James T. Patrie

Viral infections in relation to age, atopy, and season of admission among children hospitalized for wheezing.

Abstract Background Viral respiratory tract infections and atopy are associated with attacks of wheezing during childhood. However, information about the relationship between viral infections and atopy among children whose attacks of wheezing lead to hospitalization is unclear. Objective To evaluate the prevalence of viral respiratory tract pathogens among infants and children hospitalized for wheezing and to analyze the results in relation to the patients age, atopic characteristics, and season of admission. Methods This was a case-control study of children (age 2 months to 18 years) admitted for wheezing to the University of Virginia Medical Center over a period of 12 months. Children without wheezing were enrolled as controls. Nasal secretions were evaluated for viral pathogens by using cultures, PCR tests, and antigen detection. Total IgE and specific IgE antibody to common aeroallergens was measured in serum. Results Seventy percent of children hospitalized for wheezing before age 3 years (n=79) were admitted between December and March, whereas 46% of children age 3 to 18 years (n=54) were hospitalized between September and November. Among children younger than 3 years, viral pathogens were detected in 84% (66/79) of wheezing children and 55% (42/77) of controls (P < .001). Respiratory syncytial virus was the dominant pathogen during the winter months, but rhinovirus was more common during other months. Total serum IgE levels were generally low, and values from wheezing and control subjects overlapped considerably. Among children 3 years and older, 61% (33/54) of subjects admitted for wheezing tested positive for virus (predominantly rhinovirus), compared with 21% (12/56) of controls (P < .001). The total serum IgE values among wheezing children (geometric mean, 386 IU/mL; 95% CI, 259-573) were substantially elevated compared with those of controls (geometric mean, 38 IU/mL; 95% CI, 26-56; P < .001). A significantly higher percentage of wheezing children compared with controls was sensitized to at least 1 of the inhaled allergens tested: 84% (36/43) compared with 33% (15/45; P < .001). The atopic characteristics of wheezing children who tested positive or negative for virus were similar. Conclusions Viral infections were the dominant risk factor for wheezing among children hospitalized before 3 years of age. By comparison, a large majority of the wheezing children age 3 to 18 years had striking atopic characteristics that may be critical as a risk factor for hospitalization and an adverse response to viral infections, especially infections caused by rhinovirus.

Effects of an oral ghrelin mimetic on body composition and clinical outcomes in healthy older adults: a randomized trial.

