use of prolonged intravenous therapy varied significantly across hospitals (10% to 95%, P<0.001). The treatment failure rate was 5% (54 of 1021) in the prolonged intravenous therapy group and 4% (38 of 948) in the oral therapy group. There was no significant association between treatment failure and the mode of antimicrobial therapy (adjusted odds ratio=0.77, 95% confidence interval=0.49 to 1.22). Thirty-five children (3.4%) in the prolonged intravenous therapy group were readmitted for a catheter-associated complication.
Treatment of acute osteomyelitis with early transition to oral therapy is not associated with a higher risk of treatment failures and avoids the risks of prolonged intravenous therapy through central venous catheters.
PMCID: PMC3774269  PMID: 19171632
Osteomyelitis; therapy; children
21.  A panel of lung injury biomarkers enhances the definition of primary graft dysfunction (PGD) after lung transplantation 
We aimed to identify combinations of biomarkers to enhance the definition of PGD for translational research.
Biomarkers reflecting lung epithelial injury (sRAGE and SP-D), coagulation cascade (PAI-1 and Protein C), and cell adhesion (ICAM-1) were measured in the plasma of 315 subjects derived from the LTOG cohort at 6 and 24 hours after transplantation. We assessed biomarker utility in two ways: first, we tested the discrimination of grade 3 PGD within 72 hours; second, we tested the predictive utility of plasma biomarkers for 90-day mortality.
86/315 subjects (27%) developed PGD. 23 subjects (8%) died within 90 days of transplantation, of which 16 (70%) had PGD. Biomarkers measured at 24 hours had greater discrimination than at 6 hours. Individually, sRAGE (AUC 0.71) and PAI-1 (AUC 0.73) had the best discrimination of PGD. The combinations of sRAGE with PAI-1 (AUC 0.75), PAI-1 with ICAM-1 (AUC 0.75), and PAI-1 with SP-D (AUC 0.76) had the best discrimination. Combinations of greater than 2 biomarkers did not significantly enhance discrimination of PGD. ICAM-1 with PAI-1 (AUC 0.72) and ICAM-1 with sRAGE (AUC of 0.72) had the best prediction for 90-day mortality. The addition of ICAM-1, PAI-1, or sRAGE to the concurrent clinical PGD grade significantly improved prediction of 90-day mortality (p<0.001 each).
Measurement of the combination of a marker of impaired fibrinolysis with an epithelial injury or cell adhesion marker had the best discrimination for PGD and prediction for early mortality, and may provide an alternative outcome useful in future research.
PMCID: PMC3418416  PMID: 22694851
Primary Graft Dysfunction; Lung transplantation; Biomarkers; Acute Lung Injury
22.  Transparency in Evidence Evaluation And Formulary Decision-Making 
Pharmacy and Therapeutics  2013;38(8):465-483.
The authors sought to clarify the relationship between evidence-based medicine and access to drug coverage. They concluded that a structured approach to improving clarity, consistency, and transparency was lacking.
Establishing a better understanding of the relationship between evidence evaluation and formulary decision-making has important implications for patients, payers, and providers. The goal of our study was to develop and test a structured approach to evidence evaluation to increase clarity, consistency, and transparency in formulary decision-making.
Study Design:
The study comprised three phases. First, an expert panel identified key constructs to formulary decision-making and created an evidence-assessment tool. Second, with the use of a balanced incomplete block design, the tool was validated by a large group of decision-makers. Third, the tool was pilot-tested in a real-world P&T committee environment.
An expert panel identified key factors associated with formulary access by rating the level of access that they would give a drug in various hypothetical scenarios. These findings were used to formulate an evidence-assessment tool that was externally validated by surveying a larger sample of decision-makers. Last, the tool was pilot-tested in a real-world environment where P&T committees used it to review new drugs.
Survey responses indicated that a structured approach in the formulary decision-making process could yield greater clarity, consistency, and transparency in decision-making; however, pilot-testing of the structured tool in a real-world P&T committee environment highlighted some of the limitations of our structured approach.
