The Type II Error Probability of a Group Sequential Test of Efficacy and Futility,and Considerations for Power and Sample Size

For a clinical trial incorporating a group sequential test that allows early stopping for efficacy or futility (GSTEF), the primary hypothesis concerns efficacy. However, the type II error probability of the tests of efficacy is neither specified nor known. The type II error probability of a GSTEF is partitioned into the sum of its component type II error probabilities of futility and efficacy. This partitioning provides transparency, allowing researchers flexibility to set these component error probabilities directly and to know the impact on the total type II error probability and vice versa. This transparency and flexibility should improve the application of GSTEF to clinical trials.     

Biplane Correlation Imaging: A Feasibility Study Based on Phantom and Human Data

The objective of this study was to implement and evaluate the performance of a biplane correlation imaging (BCI) technique aimed to reduce the effect of anatomic noise and improve the detection of lung nodules in chest radiographs. Seventy-one low-dose posterior–anterior images were acquired from an anthropomorphic chest phantom with 0.28° angular separations over a range of ±10° along the vertical axis within an 11 s interval. Similar data were acquired from 19 human subjects with institutional review board approval and informed consent. The data were incorporated into a computer-aided detection (CAD) algorithm in which suspect lesions were identified by examining the geometrical correlation of the detected signals that remained relatively constant against variable anatomic backgrounds. The data were analyzed to determine the effect of angular separation, and the overall sensitivity and false-positives for lung nodule detection. The best performance was achieved for angular separations of the projection pairs greater than 5°. Within that range, the technique provided an order of magnitude decrease in the number of false-positive reports when compared with CAD analysis of single-view images. Overall, the technique yielded ~1.1 false-positive per patient with an average sensitivity of 75%. The results indicated that the incorporation of angular information can offer a reduction in the number of false-positives without a notable reduction in sensitivity. The findings suggest that the BCI technique has the potential for clinical implementation as a cost-effective technique to improve the detection of subtle lung nodules with lowered rate of false-positives.     

Comparing retrospective reports to real-time/real-place mobile assessments in individuals with schizophrenia and a nonclinical comparison group

Retrospective reports are often used as the primary source of information for important diagnostic decisions, treatment, and clinical research. Whether such reports accurately represent individuals' past experiences in the context of a serious mental illness such as schizophrenia is unclear. In the current study, 24 individuals with schizophrenia and 26 nonclinical participants used a mobile device to complete multiple real-time/real-place assessments daily, over 7 consecutive days. At the end of the week, participants were also asked to provide a retrospective report summarizing the same period. Comparison of the data captured by the 2 methods showed that participants from both groups retrospectively overestimated the intensity of negative and positive daily experiences. In the clinical group, overestimations for affect were greater than for psychotic symptoms, which were relatively comparable to their retrospective reports. In both samples, retrospective reports were more closely associated with the week's average than the most intense or most recent ratings captured with a mobile device. Multilevel modeling revealed that much of the variability in weekly assessments was not explained by between-person differences and could not be captured by a single retrospective estimate. Based on the findings of this study, clinicians and researchers should be aware that while retrospective summary reports of the severity of certain symptoms compare relatively well with average momentary ratings, they are limited in their ability to capture variability in one's affective or psychotic experiences over time.     

Systematic mechanism-orientated approach to chronic pancreatitis pain

Pain in chronic pancreatitis(CP) shows similarities with other visceral pain syndromes(i.e.,inflammatory bowel disease and esophagitis),which should thus be managed in a similar fashion.Typical causes of CP pain include increased intrapancreatic pressure,pancreatic inflammation and pancreatic/extrapancreatic complications.Unfortunately,CP pain continues to be a major clinical challenge.It is recognized that ongoing pain may induce altered central pain processing,e.g.,central sensitization or pro-nociceptive pain modulation.When this is present conventional pain treatment targeting the nociceptive focus,e.g.,opioid analgesia or surgical/endoscopic intervention,often fails even if technically successful.If central nervous system pain processing is altered,specific treatment targeting these changes should be instituted(e.g.,gabapentinoids,ketamine or tricyclic antidepressants).Suitable tools are now available to make altered central processing visible,including quantitative sensory testing,electroencephalograpy and(functional) magnetic resonance imaging.These techniques are potentially clinically useful diagnostic tools to analyze central pain processing and thus define optimum management approaches for pain in CP and other visceral pain syndromes.The present review proposes a systematic mechanism-orientated approach to pain management in CP based on a holistic view of the mechanisms involved.Future research should address the circumstances under which central nervous system pain processing changes in CP,and how this is influenced by ongoing nociceptive input and therapies.Thus we hope to predict which patients are at risk for developing chronic pain or not responding to therapy,leading to improved treatment of chronic pain in CP and other visceral pain disorders.     

Mechanism of intestinal secretion: effect of cyclic AMP on rabbit ileal crypt and villus cells.

