Summarizing methacholine challenges in clinical research.

In clinical trials in asthma, airway reactivity is commonly assessed by performing a methacholine challenge. Airway reactivity is thought to vary in proportion to asthma severity, and methacholine causes the airways of asthma subjects to constrict, thus lowering forced expiratory volume in 1 second (FEV(1)). A dose-response curve is obtained for each subject who meets standardized eligibility requirements to proceed with a methacholine challenge. When data from a methacholine challenge are used as an outcome variable in analysis, a univariate measure called the PC(20), the concentration of methacholine needed to produce a 20% fall in FEV(1) from baseline, is typically used to summarize the dose-response curve. Questions that arise regarding data generated from the methacholine challenge include: how to express data that do not yield a PC(20) value; whether PC(20) actually represents the best way to capture airway activity as expressed in a methacholine challenge; and whether the baseline FEV(1) is defined appropriately in calculation of PC(20). The impact of these issues on the statistical analysis of methacholine challenge data is described in this article. Some adjustments to the usual estimates of PC(20) and parametric modeling of the entire dose-response curve are proposed as alternatives that address some of the shortcomings of PC(20).

Transbronchial biopsy with virtual CT bronchoscopy and nodal highlighting.

Transbronchial biopsy to sample lymph nodes and tumors that are not visible at endoscopy has a poor (<50%) success rate. These nodes can be highlighted easily at virtual computed tomographic (CT) bronchoscopy to provide a guide. This study was performed to evaluate if the addition of this information to the bronchoscopist improved the success rate of transbronchial biopsy of subcarinal and aortopulmonary lymph nodes. The addition of virtual CT bronchoscopy with lymph node highlighting significantly (P < .5) increased biopsy success rates for pretracheal, hilar, and high pretracheal adenopathy.

CT angiography: in vitro comparison of five reconstruction methods.

OBJECTIVE: Five image reconstruction techniques have been used with CT angiography: axial (cross-sectional), maximum intensity projection (MIP), curved multiplanar reconstruction (MPR), shaded-surface display, and volume rendering. This study used a phantom to compare the accuracy of these techniques for measuring stenosis. SUBJECTS AND METHODS: A 19-vessel phantom containing various grades of concentric stenoses (0-100%) and three lengths (5, 7.5, and 10 mm) of stenoses was used for this study. Scans were obtained with a slice thickness of 2.0 mm, slice interval of 1.0 mm, pitch of 1.0, 120 kVp, 200 mA, and with the vessels oriented parallel to the z-axis and opacified with nonionic contrast material. CT angiography images were produced using five optimized techniques: axial, MIP, MPR, shaded-surface display, and volume rendering; and measurements were made with an electronic cursor in the normal lumen and mid stenosis by five separate investigators who were unaware of vessel and stenosis diameters. Each of the techniques was first optimized according to the radiology literature and our own preliminary testing. RESULTS: For vessels greater than 4 mm in diameter, axial, MIP, MPR, shaded-surface display, and volume-rendering CT angiography techniques all had a measurement error of less than 2.5%. However, axial, MIP, MPR, and shaded-surface display techniques were less accurate in estimating smaller (

Reproducibility of motor unit number estimation in individual subjects.

Although the reproducibility of motor unit number estimation (MUNE) for groups of subjects has been studied, there is little such data for individuals. Prediction intervals represent a tool to study individual MUNE reproducibility and represent the range of values expected for a future MUNE if the true number of motor units remains unchanged. MUNE was performed using the statistical method on 48 normal individuals. The prediction interval was found to be a function of the intrasubject coefficient of variation. Using a commercial manufacturer's recommended technique and software, prediction intervals were found to be so broad as to be of uncertain value. We found that by averaging two MUNE observations for each determination, and using the method of weighted averages for calculating the size of an average single motor unit potential, the intrasubject coefficient of variation was reduced from 16.48% to 8.77%, and the 90% prediction interval became sufficiently narrow to be clinically useful. False-negative rates were also lowered substantially using these techniques. Thus, simple modifications of an existing MUNE program improved the clinical utility of this program for the longitudinal study of patients in whom changes in motor unit number over time are of importance, such as those with motor neuron diseases.

