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Objectives: Autoimmune hepatitis (AIH) is a progressive liver disease managed with corticosteroids and immunosuppression and monitored using a combination of liver biochemistry and histology. However, liver biopsy is invasive with risk of pain and bleeding. The aim of the present study was to investigate the utility of noninvasive imaging with multiparametric magnetic resonance imaging (MRI) (mpMRI) to provide clinically useful information on the presence and extent of hepatic inflammation, potentially guiding immunosuppression., Methods: Eighty-one participants (aged 6-18), 21 healthy and 60 AIH patients, underwent multiparametric MRI to measure fibro-inflammation with iron-corrected T1 (cT1) at the Children's Memorial Health Institute in Warsaw alongside other clinical blood tests and liver biopsy at recruitment and after an average of 16-month follow-up (range 9-22 months). Correlation analyses were used to investigate the associations between cT1 with blood serum markers and histological scores., Results: At recruitment, patients with AIH had a higher cT1 value than healthy controls (P < 0.01). cT1 correlated significantly with key histopathological features of disease. Treatment naïve AIH patients showed evidence of inflammation and heterogeneity across the liver compared to healthy controls.At follow-up, cT1 showed utility in monitoring disease regression as most patients showed significantly reduced fibro-inflammation with treatment (P < 0.0001) over the observational period. Six patients had histological fibrosis and clear fibro-inflammation on MR despite biochemical remission (normalized aspartate aminotransferase (AST), alanine aminotransferase (ALT), and immunoglobulin G [IgG])., Conclusions: Multiparametric MRI can measure disease burden in pediatric AIH and can show changes over time in response to therapy. Active disease can be seen even in biochemical remission in children., Competing Interests: The authors report no conflicts of interest., (Copyright © 2020 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the European Society for Pediatric Gastroenterology, Hepatology, and Nutrition and the North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition.)

The use of centralized raters who are remotely linked to sites and interview patients via videoconferencing or teleconferencing has been suggested as a way to improve interrater reliability and interview quality. This study compared the effect of site-based and centralized ratings on patient selection and placebo response in subjects with major depressive disorder. Subjects in a 2-center placebo and active comparator controlled depression trial were interviewed twice at each of 3 time points: baseline, 1-week postbaseline, and end point--once by the site rater and once remotely via videoconference by a centralized rater. Raters were blind to each others' scores. A site-based score of greater than 17 on the 17-item Hamilton Depression Rating Scale (HDRS-17) was required for study entry. When examining all subjects entering the study, site-based raters' HDRS-17 scores were significantly higher than centralized raters' at baseline and postbaseline but not at end point. At baseline, 35% of subjects given an HDRS-17 total score of greater than 17 by a site rater were given an HDRS total score of lower than 17 by a centralized rater and would have been ineligible to enter the study if the centralized rater's score was used to determine study entry. The mean placebo change for site raters (7.52) was significantly greater than the mean placebo change for centralized raters (3.18, P < 0.001). Twenty-eight percent were placebo responders (>50% reduction in HDRS) based on site ratings versus 14% for central ratings (P < 0.001). When examining data only from those subjects whom site and centralized raters agreed were eligible for the study, there was no significant difference in the HDRS-17 scores. Findings suggest that the use of centralized raters could significantly change the study sample in a major depressive disorder trial and lead to significantly less change in mood ratings among those randomized to placebo.