Cyclic AMP-dependent secretagogues such as cholera toxin inhibit the coupled absorption of Na+ and Cl- and stimulate the secretion of HCO3- and Cl- in the ileum. Aside from Cl- secretion, little is known about the mechanism of these cyclic AMP-mediated effects. We therefore determined the effect of forskolin, an agent known to increase intracellular cyclic AMP by stimulation of adenylyl cyclase, on Na+/H+ and Cl-/HCO3- exchange in isolated crypt and villus cells from rabbit ileum. Forskolin increased cyclic AMP in the villus cells and decreased intracellular pH. The effect of forskolin on pH in villus cells was HCO3- independent, Na+ dependent, and amiloride sensitive. Further, the rate of recovery from an acid load was decreased by forskolin. These data suggest that increasing cyclic AMP inhibits Na+/H+ exchange in villus cells. In crypt cells also, forskolin increased cyclic AMP; however, forskolin increased intracellular pH in these cells. The effect of forskolin in crypt cells was also HCO3- independent, Na+ dependent, and amiloride sensitive. However, the rate of recovery from an acid load was increased by forskolin, the opposite effect of that seen in villus cells. These data suggest that increasing cyclic AMP in crypt cells stimulates Na+/H+ exchange. Inhibition of Na+/H+ exchange on the brush border membrane in villus cells would be expected to inhibit coupled NaCl absorption (which occurs by coupling of Na+/H+ and Cl-/HCO3- exchange). Stimulation of Na+/H+ exchange in crypt cells, present only on the basolateral membrane, alkalinizes the cell, which would be expected to stimulate HCO3- secretion by stimulating the Cl-/HCO3- exchanger on the brush border membrane. Thus, these results provide a mechanism for some of the previously unexplained in vivo and in vitro effects of cyclic AMP on ileal electrolyte transport.     

Immunohistological characterization of intraepithelial and lamina propria lymphocytes in control ileum and colon and in inflammatory bowel disease

Using monoclonal antibodies to T and B lymphocytes, to natural killer cells, and to HLA-DR antigen, we characterized the lymphocyte population within the epithelial and lamina propria regions in control intestine and colon, and in grossly involved and in grossly uninvolved intestine and colon of patients with active inflammatory bowel disease. There were significantly more intraepithelial T cells in control ileum than in control colon. In comparison to control, there was a heterogeneity of alterations in intraepithelial and lamina propria T lymphocyte subsets (T11⁺, T8⁺, T4⁺) in inflammatory bowel disease. B lymphocytes were not detected within the lamina propria, except when found in and adjacent to lymphoid aggregates. Leu 7⁺ cells were uncommon in the lamina propria of control ileum and colon and in diseased tissues. The majority of intraepithelial lymphocytes did not express HLA-DR. Epithelial cells of control colon did not express HLA-DR while epithelial cells of control ileal tissues and of diseased colonic and ileal specimens expressed HLA-DR antigen. Only small numbers of lamina propria T cells expressed HLA-DR in both control and disease tissues. There was intense expression of HLA-DR by monocytes and modest expression of HLA-DR by capillary and lymphatic endothelial cells. The induction of HLA-DR expression by diseased colonic epithelium and the observation that lymphatic endothelium expresses HLA-DR are new observations, and we established that Leu 7⁺ cells are present in very small numbers in both normal and diseased intestine and colon.Supported by funding from the National Foundation for Ileitis and Colitis and by Merit Review funds from the Veterans Administration.     

Studies of the rectal mucosa in coeliac sprue: the intraepithelial lymphocyte.

The dynamics of the rectal surface epithelial lymphocyte and leucocyte response to wheat, gluten, and gliadin enema challenges in control individuals and in patients with coeliac sprue in remission is shown. There is a clear increase in intraepithelial lymphocytes and polymorphonuclear (PMN) leucocytes in response to these enemas in coeliac sprue, but not in controls. The peak response was at eight hours and cleared within 24 hours. There was no change in the crypt epithelium. These data add further support to the role of wheat, gluten, and gliadin in the pathogenesis of coeliac sprue, at least in the rectal mucosa.     

Digital beam attenuator technique for compensated chest radiography

The feasibility of producing patient-specific beam attenuators for chest radiography has been investigated using an anthropomorphic phantom and a human volunteer. A low-dose test exposure is digitized, processed, and used to print a small cerium filter, which is placed in the x-ray beam near the collimator. The final radiograph is recorded on film. The technique results in relatively uniform film exposure, so that structures in all regions of the chest are simultaneously displayed with optimal film contrast. The equalized exposure improves image quality in the normally underpenetrated regions and reduces the role of cross-scatter from the lungs. The image is analogous to optical or computer-processed unsharp masking techniques, but the processing is accomplished in the x-ray beam and results in an improved exposure distribution, giving advantages that cannot be achieved with image processing techniques alone.