Rationing HIV medications: what do patients and the public think about allocation policies?

BACKGROUND: New medications for treating HIV/AIDS are effective, but expensive, and funding shortfalls have led many state AIDS Drug Assistance Programs (ADAPs) to ration these drugs. Little is known about the views of those most directly affected by rationing policies. This study explores attitudes of patients with HIV and the general public toward specific rationing strategies. METHODS: A Likert-style, self-administered questionnaire about rationing expensive HIV medications in the context of a budget shortfall was administered to patients with HIV and shopping mall patrons in central Pennsylvania. Subjects were asked how much they agreed or disagreed with seven drug rationing policies. RESULTS: In all, 100 patients and 101 shoppers completed the survey (response rate = 89%). A majority in both groups "strongly" or "somewhat" disagreed with six of the seven rationing policies described, and patients more strongly disagreed with the policies than did the public. The five policies actually used by state ADAPs (first come first serve, limiting expensive medicines, limiting new patient enrollment, giving the expensive medicines to the sickest, using a spending cap) lacked support in either group. CONCLUSIONS: HIV drug rationing policies currently in use do not reflect the preferences of patients and the public. Integrating the views of those affected by the rationing decisions would raise difficult challenges to current programs.

CT angiographic measurement of the carotid artery: optimizing visualization by manipulating window and level settings and contrast material attenuation.

PURPOSE: To evaluate a broad range of window and level settings for various contrast material attenuation coefficients and degrees of vascular stenosis to obtain the most accurate computed tomographic (CT) angiographic measurements. MATERIALS AND METHODS: A total of 25, 480 measurements were made transversely (perpendicular to the lumen) and by means of maximum intensity projection (MIP) in a phantom with stenoses of 0%-100%, contrast material with attenuation coefficients of 150-350 HU, and 14 window and 13 level settings. Edge definition was also evaluated. RESULTS: There was an inherent relationship between the contrast material attenuation coefficient and the optimal window and level settings in the measurement of stenoses at both transverse and MIP CT angiography. This relationship between the contrast material attenuation coefficient D: and the optimal settings for window W: and level L: was represented by the following simple equations: W:/D: = [-2 x (L:/D:)] + 1.3, where -0.2 < L:/D: < 0.5, and W:/D: = [3.3 x (L:/D:)] - 1.3, where 0.5 < L:/D: < 1.0. With a vascular contrast material attenuation coefficient of 250-350 HU, the best transverse and MIP display settings for the window and level were 96 and 150 HU, respectively. CONCLUSION: The use of optimized window and level settings at CT angiography reduces measurement variability.

An alternative index for assessing profile similarity in bioequivalence trials.

In a typical bioequivalence trial, summary measures of the plasma concentration versus time profile are used to compare two formulations of a drug product. Commonly used measures include area under the curve (AUC), maximum plasma concentration (C(max)) and time to maximum concentration (T(max)). Equivalence of these summary measures, in general, does not guarantee equivalence of the entire profile. Rescigno and Chinchilli and Elswick propose indices which measure profile similarity, but can be overly sensitive to unimportant differences and are not easily interpreted pharmacologically. We propose an alternative index based on smoothing the relative difference between bioavailability profiles. This provides a method for assessing bioequivalence over the entire profile which has a familiar interpretation and can be tuned to provide a compromise between the insensitivity to pattern differences of summary measures and the oversensitivity of pointwise comparisons.

Impact of the Armed Forces Institute of Pathology Radiologic Pathology Course on radiology resident performance on the ACR In-Training and ABR written Examinations. American College of Radiology. American Board of Radiology.

