Faculty Bibliography

The acetylcholinesterase inhibitor donepezil hydrochloride improves cognitive function in patients with Alzheimer's disease and vascular dementia. Given acetylcholine's important actions on the heart, we undertook a retrospective cohort investigation to assess whether donepezil usage affects cardiovascular mortality. In patients treated with donepezil, hazard ratios for total and cardiovascular mortality were 0.68 (P = 0.045, 95% confidence interval 0.46-0.99) and 0.54 (P = 0.042, 95% confidence interval 0.30-0.98), respectively. The apparent survival benefit in donepezil-treated patients should not be overinterpreted. Prospective clinical trials are warranted.

BACKGROUND: Chest CT after pediatric trauma is frequently performed but its clinical impact, particularly with respect to surgical intervention, has not been adequately evaluated. OBJECTIVE: To assess the impact of chest CT compared with chest radiography on pediatric trauma management. MATERIALS AND METHODS: Two hundred thirty-five consecutive pediatric trauma patients who had both chest CT and radiography were identified. Images were reviewed and findings were categorized and correlated with subsequent chest interventions, blinded to final outcome and management. RESULTS: Of the 235 children, 38.3% (90/235) had an abnormal chest radiograph and 63.8% (150/235) had an abnormal chest CT (P < 0.0001). Chest interventions followed in 4.7% (11/235); of these, the findings could be made 1 cm above the dome of the liver in 91% (10/11). Findings requiring chest intervention included pneumothorax (PTX) and vertebral fractures. PTX was found on 2.1% (5/235) of chest radiographs and 20.0% (47/235) of chest CTs (P < 0.0001); 1.7% (4/235) of the children received a chest tube for PTX, 0.85% (2/235) seen on chest CT only. Vertebral fractures were present in 3.8% of the children (9/235) and 66.7% (6/9) of those cases were treated with spinal fusion or brace. There were no instances of mediastinal vascular injury. CONCLUSION: Most intrathoracic findings requiring surgical management in our population were identified in the lower chest and would be included in routine abdominopelvic CT exams; this information needs to be taken into consideration in the diagnostic algorithm of pediatric trauma patients

BACKGROUND:Previous studies of children with homozygous sickle cell anemia (SCA) show impaired growth and maturation. The correlation of this suboptimal growth with metabolic and hematological factors during puberty is poorly understood. PROCEDURE/METHODS:We studied a group of pre-adolescent children with SCA (19 males, 14 females) and healthy controls (16 males, 15 females) matched for race, sex, body size, and pubertal development. Height, weight, body mass index (BMI), and body composition changes were longitudinally assessed over a 2-year period and compared between the groups and with Z scores based on US growth charts. These changes were correlated with hemoglobin (Hgb) concentration and with energy expenditure (EE) measured using indirect whole-room calorimetry. RESULTS:Children with SCA progressed through puberty slower than control children. While, after 2 years, pubertal males with SCA were shorter, their annual increases in weight were not different from controls. The mean fat free mass (FFM) increments were significantly less in males and females with SCA than in control children. In males with SCA, growth in height declined over time and was significantly slower than in matched controls (P < 0.05). CONCLUSION/CONCLUSIONS:Growth delays were present during puberty in children with SCA. Decreased growth velocity in children with SCA was independently associated with decreased Hgb concentration and increased total EE.

BACKGROUND:Autosomal dominant inheritance of germline mutations in the bone morphogenetic protein receptor type 2 (BMPR2) gene are a major risk factor for pulmonary arterial hypertension (PAH). While previous studies demonstrated a difference in severity between BMPR2 mutation carriers and noncarriers, it is likely disease severity is not equal among BMPR2 mutations. We hypothesized that patients with missense BMPR2 mutations have more severe disease than those with truncating mutations. METHODS:Testing for BMPR2 mutations was performed in 169 patients with PAH (125 with a family history of PAH and 44 with sporadic disease). Of the 106 patients with a detectable BMPR2 mutation, lymphocytes were available in 96 to functionally assess the nonsense-mediated decay pathway of RNA surveillance. Phenotypic characteristics were compared between BMPR2 mutation carriers and noncarriers, as well as between those carriers with a missense versus truncating mutation. RESULTS:While there was a statistically significant difference in age at diagnosis between carriers and noncarriers, subgroup analysis revealed this to be the case only for females. Among carriers, there was no difference in age at diagnosis, death, or survival according to exonic location of the BMPR2 mutation. However, patients with missense mutations had statistically significant younger ages at diagnosis and death, as well as shorter survival from diagnosis to death or lung transplantation than those with truncating mutations. Consistent with this data, the majority of missense mutations were penetrant prior to age 36 years, while the majority of truncating mutations were penetrant after age 36 years. CONCLUSION/CONCLUSIONS:In this cohort, BMPR2 mutation carriers have more severe PAH disease than noncarriers, but this is only the case for females. Among carriers, patients with missense mutations that escape nonsense-mediated decay have more severe disease than those with truncating mutations. These findings suggest that treatment and prevention strategies directed specifically at BMPR2 pathway defects may need to vary according to the type of mutation.

Testing Hardy-Weinberg equilibrium (HWE) in the control group is commonly used to detect genotyping errors in genetic association studies. We propose a likelihood ratio test for testing HWE in the study population using both case and control samples. This test incorporates underlying association models. Another feature is that, when we infer the disease-genotype association, we explicitly incorporate HWE or a possible departure from Hardy-Weinberg equilibrium (DHWE) into the model. Our unified framework enables us to infer the disease-genotype association when a detected DHWE needs to be part of the model after causes for the DHWE are explored. Real data sets are used to illustrate the application of the methodology and its implication in genetic association studies. Our analysis and interpretation touch on issues such as genotyping errors, population selection, population stratification, or the study sampling plan, that all could be the cause of DHWE.