Context The age-related decline of growth hormone secretion may play a role in sarcopenia and frailty. Content In this randomized trial, 65 healthy older adults were assigned to receive placebo or MK-677, an oral ghrelin mimetic that increased pulsatile growth hormone secretion to young-adult levels. Over 1 year, lean fat-free mass increased 1.1 kg with MK-677 and decreased 0.5 kg with placebo. MK-677 did not affect strength and function, but insulin sensitivity declined and mean serum glucose levels increased 0.28 mmol/L (5 mg/dL). Caution This short-term trial was underpowered to detect functional changes and adverse events. Implication An oral ghrelin mimetic increases pulsatile growth hormone secretion and alters body composition in healthy older adults. The Editors Aging is an inevitable process across all species. In humans, muscle mass declines after reaching its peak in the third decade of life. Muscle mass is important for physical fitness and metabolic regulation; sarcopenia is a major risk factor for frailty, loss of independence, and physical disability in elderly persons (1) and is associated with shortened survival in critically ill patients (2). As lifespans increase, more adults are becoming frail and dependent on others, which creates challenges for them, their families, and society. The decrease in fat-free mass correlates with the aging-associated decrease in growth hormone secretion (3, 4). Aging adults show decreases in fat-free mass and growth hormone secretion similar to those seen in growth hormonedeficient young adults (5). By the eighth decade, men and women lose approximately 7 and 3.8 kg of muscle mass, respectively (3), and gain intra-abdominal fat (6, 7). Previous trials in which growth hormone was administered to elderly persons were small, poorly controlled, or too short (8); in addition, growth hormone replacement does not restore pulsatile growth hormone secretion. MK-677, the first orally active ghrelin mimetic (a growth hormone secretagogue and growth hormone secretagoguereceptor agonist), increases pulsatile growth hormone secretion in older adults to levels observed in young adults (9, 10). Our primary objectives were to determine whether 25 mg of oral MK-677 daily would increase growth hormone and insulin-like growth factor I (IGF-I) levels in healthy older adults, prevent the decline in fat-free mass, and decrease abdominal visceral fat, with acceptable tolerability. Methods Design The General Clinical Research Center (GCRC) and the University of Virginia institutional review boards approved this study. All participants gave written informed consent. We performed a 2-year, randomized, double-blind, modified crossover trial in which healthy older men, women receiving hormone replacement therapy, and women not receiving hormone replacement therapy received oral MK-677, 25 mg, or placebo (in a 2:1 ratio) daily. After 1 year, participants receiving MK-677 were randomly assigned to continue receiving MK-677 (group 1) or change to placebo (group 2); participants receiving placebo were given MK-677 during year 2 (group 3). Appendix Figure 1 shows the study design. Supplement. Appendix Materials Setting and Participants We recruited healthy volunteers older than 60 years of age from the general population by advertisement and screened them by medical history, physical examination, and laboratory testing to rule out underlying disease. Exclusion criteria were body mass index greater than 35 kg/m2, strenuous exercise for more than 60 minutes per day, smoking, diabetes, history of cancer (other than some types of skin cancer), untreated hypertension or thyroid disease, or medications known to affect growth hormone secretion. We asked participants to maintain their typical diet and exercise throughout the study and to report any illnesses, medical procedures, or adverse effects. All participants were white, with the exception of 1 Hispanic and 1 African-American man. At baseline and every 6 months for 2 years, we admitted participants to the GCRC for measurement of body composition, body water, lipids, and bone mineral density; frequent blood sampling; and completion of quality-of-life questionnaires. We also performed tests of strength and function. During GCRC admissions, we standardized meals for caloric and nutrient content. Blood samples for growth hormone were drawn through an indwelling venous cannula every 10 minutes for 24 hours; participants were allowed to sleep after 9 p.m. Randomization and Intervention MK-677 and placebo tablets were provided by Merck Research Laboratories (Rahway, New Jersey) in a blinded manner and stored by a research pharmacist and dispensed in a blinded manner according to a randomization table with stratification for sex and hormone replacement therapy. Ten-mg tablets were provided for blinded back-titration. Participants were instructed to take the placebo or MK-677 tablets once daily between 7:00 and 9:00 a.m. (or at 9:00 a.m. during admissions). All research staff and volunteers remained blinded throughout the study and during data verification. We monitored adherence by pill counts. Outcome Measures We measured serum growth hormone and IGF-I levels in duplicate in the GCRC Core Laboratory. We assessed 24-hour mean growth hormone and endogenous growth hormone secretory dynamics by using the cluster method (11) and an automated multiple-parameter deconvolution method (9, 12). The Appendix provides details of all assay methods. We evaluated fat-free mass and total body fat by using a 4-compartment model (13) and dual x-ray absorptiometry (DXA) on a Hologic QDR-2000 (Hologic, Bedford, Massachusetts) in pencil-beam mode (14). Dual x-ray absorptiometry measurements included appendicular lean soft tissue of the arms and legs as an estimate of total appendicular skeletal muscle mass (TASM) (15); appendicular fat; and bone mineral density of the femoral neck, spine (L2L4), and total hip. We divided the DXA TASM estimates by height in square meters (TASM [kg]/m2) (15). We used this index of relative limb muscle mass to compute a T-score for each individual, relating the TASM/m2 to that of sex-concordant young adults (16). We defined sarcopenia as values more than 2 SD below values in young, sex-specific reference populations (17, 18). We used cross-sectional computed tomographic images to measure the areas of abdominal visceral and subcutaneous fat and midthigh skeletal muscle at predefined anatomical locations (19); we excluded data if the subsequent scan location differed or we had technical difficulties (4 placebo group recipients and 3 MK-677 recipients). One blinded observer analyzed the dual x-ray absorptiometry and computed tomographic scans. We measured total body water by using the deuterium oxide dilution technique (20) and extracellular water by using bromide dilution (21). We assessed intracellular water as the difference between total body water and extracellular water. To determine the relative relationships among total, extracellular, and intracellular water, we expressed each component in terms of kilograms of fat-free mass at each point. We chose the scale of measure for the analysis a priori. We also report the raw data in typical units for comparison. We determined concentric force during flexion and extension of the knee and shoulder every 6 months by using a Cybex II isokinetic dynamometer (CSM, Boston, Massachusetts). Participants performed 6 repetitions of maximal effort over 90 degrees at 60 degrees/s, and the mean of the last 5 repetitions was computed by using proprietary software (22). We calculated total work by multiplying the mean per repetition by 5. Function tests performed every 6 months included walking 30 meters as quickly as possible (best of 2 trials), walking as far as possible in 6 minutes on an indoor track, descending and ascending 4 flights of stairs, and rising and sitting 5 times from an armless chair with an 18-inch seat height. To compensate for differences in muscle mass between men and women, we analyzed all strength and function measurements in terms of kilograms of baseline appendicular skeletal muscle (lean) from DXA. We used arm lean and leg lean for shoulder and knee strength, respectively, and baseline TASM (sum of arms and legs) for the function tests. We chose the scale of measure used in this analysis a priori; the raw data are also reported. Participants completed 4 questionnaires every 6 months to assess quality of life and general well-being: the 20-item Short Form Health Survey, the Beck Depression Inventory, the Pittsburgh Sleep Quality Index, and the Body Cathexis Scale. The Appendix provides additional details of quality of life, muscle strength, and function assessments. We measured cholesterol, cortisol, and insulin sensitivity (estimated by the Quicki Index method [23] from fasting insulin and glucose) every 6 months. To determine whether the effects of MK-677 treatment were sustained for 2 years or reversed when changed to placebo, we analyzed several end points in a subgroup of participants who completed 24 months in each of the 3 treatment groups (Figure 1). Figure 1. Study flow diagram. FBG= fasting blood glucose; HRT= hormone replacement therapy; MI= myocardial infarction. Monitoring for Adverse Effects Each year, volunteers were seen monthly for the first 3 months and every 3 months thereafter for a physical examination, documentation of medications and vital signs, and questioning about side effects and overall well-being. We performed a complete blood count and chemistry panel and monitored levels of hemoglobin A1c (HbA1c) and fasting blood glucose in all participants and prostate-specific antigen and testosterone in men. Women received annual Papanicolaou smears and mammography. Statistical Analysis The 2 primary end points were fat-free mass and abdominal visceral fat. The study was powered for the pivotal first 12 months; the Appendix describes the power analysis in detail.