RATIONALE AND OBJECTIVES: The purpose of this study was to assess resident scores on the American College of Radiology (ACR) In-Training Examination and on the written American Board of Radiology (ABR) Examination relative to attendance at and timing of the Armed Forces Institute of Pathology (AFIP) Radiologic Pathology Course. MATERIALS AND METHODS: A survey of 200 radiology residency program directors requested the type of residency program, whether the program sent residents to the AFIP course, dates of AFIP attendance for individual residents, percentile scores of residents on the ACR examination from 1995 through 1998, and ABR examination scores for 1997. Scores were analyzed before and after AFIP attendance and also temporally for examinations during or after AFIP attendance. Improvement in percentile scores for residents undergoing the ACR examination while attending the AFIP were compared with scores of matched residents from their programs who had not attended. RESULTS: Thirty-six (18%) program directors responded, providing data on 619 residents who underwent the ACR examination, ABR examination, or both. No significant improvement was found between pre- and post-AFIP ACR Examination scores for residents at university or military programs. There were statistically significantly improved scores for residents at community programs (mean percentile improvement, 8.1 points; P = .0064). Residents who underwent the ACR examination during the AFIP course improved their scores by 10.7 percentile points compared with matched residents who had not attended the AFIP course (P = .041). CONCLUSION: Residents undergoing the ACR examination while attending the AFIP improve their percentile scores more than residents who have not attended the AFIP.

Lying to each other: when internal medicine residents use deception with their colleagues.

BACKGROUND: While lying is morally problematic, physicians have been known to use deception with their patients and with third parties. Little is known, however, about the use of deception between physicians. OBJECTIVES: To determine the likelihood that resident physicians say they would deceive other physicians in various circumstances and to examine how variations in circumstances affect the likelihood of using deception. METHODS: Two versions of a confidential survey using vignettes were randomly distributed to all internal medicine residents at 4 teaching hospitals in 1998. Survey versions differed by introducing slight variations to each vignette in ways we hypothesized would influence respondents' willingness to deceive. The likelihood that residents say they would use deception in response to each vignette was compared between versions. RESULTS: Three hundred thirty surveys were distributed (response rate, 67%). Of those who responded, 36% indicated they were likely to use deception to avoid exchanging call, 15% would misrepresent a diagnosis in a medical record to protect patient privacy, 14% would fabricate a laboratory value to an attending physician, 6% would substitute their own urine in a drug test to protect a colleague, and 5% would lie about checking a patient's stool for blood to cover up a medical mistake. For some of the scenarios, the likelihood of deceiving was influenced by variations in the vignettes. CONCLUSIONS: A substantial percentage of internal medicine residents report they would deceive a colleague in various circumstances, and the likelihood of using deception depends on the context. While lying about clinical issues is not common, it is troubling when it occurs at any time. Medical educators should be aware of circumstances in which residents are likely to deceive, and discuss ways to eliminate incentives to lie.

Mucosal detail at CT virtual reality: surface versus volume rendering.

PURPOSE: To evaluate computed tomographic virtual reality with volumetric versus surface rendering. MATERIALS AND METHODS: Virtual reality images were reconstructed for 27 normal or pathologic colonic, gastric, or bronchial structures in four ways: the transition zone (a) reconstructed separately from the wall by using volume rendering; (b) with attenuation equal to air; (c) with attenuation equal to wall (soft tissue); (d) with attenuation halfway between air and wall. The four reconstructed images were randomized. Four experienced imagers blinded to the reconstruction graded them from best to worst with predetermined criteria. RESULTS: All readers rated images with the transition zone as a separate structure as overwhelmingly superior (P <.001): Nineteen cases had complete concurrence among all readers. The best of the surface-rendering reconstructions had the transition zone attenuation equal to the wall attenuation (P <.001). The third best reconstruction had the transition zone attenuation equal to the air attenuation, and the worst had the transition zone attenuation halfway between the air and wall attenuation. CONCLUSION: Virtual reality is best with volume rendering, with the transition zone (mucosa) between the wall and air reconstructed as a separate structure.

Postnatal pulmonary hypertension after repair of congenital diaphragmatic hernia: predicting risk and outcome.