PURPOSE: To determine whether lack of visualization of the appendix on otherwise normal abdominopelvic computed tomographic (CT) images can help exclude appendicitis in the pediatric population. MATERIALS AND METHODS: The study was institutional review board approved and HIPAA compliant. One thousand one hundred thirty-nine children suspected of having appendicitis were referred for CT examination between July 2002 and December 2006. Exclusion criteria included CT diagnosis of appendicitis or other cause of symptoms and lack of clinical follow-up. Consensus review was performed by two pediatric radiologists to determine normal examinations, leaving a final study group (nonvisualized appendix) of 156 patients (mean age, 9.6 years; boys, 7.2 years; girls, 10.2 years) and a control group (visualized appendix) of 421 patients (mean age, 11.0 years; boys, 9.8 years; girls, 11.2 years). In the control group, there were 168 subjects with a partially visualized (PV) appendix and 253 with a fully visualized (FV) appendix. Pericecal fat was graded according to published criteria. Diagnosis was confirmed at surgery or clinical follow-up. Negative predictive values were calculated with 95% confidence intervals (CIs). RESULTS: There were three false-negative findings (study group, two; control group, one [FV]). The negative predictive value of a normal CT examination in pediatric patients with a nonvisualized appendix was 98.7% (95% CI: 95.5%, 99.8%); that with a visualized appendix, 99.8% (95% CI: 98.7%, 99.99%); that with a PV appendix, 100% (95% CI: 97.8%, 100%); and that with a FV appendix, 99.6% (95% CI: 97.8%, 99.99%). CONCLUSION: Pediatric abdominopelvic CT images with nonvisualized appendix have a high negative predictive value, without significant difference from cases with a PV or even FV appendix. The false-negative rate was similar to those reported in two adult series

OBJECTIVE: The purpose of our study was to evaluate the diagnostic efficacy and impact of emergent MRI after recent intervention in children with suspected osteomyelitis or septic arthritis. MATERIALS AND METHODS: This retrospective case-control study in children with suspected osteomyelitis or septic arthritis consisted of 34 study subjects (mean age, 5.3 years) who underwent MRI after intervention and 96 control subjects (mean age, 8.7 years) who underwent MRI without prior intervention. Final diagnosis and management were abstracted from medical records. Consensus MRI review of the study group was performed to evaluate whether objective MRI criteria of osteomyelitis can be applied to patients who have undergone prior intervention. RESULTS: For the study and control groups, no difference was seen in the final diagnosis of osteomyelitis (26.5% [9/34] and 29.2% [28/96], p = 0.76), osteomyelitis or septic arthritis (41.2% [14/34] and 37.5% [36/96], p = 0.70), cellulitis or pyomyositis (20.6% [7/34] and 34.4% [33/96], p = 0.13), and noninfectious conditions (23.5% [8/34] and 13.5% [13/96], p = 0.17). Objective MRI criteria for osteomyelitis were present in all nine patients with a final diagnosis of osteomyelitis and were not present in the remaining 25 who did not have a final diagnosis of osteomyelitis despite recent intervention. Repeat interventions were necessary in the study group at a rate not significantly different from single interventions in the control group (29.4% [10/34] and 27.1% [26/96], p = 0.79). CONCLUSION: Iatrogenic soft-tissue and bone edema related to recent intervention in children with suspected osteomyelitis or septic arthritis does not affect the diagnostic efficacy of MRI. Performing MRI before intervention adds efficacy to patient management, prevents unnecessary interventions, and guides surgical procedures when indicated

BACKGROUND:Postoperative atrial fibrillation (AF), a frequent complication after cardiac surgery, causes morbidity and prolongs hospitalization. Inotropic drugs are commonly used perioperatively to support ventricular function. This study tested the hypothesis that the use of inotropic drugs is associated with postoperative AF. METHODS AND RESULTS/RESULTS:We evaluated perioperative risk factors in 232 patients who underwent elective cardiac surgery. All patients were in sinus rhythm at surgery. Sixty-seven patients (28.9%) developed AF a mean of 2.9+/-2.1 days after surgery. Patients who developed AF stayed in the hospital longer (P<0.001) and were more likely to die (P=0.02). Milrinone use was associated with an increased risk of postoperative AF (58.2% versus 26.1% in nonusers; P<0.001). Older age (63.4+/-10.7 versus 56.7+/-12.3 years; P<0.001), hypertension (P=0.04), lower preoperative ejection fraction (P=0.03), mitral valve surgery (P=0.02), right ventricular dysfunction (P=0.03), and higher mean pulmonary artery pressure (27.1+/-9.3 versus 21.8+/-7.5 mm Hg; P=0.001) also were associated with postoperative AF. In multivariable logistic regression, age (P<0.001), ejection fraction (P=0.02), and milrinone use (odds ratio, 4.86; 95% confidence interval, 2.31 to 10.25; P<0.001) independently predicted postoperative AF. When only data from patients with pulmonary artery catheters were analyzed and pulmonary artery pressure was included in the model, age, milrinone use (odds ratio, 4.45; 95% confidence interval, 2.01 to 9.84; P<0.001), and higher pulmonary artery pressure (P=0.02) were associated with an increased risk of postoperative AF. Adding other potential confounders or stratifying analysis by mitral valve surgery did not change the association of milrinone use with postoperative AF. CONCLUSIONS:Milrinone use is an independent risk factor for postoperative AF after elective cardiac surgery.