Although a structured approach to formulary decision-making is beneficial for patients, health care providers, and other stakeholders, this benefit was not realized in a real-world environment. A method to improve clarity, consistency, and transparency is still needed.
PMCID: PMC3814436  PMID: 24222979
evidence; decision-making; formulary; access
23.  Risk Factors and Predictors for Candidemia in Pediatric Intensive Care Unit Patients: Implications for Prevention 
Few data exist on risk factors for candidemia in pediatric intensive care unit (PICU) patients who are at high risk of mortality from infection. We conducted a population-based case-control study to determine risk factors and predictors for candidemia in the PICU.
Candida species are the leading cause of invasive fungal infections in hospitalized children and are the third most common isolates recovered from pediatric healthcare-associated bloodstream infection in the US [1]. Few data exist on risk factors for candidemia in pediatric intensive care unit (PICU) patients.
We conducted a population-based case-control study of PICU patients at Children's Hospital of Philadelphia (CHOP) from 1997-2004. Cases were identified using laboratory records, controls were selected from PICU rosters. Controls were matched to cases by incidence density sampling, adjusting for time at risk. Following conditional multivariate analysis, we performed weighted multivariate analysis to determine predicted probabilities for candidemia given certain risk factor combinations.
We identified 101 cases of candidemia(incidence,3.5/1,000 PICU admissions). Factors independently associated with candidemia included presence of a central venous catheter(OR 30.4;CI,7.7,119.5), malignancy(OR 4.0;CI,1.23,13.1), use of vancomycin for >3 days in the prior two weeks(OR 6.2;CI,2.4,16), and receipt of agents with activity against anaerobic organisms for >3 days in the prior two weeks(OR 3.5;CI, 1.5,8.4). Predicted probability of various combinations of the factors above ranged from 10.7%-46%. The 30-day mortality rate was 44% in cases compared to 14% in controls (OR 4.22;CI,2.35,7.60).
To our knowledge, this is the first study to evaluate independent risk factors and to determine a population of children in PICUs at high risk for developing candidemia. Future efforts should focus on validation of these risk factors identified in a different PICU population and development of interventions for prevention of candidemia in critically ill children.
PMCID: PMC3753770  PMID: 20636126
Candidemia; Pediatrics; Risk factors; Intensive Care
25.  The Adult Respiratory Distress Syndrome Cognitive Outcomes Study 
Rationale: Cognitive and psychiatric morbidity is common and potentially modifiable after acute lung injury (ALI). However, practical measures of neuropsychological function for use in multicenter trials are lacking.
Objectives: To determine whether a validated telephone-based neuropsychological test battery is feasible in a multicenter trial. To determine the frequency and risk factors for long-term neuropsychological impairment.
Methods: As an adjunct study to the Acute Respiratory Distress Syndrome Clinical Trials Network Fluid and Catheter Treatment Trial, we assessed neuropsychological function at 2 and 12 months post–hospital discharge.
Measurements and Main Results: Of 406 eligible survivors, we approached 261 to participate and 213 consented. We tested 122 subjects at least once, including 102 subjects at 12 months. Memory, verbal fluency, and executive function were impaired in 13% (12 of 92), 16% (15 of 96), and 49% (37 of 76) of long-term survivors. Long-term cognitive impairment was present in 41 of the 75 (55%) survivors who completed cognitive testing. Depression, post-traumatic stress disorder, or anxiety was present in 36% (37 of 102), 39% (40 of 102), and 62% (63 of 102) of long-term survivors. Enrollment in a conservative fluid-management strategy (P = 0.005) was associated with cognitive impairment and lower partial pressure of arterial oxygen during the trial was associated with cognitive (P = 0.02) and psychiatric impairment (P = 0.02).
Conclusions: Neuropsychological function can be assessed by telephone in a multicenter trial. Long-term neuropsychological impairment is common in survivors of ALI. Hypoxemia is a risk factor for long-term neuropsychological impairment. Fluid management strategy is a potential risk factor for long-term cognitive impairment; however, given the select population studied and an unclear mechanism, this finding requires confirmation.
PMCID: PMC3381234  PMID: 22492988
acute respiratory distress syndrome; acute lung injury; cognitive function; critical illness

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