BACKGROUND: Pulmonary hypertension (PH) after congenital diaphragmatic hernia (CDH) repair remains a significant cause of morbidity and mortality. Although treatment advances have improved overall survival, a new cohort of patients is surviving with PH beyond the postnatal period. Because the clinical entity of postnatal persistent pulmonary hypertension (PPHTN) in CDH patients has not been published, the authors undertook a retrospective study of our neonatal CDH experience to characterize this group of infants. METHODS: Charts of all infants with CDH treated at this institution from January 1991 to June 1997 were reviewed (n = 51). Persistent pulmonary hypertension by echocardiographic (Echo) measurements at the time of discharge identified PPHTN patients. Control survivors had normal pulmonary artery pressures at discharge. Physiological parameters and the results of therapeutic interventions were analyzed to predict PPHTN. RESULTS: Seven infants (four boys, three girls) had PPHTN at discharge. Significant differences with the control group were noted in length of stay, duration of intubation, and duration of nitric oxide therapy. Extracorporeal membrane oxygenation (ECMO) duration was not significantly different between the groups. By 12 months of age, PPHTN resolved in six patients (87%), and one died at 13 months. Regardless of therapy, two parameters showed 100% positive predictive value for identifying patients with PPHTN (P < .001): an Echo demonstrating PH at 2 months of age or continued oxygen requirement at 3 months. Oxygen requirement at 2 months had a 67% predictive value of PPHTN. CONCLUSIONS: With current treatment strategies for CDH, infants can survive with persistent pulmonary hypertension beyond the newborn period. The long-term survival rate is excellent, and normalization of pulmonary artery pressures can be expected. PPHTN can be predicted in those infants with Echo-defined pulmonary hypertension at 2 months.

Rat model of perinatal hypoxic-ischemic brain damage.

To gain insights into the pathogenesis and management of perinatal hypoxic-ischemic brain damage, the authors have used an immature rat model which they developed many years ago. The model entails ligation of one common carotid artery followed thereafter by systemic hypoxia. The insult produces permanent hypoxic-ischemic brain damage limited to the cerebral hemisphere ipsilateral to the carotid artery occlusion. The mini-review describes recently accomplished research pertaining to the use of the immature rat model, specifically, investigations involving energy metabolism, glucose transporter proteins, free radical injury, and seizures superimposed upon cerebral hypoxia-ischemia. Future research will focus on molecular mechanisms of neuronal injury with a continuing focus on therapeutic strategies to prevent or minimize hypoxic-ischemic brain damage.

In vitro-in vivo relationships for oral extended-release drug products.

It is of interest to predict the in vivo behavior of an oral extended-release drug product based on its in vitro dissolution profile. In some cases a suitable convolution-based prediction model can be found. We present a methodology for developing statistical models of in vitro-in vivo relationships under the framework of the mixed-effects nonlinear model and discuss methods for assessing the validity and strength of the relationship. These methods are illustrated and contrasted with a level A in vitro-in vivo correlation using data from a study involving four different formulations of an oral extended-release drug product.

Nonclassical secretory dynamics of LH revealed by hypothalamo-hypophyseal portal sampling of sheep.

Continuous withdrawal of hypophyseal portal blood from unrestrained sheep has permitted detailed assessments of the pulsatile secretion of gonadotrophin-releasing hormone (GnRH). To determine if this blood can also be used to characterize the sensory dynamics of pituitary hormones, patterns of luteinizing hormone (LH) in the hypophyseal portal blood of ovariectomized ewes was compared with previous patterns of GnRH and peripheral LH. Hypophyseal portal blood and jugular vein blood were collected every 5 min from six ovariectomized ewes over 6-12 h. Hypophyseal portal blood contained GnRH-associated, sharply defined LH pulses that were much larger than in the periphery. Pulses of secreted LH (hypophyseal portal LH less peripheral LH) showed much faster rates of rise and fall than peripheral and followed pulses of GnRH by an average of 1.26 min. In contrast to pulses in jugular blood, secreted LH pulses often reached a relatively unchanging interpulse nadir-plateau and thereby approached closely algorithm-estimated, extrapolated baselines. The interpulse baseline concentrations of secreted LH (99.6 ng/mL) in hypophyseal portal blood were 31-fold higher than those for jugular LH (3.23 ng/mL). These elevated concentrations also exceeded mean jugular peak concentrations (11.1 ng/mL) and, thus, primarily must represent newly secreted LH. The non-Gaussian profiles of this secreted LH were substantially more complex than the inputs predicted from jugular LH measurements by deconvolution. Furthermore, regardless of the analytical approach, estimations of the mass of secreted LH in each pulse did not correlate well with inputs predicted by deconvolution or Kushler-Brown pulsefit analysis of corresponding pulses in jugular blood (r2 ranging 0.40-0.48). Among alternative explanations is the possibility of heterogeneity in concentrations of GnRH in the portal vessels and variable distribution within the hypophysis. In summary, assay of hypophyseal portal blood obtained directly from the pituitary provides a method for direct assessment of secretory responses to hypothalamic peptides, and thereby serves as an unmatched method for studying the dynamics of LH secretion in vivo. With this approach, LH is revealed to be secreted as complex, non-Gaussian pulses that are far more sharply defined that those in the periphery, include non-GnRH-dependent, secretory components that cannot be predicted by deconvolution and are followed by periods of relatively constant, basal secretion.