Efforts to improve the Hamilton Rating Scale for Depression (HRSD) have included shortening the scale by selecting the best performing items, lengthening the scale by assessing additional symptoms, modifying the format and scoring of existing items, and developing structured interview guides for administration. We defined item performance exclusively in terms of the ability of items to discriminate differences among levels of depressive severity which has not be used to guide any revisions of the HRSD conducted to date. Two techniques derived from item response theory were used to improve the ability of the HRSD to discriminate among individuals with different degrees of depressive severity. Item response curves were used to quantify the ability of items to discriminate among individual differences in depressive severity, on the basis of which the most discriminating items were selected. Maximum likelihood estimates were used to compute an optimal depressive severity score, using all items, but which weighted highly discriminating items more so than items that did not discriminate well. The utility of each method was evaluated by comparing a subset of optimally discriminating items and maximum likelihood estimates of depressive severity to the Maier Philipp subscale of the HRSD, in terms of how well scales discriminate treatment effects. Effect sizes for overall change in depression severity as well as effect sizes differentiating response to treatment versus placebo were evaluated in a sample of 491 patients receiving fluoxetine and 494 patients receiving placebo. Results of analyses identified a new subset of items (IRT-6), selected on the basis of their ability to discriminate among differences in depressive severity, that accounted for more variance in full-scale HRSD scores and was better at detecting change in illness severity than the Maier Philipp subscale of the HRSD. The IRT-6 subscale was equally good as the Maier Philipp subscale in differentiating treatment from placebo response. No evidence supporting the benefits of using maximum likelihood estimates to develop optimally performing subscales was found. Implications of the results are discussed in terms of strategies for optimizing the assessment of change in overall depression severity as well as differentiating treatment response., ((c) 2007 Wiley-Liss, Inc.)

Aims: To distinguish the most sensitive markers of methylphenidate (MPH) effects on behavior and underlying biology using an integrated cognitive and brain function test battery., Methods: A randomized placebo-controlled trial with 32 healthy adult males. Subjects were tested on MPH doses across 18 sessions with subjective mood, objective behavioral and biological endpoints. From a computerized battery of tests, behavioral measures were cognitive performance scores, while biological measures of brain function included electroencephalographs (EEG) and event-related potentials (ERPs) with complementary measures of autonomic arousal. Using mixed modeling analyses; we determined which measures were most affected by MPH dose and correlation analyses determined the associations among them., Results: MPH dose had the most pronounced effect on cognitive performance (sustained attention/vigilance), baseline autonomic arousal (heart rate, blood pressure) and baseline brain activity (EEG theta power). The faster reaction time, reduced errors, increased autonomic arousal and reductions in theta showed strong to moderate inter-correlations. MPH least affected subjective mood measures and early sensory ERP components., Discussion: These findings suggest that MPH increases cortical and autonomic arousal, facilitating vigilance. The combination of behavioral and biological measures may provide an objective set of markers of MPH response., Integrative Significance: This approach has provided additional insight into the mechanism of the stimulant medication, MPH, which would not be achieved by using such measures in isolation.

The effects of methylphenidate (MPH) on 32 healthy human male volunteers (aged 18 to 25 years, mean age=22.26) were examined using a within-subject design. Each participant attended six testing periods, held once per week. Within each testing period, three repeat testing sessions were undertaken: pre-medication, on-medication and two hours post-medication. In these sessions, dose was manipulated (placebo, 5 mg, 15 mg or 45 mg) according a double-blind placebo design. In this report, we focus on behavioral, autonomic arousal (heart rate, skin conductance) and psychophysiological (ERP) data acquired during the working memory task. We found increased autonomic arousal (heart rate, skin conductance and blood pressure) with MPH. A linear reduction in reaction time, omission errors and target P3 latency, and a corresponding increase in background P3 amplitude was observed with increased MPH dose. The relationship between these measures supported an increase in performance and underlying brain function with MPH. To our knowledge, this is the first paper to use behavioral, arousal and electrophysiological measures in an integrative approach to study the effects of MPH on healthy adults.