Is NASH underdiagnosed among African Americans

OBJECTIVE:Obesity and type 2 diabetes mellitus are considered risk factors for nonalcoholic steatohepatitis (NASH) and cryptogenic cirrhosis. Because obesity and type 2 diabetes are prevalent among African American females by the 5th and 6th decades, one would expect an increased number of African Americans among patients with NASH and cryptogenic cirrhosis.METHODS:We determined the percentage of patients of African American and European American descent among all of the patients in our liver disease registry and those with NASH and cryptogenic cirrhosis. We also assessed the ethnicity of patients in our registry with other common liver diseases including hepatitis C, and we determined the ethnicity of patients seen at our center with type 2 diabetes and a primary diagnosis of obesity over a 4-yr period. Using census data, we compared these results to our local and regional ethnic demographics.RESULTS:Overall, 199 of 2253 patients (9%) in the registry were of African American descent, whereas 1906 were of European American descent (85%). This distribution is similar to the ethnic mix in central Virginia (12% African American, 86% European American) and Albemarle County (12% African American, 83% European American). The prevalence of African American patients among individuals seen at our center for either type 2 diabetes or a primary diagnosis of obesity was over two times the prevalence of African Americans in the county or regional population. In contrast, of 159 NASH patients only one (0.6%) was of African American descent and 154 (97%) were of European American descent (p < 0.001 compared to the total registry, county, or region). Among 206 cryptogenic cirrhosis patients, only two (1%) were of African American descent, whereas 195 (95%) were of European American descent (p < 0.001 compared to the total registry). With regard to other liver diseases, African American patients were slightly overrepresented among hepatitis C patients and markedly overrepresented among patients with hepatic sarcoidosis, similar to previously reported national figures.CONCLUSION:Although there is overrepresentation of African Americans among patients with major risk factors for NASH, individuals of primarily African American descent are infrequently represented among our patients with NASH or cryptogenic cirrhosis. This could result from underrecognition, underreferral, or a true lower prevalence of these disorders among African Americans.