Neuroendocrine control of follicle-stimulating hormone (FSH) secretion. I. Direct evidence for separate episodic and basal components of FSH secretion.

Continuous sampling of hypophyseal portal blood from unrestrained sheep is providing an unprecedented means for measuring and defining the characteristics of the secretory profile of GnRH. With this method, GnRH has been shown to be released in discrete pulses lasting 5-8 min, with the amplitude of some pulses exceeding 50-fold. Although the relationship between these pulses and the accompanying pulses of LH measured in the jugular vein are unambiguous, the relationship of GnRH pulses to the release of FSH has not been well defined due to the longer clearance of FSH. In previous studies we have shown that hypophyseal portal blood, in addition to serving as a source material for hypothalamic secretions, provides a means to define secretory patterns of pituitary hormones. Because of this we hypothesized that the GnRH-FSH secretory relationship would be easier to define in hypophyseal portal than in jugular vein blood before the secretory products are subjected to dispersion and clearance in circulation. To test this possibility, we monitored hormonal patterns in blood collected at 5-min intervals for 6-12 h from the peripheral and hypophyseal portal circulation of six ovariectomized ewes from a previous study. In contrast to the nonpulsatile pattern of FSH in the peripheral blood, 93% of the GnRH pulses were associated with essentially coincident, discrete pulses of FSH in the portal plasma. Of potentially even greater interest, additional episodes of FSH release were clearly discernible between the GnRH-associated pulses of FSH. As concentrations of peripheral plasma FSH did not reach those in hypophyseal portal plasma, the inter-GnRH episodes of FSH secretion could not result from contaminating peripheral blood. In addition to the episodic mode of secretion, substantial amounts of FSH were found between FSH pulses. This basal component of FSH appeared to be the dominant mode of secretion rather than pulses. The results of this study not only confirm that GnRH pulses lead to pulsatile release of FSH, they also suggest that some other mechanism or factor may be controlling the non-GnRH-associated episodes as well as the basal components of FSH secretion.

Multiplanar image reconstruction and 3D imaging using a musculoskeletal phantom: conventional versus helical CT.

PURPOSE: Our goal was to perform a detailed comparison of the relative performances of helical CT (pitches 1.0, 1.5, and 2.0) and conventional (overlapped and nonoverlapped) CT in detailed 3D and MPR musculoskeletal imaging. METHOD: A specially designed bone fragment phantom was imaged with multiple slice thicknesses using conventional (overlapped and nonoverlapped) and helical (varying pitch and slice index) CT. Studies were randomized, blinded, and graded using predetermined criteria by 10 radiologists. Statistical analysis included an assessment of raw image scores, a separate testing using duplicate copies of the conventional images as gold standards, and a multivariate model based upon the results of both scoring systems. RESULTS: When assessing raw scores of the images, conventional scans were consistently scored more favorably than helical studies. Decreasing the slice index improved conventional CT studies and helical studies with a pitch of 1.0, but showed no effect on helical studies with a pitch of > 1.0. When using the conventional studies as gold standards, the helical studies were consistently graded as poorer than conventional overlapped and nonoverlapped studies. CONCLUSION: For detailed musculoskeletal 3D and MPR work, helical CT may not adequately compare with conventional CT and offers no discernible advantage, particularly for pitches of > 1.0.