Objective: Lanepitant selectively blocks substance P binding to the neurokinin-1 receptor, preventing neurogenic inflammation and pain transmission. Substance P is present in synovial fluid and in excess in cerebral spinal fluid. We investigated the effect of lanepitant on pain caused by osteoarthritis to evaluate the role of neurokinin-1 blockade., Methods: Outpatients (n = 214) with moderate to severe lower-limb osteoarthritis pain were treated for 3 weeks in a parallel, randomized double-blind study with initial doses of 20, 60, 200, or 600 mg lanepitant, 375 mg naproxen, or placebo, followed by 10, 30, 100, or 300 mg lanepitant twice a day, 375 mg naproxen twice a day, or placebo twice a day in the multiple-dose period. Pain intensity, pain relief, patient global impression, and adjunctive analgesic use were compared across treatments. Safety was evaluated with adverse events, vital signs, and laboratory assessments., Results: There was no statistically significant difference in efficacy or safety across treatments for the initial dose assessment. After 1 week of therapy, naproxen was statistically significantly (P < .05) better than placebo and lanepitant in reducing average pain. During the second and third weeks of therapy, patients receiving naproxen continued to have statistically significantly (P < .05) less pain than those receiving placebo or lanepitant despite using significantly less adjunctive analgesic medication. There were no statistically significant differences in rates of discontinuation across treatments. Lanepitant treatment was associated with diarrhea, whereas naproxen treatment was associated with gastric discomfort. There were no clinically relevant changes in vital signs or laboratory analytes for any of the treatments., Conclusion: Lanepitant was ineffective in relieving osteoarthritis pain, possibly because neurokinin-1 binding of substance P does not play a significant role in osteoarthritis pain or because lanepitant fails to adequately penetrate the blood-brain barrier to affect central pain perception.

In the study of depression, most randomized clinical trials have design features that attempt to sample from a stable patient population. One commonly used design feature is to require patients to maintain some minimum baseline symptom severity score during a placebo lead-in period. One intent of this design feature is to evaluate the behavior of patients prior to administration of active medication. If, during the lead-in period, patients do not maintain minimum symptom severity, the patients are excluded from the remainder of the study, the theory being that the excluded patients are not part of a stable patient population and hence are not likely to demonstrate efficacy of a truly effective treatment. This presentation investigates the effectiveness of a restrictive entry criterion and proposes an alternative explanation for what is usually defined as placebo response.

In clinical studies of antidepressants, the Hamilton Depression Rating Scale (HAMD) total score has been the gold standard instrument for establishing and comparing the efficacy of new treatments. However, the HAMD is a multidimensional measure, which may reduce its ability to detect differences between treatments, in particular, changes in core symptoms of depression. Two meta-analyses were conducted to compare the responsiveness of the HAMD total score with several published unidimensional subscale scores based upon core symptoms of depression. The first compared the above instrument's ability to detect differences between fluoxetine and placebo across eight studies involving over 1600 patients. The second analysis involved four studies and over 1200 patients randomized to tricyclic antidepressants and placebo. In both meta-analyses, the unidimensional core subscales outperformed the HAMD total score at detecting treatment differences. The implications of this on sample sizes and power for clinical studies will be discussed. In fact, studies based on the observed effect sizes from the core subscales would require approximately one-third less patients than studies based on the HAMD total score. Effect sizes from each individual HAMD item will also be presented to help explain the differences in responsiveness between the scales.

The implementation of a multisite, randomized, clinical psychopharmacologic trial involves a substantial investment of time and effort on the part of all participants. Because of their complexity, such clinical trials present unique methodological and design challenges. Indeed, it is not uncommon for such studies to conclude with uninterpretable results, due in part to such methodological pitfalls. It has been suggested that clarification of such methodologic dilemmas is one of the most important challenges facing the future of industry-sponsored psychopharmacologic drug development. Among the many factors that may contribute to problematic clinical trial results, error in measuring the phenomena being studied is of particular concern. In this article, we describe the outcome of an intensive series of interrater reliability training sessions for the 17-item Hamilton Depression Rating Scale conducted at the start of a Phase II multisite clinical drug trial. The data underscore the magnitude of error present in such a test setting and provide preliminary evidence for the potential effect of this problem on the detection of clinical change.

The care of patients is an information-intensive activity in which a large number of decisions must be made. Through the support of more rapid, less expensive, and better decisions, workstations can contribute positively to the science, the art, and the economics of health-care. They have greatest potential value when they have access to a large amount of information relevant to the decisions which must be made jointly by patients and their care providers. Technological and psychological barriers to the acceptance of workstations are becoming increasingly surmountable. Workstations may increase patients' satisfaction with the care they are provided, reduce the total cost of care, and reduce the cost of clinical information to third parties, by economically enabling comprehensive, up-to-date, and accurate medical records from which information can be rapidly and cheaply extracted and made accessible to all who need to use it.