Development and Preliminary Validation of Heart Rate and Breathing Rate Detection Using a Passive, Ballistocardiography-Based Sleep Monitoring System

Techniques such as ballistocardiography (BCG) that can provide noninvasive long-term physiological monitoring have gained interest due to a growing recognition of adverse effects from poor sleep and sleep disorders. The noninvasive analysis of physiological signals (NAPS) system is a BCG-based monitoring system developed to measure heart rate, breathing rate, and musculoskeletal movement that shows promise as a general sleep analysis tool. Overnight sleep studies were conducted on 40 healthy subjects during a clinical trial at the University of Virginia. The NAPS systems measures of heart rate and breathing rate were compared to ECG, pulse oximetry, and respiratory inductance plethysmography (RIP). The subjects were split into a training dataset and a validation dataset, maintaining similar demographics in each set. The NAPS system accurately detected heart rate, averaged over the prescribed 30-s epochs, to within less than 2.72 beats per minute of ECG, and accurately detected breathing rate, averaged over the same epochs, to within 2.10 breaths per minute of RIP bands used in polysomnography.

Impact of the Accreditation Council for Graduate Medical Education work-hour regulations on neurosurgical resident education and productivity.

OBJECT Recently, the Institute of Medicine examined resident duty hours and their impact on patient safety. Experts have suggested that reducing resident work hours to 56 hours per week would further decrease medical errors. Although some reports have indicated that cutbacks in resident duty hours reduce errors and make resident life safer, few authors have specifically analyzed the effect of the Accreditation Council for Graduate Medical Education (ACGME) duty-hour limits on neurosurgical resident education and the perceived quality of training. The authors have evaluated multiple objective surrogate markers of resident performance and quality of training to determine the impact of the 80-hour workweek. METHODS The United States Medical Licensing Examination (USMLE) Step 1 data on neurosurgical applicants entering ACGME-accredited programs between 1998 and 2007 (before and after the implementation of the work-hour rules) were obtained from the Society of Neurological Surgeons. The American Board of Neurological Surgery (ABNS) written examination scores for this group of residents were also acquired. Resident registration for and presentations at the American Association of Neurological Surgeons (AANS) annual meetings between 2002 and 2007 were examined as a measure of resident academic productivity. As a case example, the authors analyzed the distribution of resident training hours in the University of Virginia (UVA) neurosurgical training program before and after the institution of the 80-hour workweek. Finally, program directors and chief residents in ACGME-accredited programs were surveyed regarding the effects of the 80-hour workweek on patient care, resident training, surgical experience, patient safety, and patient access to quality care. Respondents were also queried about their perceptions of a 56-hour workweek. RESULTS Despite stable mean USMLE Step 1 scores for matched applicants to neurosurgery programs between 2000 and 2008, ABNS written examination scores for residents taking the exam for self-assessment decreased from 310 in 2002 to 259 in 2006 (16% decrease, p < 0.05). The mean scores for applicants completing the written examination for credit also did not change significantly during this period. Although there was an increase in the number of resident registrations to the AANS meetings, the number of abstracts presented by residents decreased from 345 in 2002 to 318 in 2007 (7% decrease, p < 0.05). An analysis of the UVA experience suggested that the 80-hour workweek leads to a notable increase in on-call duty hours with a profound decrease in the number of hours spent in conference and the operating room. Survey responses were obtained from 110 program directors (78% response rate) and 122 chief residents (76% response rate). Most chief residents and program directors believed the 80-hour workweek compromised resident training (96%) and decreased resident surgical experience (98%). Respondents also believed that the 80-hour workweek threatened patient safety (96% of program directors and 78% of chief residents) and access to quality care (82% of program directors and 87% of chief residents). When asked about the effects of a 56-hour workweek, all program directors and 98% of the chief residents indicated that resident training and surgical education would be further compromised. Most respondents (95% of program directors and 84% of chief residents) also believed that additional work-hour restrictions would jeopardize patient care. CONCLUSIONS Neurological surgery continues to attract top-quality resident applicants. Test scores and levels of participation in national conferences, however, indicate that the 80-hour workweek may adversely affect resident training. Subjectively, neurosurgical program directors and chief residents believe that the 80-hour workweek makes neurosurgical training and the care of patients more difficult. Based on experience with the 80-hour workweek, educators think that a 56-hour workweek would further compromise neurosurgical training and patient care in the US.