Does estradiol induce the preovulatory gonadotropin-releasing hormone (GnRH) surge in the ewe by inducing a progressive change in the mode of operation of the GnRH neurosecretory system.

Estradiol profoundly influences GnRH secretion during the follicular phase of the estrous cycle of the sheep. Estradiol not only regulates the frequency and amplitude of GnRH pulses, but also produces qualitative changes in its pattern of release and induces a sustained GnRH surge during which discrete pulses are not readily evident. In this study, we tested the hypothesis that qualitative changes in GnRH secretion are an integral part of an estradiol-induced change in the mode of operation of the GnRH neurosecretory system that leads to generation of the GnRH surge. This was achieved by the measurement of GnRH in samples of pituitary portal blood collected at 1-min intervals for an 11-h period encompassing the pre- and early surge periods in an artificial follicular phase model. In each of the seven ewes studied, a highly characteristic alteration in the moment to moment pattern of GnRH was observed. This consisted of a progressive change from a strictly episodic pattern of GnRH release to one containing both episodic and nonepisodic components and, after amplification of both components, a period of extremely high values during which individual episodic increases were no longer readily recognizable. Preliminary mathematical modeling of the data suggested that these patterns could be produced by a change in GnRH from a predominantly low to a mixture of low and high amplitude inputs. Similar changes in minute to minute patterns of GnRH secretion were observed during the natural follicular phase. These findings are consistent with the hypothesis that estradiol induces the GnRH surge by altering the mode of neurosecretion, rather than by merely causing quantitative changes in the episodic pattern of release.

Evidence for short or ultrashort loop negative feedback of gonadotropin-releasing hormone secretion.

The present studies tested the hypothesis that either short or ultrashort loop negative feedback regulation of gonadotropin-releasing hormone (GnRH) secretion occurs in the ewe. As part of ongoing studies investigating the regulation of follicle-stimulating-hormone secretion, we obtained the unexpected result that a GnRH antagonist (Nal-Glu) may stimulate GnRH secretion. In that experiment, hypophyseal portal blood was collected from five short-term ovariectomized ewes at 5-min intervals for 6 h before and 6 h after intravenous injection of Nal-Glu (10 micrograms/kg body weight). An increase in GnRH pulse frequency in association with the blockade of luteinizing hormone (LH) release was evident in 3 of the 5 animals. To determine if an effect of Nal-Glu on episodic GnRH secretion would be more evident in an animal model in which low-frequency pulses of GnRH prevail, the study was repeated in six ewes in the midluteal phase of the estrous cycle and six ovariectomized ewes bearing estradiol and progesterone implants to suppress GnRH release (artificial luteal model). In luteal-phase ewes, administration of Nal-Glu was followed by an increase in GnRH pulse frequency, pulse size and the secretion of GnRH between pulses, and by a blockade of LH release. In ovariectomized ewes treated with estradiol and progesterone, Nal-Glu administration also stimulated GnRH and inhibited LH secretion. Our finding that the GnRH antagonist stimulated GnRH secretion is consistent with the hypothesis that endogenous GnRH may influence its own release via either a short or ultrashort loop feedback mechanism.

A comparison of methods that characterize pulses in a time series.

There is general recognition that some glands secrete hormones primarily as a series of pulses. One can generally classify the proposed methods of pulse identification and characterization as either (i) criterion-based, that is, they use a criterion such as a test statistic to identify a rise and/or fall in hormone level within a moving window, or (ii) model-based, that is, they specify a statistical model for the time-varying portion of the signal and estimate its parameters. Using simulated data, we compare and contrast seven criterion-based methods and three model-based methods. The model-based methods perform better in estimating the parameters of interest; they are most effective with the sampling rate chosen so that there are 3-5 samples taken during the half-life of the hormone. At higher sampling rates the methods may overidentify pulses (false positives) and at lower sampling rates they may miss pulses (false negatives), both of which lead to biased estimates for the parameters of the signal.