Changes in Regional Airflow Obstruction over Time in the Lungs of Patients with Asthma: Evaluation with 3He MR Imaging

PURPOSE To determine changes in regional airflow obstruction over time in the lungs of patients with asthma, as demonstrated with hyperpolarized helium 3 ((3)He) magnetic resonance (MR) imaging, and to assess correlations with disease severity and use of asthma medications. MATERIALS AND METHODS Institutional review board approval and written informed consent were obtained for this HIPAA-compliant study. Use of (3)He was approved by the U.S. Food and Drug Administration. Forty-three patients underwent 103 MR imaging studies in total; 26 were imaged twice within 42-82 minutes (same day), and 17 were imaged on 3 days between 1 and 476 days (multiday). Each day, spirometry was performed, disease severity was determined, and the use of asthma medications was recorded. Images were reviewed in a pairwise fashion to determine total ventilation defect number, defects in same location between imaging studies, and size. Parametric and nonparametric statistical methods were used. RESULTS For the same-day examinations, the mean number of defects per image section was similar at baseline and repeat imaging (1.8 +/- 1.9 [standard deviation] vs 1.6 +/- 1.9, respectively; P = .15), with 75% of defects remaining in the same location and 71% of these not changing size. For the multiday examinations, the mean number of defects per section was higher for study 2 (2.4 +/- 1.5) than study 1 (1.7 +/- 0.9, P = .02), was lower for study 3 (1.5 +/- 1.1) than for study 2 (P < .01), and was similar for studies 1 and 3 (P = .56). Time between examinations was not associated with change in mean number of defects per section (median intrasubject correlation [r(m)] = 0.01, P = .64) or change in spirometric values (range of r(m) values: -0.56 to -0.31; range of P values: .09-.71). Defects in the same location decreased with time (r(m) = -0.83, P < .01), with 67% persisting between studies 1 and 2 (median interval, 31 days), 43% persisting between studies 2 and 3 (median interval, 41 days), and 38% persisting between studies 1 and 3 (median interval, 85 days); 46%-58% of defects remained unchanged in size. These trends were the same regardless of disease severity or medication use. CONCLUSION In asthma, focal airflow impediment within the lungs can be markedly persistent over time, regardless of disease severity or treatment.

The Axial Injury Tolerance of the Human Foot/Ankle Complex and the Effect of Achilles Tension

Axial loading of the foot/ankle complex is an important injury mechanism in vehicular trauma that is responsible for severe injuries such as calcaneal and tibial pilon fractures. Axial loading may be applied to the leg externally, by the toepan and/or pedals, as well as internally, by active muscle tension applied through the Achilles tendon during pre-impact bracing. The objectives of this study were to investigate the effect of Achilles tension on fracture mode and to empirically model the axial loading tolerance of the foot/ankle complex. Blunt axial impact tests were performed on forty-three (43) isolated lower extremities with and without experimentally simulated Achilles tension. The primary fracture mode was calcaneal fracture in both groups. However, fracture initiated at the distal tibia more frequently with the addition of Achilles tension (p < 0.05). Acoustic sensors mounted to the bone demonstrated that fracture initiated at the time of peak local axial force. A survival analysis was performed on the injury data set using a Weibull regression model with specimen age, gender, body mass, and peak Achilles tension as predictor variables (R2 = 0.90). A closed-form survivor function was developed to predict the risk of fracture to the foot/ankle complex in terms of axial tibial force. The axial tibial force associated with a 50% risk of injury ranged from 3.7 kN for a 65 year-old 5th percentile female to 8.3 kN for a 45 year-old 50th percentile male, assuming no Achilles tension. The survivor function presented here may be used to estimate the risk of foot/ankle fracture that a blunt axial impact would pose to a human based on the peak tibial axial force measured by an anthropomorphic test device.

The correlations between estradiol, estrone, estriol, progesterone, and sex hormone-binding globulin and anterior cruciate ligament stiffness in healthy, active females.

BACKGROUND Injury to the anterior cruciate ligament (ACL) often requires surgery and extensive rehabilitation. Women who participate in collegiate sports and military drills are more likely to injure their ACL than are men participating in similar activities. The influence of the normal fluctuation of sex hormones on the physical properties of the ACL is one potential cause for this disparity. The purpose of this study was to report the correlation between estradiol, estrone, estriol, progesterone, and sex hormone binding globulin (SHBG) and ACL stiffness during three phases of the menstrual cycle in normally cycling, healthy females. METHODS We tested ACL stiffness and collected blood from 20 female subjects who were not using oral contraception during three phases of their menstrual cycle. Ligament stiffness was tested with the KT-2000 trade mark knee arthrometer (MEDmetric, San Diego, CA). Concentrations of estradiol and SHBG were assessed via radioimmunoassay (RIA). Progesterone, estriol, and estrone concentrations were determined via enzyme-linked immunoassay. RESULTS Spearman rank correlation analysis indicated a significant correlation between estradiol concentration and ACL stiffness (-0.70, p < 0.001) and estrone concentration and ACL stiffness near ovulation (0.46, p = 0.040). With the effects of the other variables controlled, there was a significant partial correlation between estradiol (-0.80, p < 0.001), estriol (0.70, p = 0.003), and progesterone (0.66, p = 0.005) and ACL stiffness near ovulation. CONCLUSIONS Our results indicate that there is a significant correlation between estradiol, estriol, and progesterone and ACL stiffness suggesting that fluctuating levels of sex hormones may influence the stiffness of the ACL near ovulation. Future studies that examine the relationship between sex hormones and the physical properties of the ACL should be focused near the ovulation phase of the menstrual cycle.

N-2-butyl-cyanoacrylate for bleeding gastric varices: a United States pilot study and cost analysis

OBJECTIVES:N-butyl-2-cyanoacrylate has been reported to be effective for bleeding varices but is not available in the United States. We report the initial US experience with cyanoacrylate in this prospective trial and evaluate its safety, efficacy, and relative costs.METHODS:Patients with active or recent gastric variceal bleeding were eligible. Cyanoacrylate therapy was performed until variceal occlusion was achieved. Rebleeding was assessed at 72 h (acute phase), 6 wk (subacute phase), and 1 yr (chronic phase). Survival was assessed at 3 months and 1 yr. Cost analysis was performed comparing the first 17 patients to historical control patients not treated with cyanoacrylate.RESULTS:A total of 44 patients were enrolled, 37 with cirrhosis and seven with noncirrhotic portal hypertension (NCPH). In cirrhotic patients, rebleeding was seen in two of 37 (5%) at 72 h, one of 30 (3%) at 6 wk, and five of 28 (18%) at 1 yr. Survival without shunt at 3 months was 30 of 34 (88%) and at 1 yr was 24 of 31 (77%). In NCPH patients, rebleeding was seen in two of seven (29%) at 72 h. These patients received definitive therapy for NCPH after diagnosis. Mortality and costs were substantially higher in the non-cyanoacrylate group. The odds of death were greater by 7-fold in the non-cyanoacrylate group than within the cyanoacrylate group (95% CI = 1.18–41.36, p = 0.0318). At 3 months, there was a 3.18-fold difference (95% CI = 1.05–9.64, p = 0.0411) in accrued costs; at 1 yr, the difference was 2.55-fold (95% CI = 0.96–6.94, p = 0.0585). The cost-effective ratio was estimated as

Effects of n-3 fish oil on metabolic and histological parameters in NASH: A double-blind, randomized, placebo-controlled trial

108,237/death averted, reflecting marked cost reduction with improved survival in the cyanoacrylate-treated group. This is believed to result largely from avoidance of shunt interventions.CONCLUSION:Cyanoacrylate treatment of gastric varices is safe, clinically effective, and cost effective.