319 research outputs found
Adoptive transfer of cytomegalovirus-specific CTL to stem cell transplant patients after selection by HLA–peptide tetramers
Stem cell transplantation is used widely in the management of a range of diseases of the hemopoietic system. Patients are immunosuppressed profoundly in the early posttransplant period, and reactivation of cytomegalovirus (CMV) remains a significant cause of morbidity and mortality. Adoptive transfer of donor-derived CMV-specific CD8(+) T cell clones has been shown to reduce the rate of viral reactivation; however, the complexity of this approach severely limits its clinical application. We have purified CMV-specific CD8(+) T cells from the blood of stem cell transplant donors using staining with HLA-peptide tetramers followed by selection with magnetic beads. CMV-specific CD8(+) cells were infused directly into nine patients within 4 h of selection. Median cell dosage was 8.6 x 10(3)/kg with a purity of 98% of all T cells. CMV-specific CD8(+) T cells became detectable in all patients within 10 d of infusion, and TCR clonotype analysis showed persistence of infused cells in two patients studied. CMV viremia was reduced in every case and eight patients cleared the infection, including one patient who had a prolonged history of CMV infection that was refractory to antiviral therapy. This novel approach to adoptive transfer has considerable potential for antigen-specific T cell therapy
Money in monetary policy design: monetary cross-checking in the New-Keynesian model
In the New-Keynesian model, optimal interest rate policy under uncertainty is formulated without reference to monetary aggregates as long as certain standard assumptions on the distributions of unobservables are satisfied. The model has been criticized for failing to explain common trends in money growth and inflation, and that therefore money should be used as a cross-check in policy formulation (see Lucas (2007)). We show that the New-Keynesian model can explain such trends if one allows for the possibility of persistent central bank misperceptions. Such misperceptions motivate the search for policies that include additional robustness checks. In earlier work, we proposed an interest rate rule that is near-optimal in normal times but includes a cross-check with monetary information. In case of unusual monetary trends, interest rates are adjusted. In this paper, we show in detail how to derive the appropriate magnitude of the interest rate adjustment following a significant cross-check with monetary information, when the New-Keynesian model is the central bank’s preferred model. The cross-check is shown to be effective in offsetting persistent deviations of inflation due to central bank misperceptions. Keywords: Monetary Policy, New-Keynesian Model, Money, Quantity Theory, European Central Bank, Policy Under Uncertaint
Computer-assisted mitotic count using a deep learning–based algorithm improves interobserver reproducibility and accuracy
The mitotic count (MC) is an important histological parameter for prognostication of malignant neoplasms. However, it has inter- and intraobserver discrepancies due to difficulties in selecting the region of interest (MC-ROI) and in identifying or classifying mitotic figures (MFs). Recent progress in the field of artificial intelligence has allowed the development of high-performance algorithms that may improve standardization of the MC. As algorithmic predictions are not flawless, computer-assisted review by pathologists may ensure reliability. In the present study, we compared partial (MC-ROI preselection) and full (additional visualization of MF candidates and display of algorithmic confidence values) computer-assisted MC analysis to the routine (unaided) MC analysis by 23 pathologists for whole-slide images of 50 canine cutaneous mast cell tumors (ccMCTs). Algorithmic predictions aimed to assist pathologists in detecting mitotic hotspot locations, reducing omission of MFs, and improving classification against imposters. The interobserver consistency for the MC significantly increased with computer assistance (interobserver correlation coefficient, ICC = 0.92) compared to the unaided approach (ICC = 0.70). Classification into prognostic stratifications had a higher accuracy with computer assistance. The algorithmically preselected hotspot MC-ROIs had a consistently higher MCs than the manually selected MC-ROIs. Compared to a ground truth (developed with immunohistochemistry for phosphohistone H3), pathologist performance in detecting individual MF was augmented when using computer assistance (F1-score of 0.68 increased to 0.79) with a reduction in false negatives by 38%. The results of this study demonstrate that computer assistance may lead to more reproducible and accurate MCs in ccMCTs
Nuclear Morphometry using a Deep Learning-based Algorithm has Prognostic Relevance for Canine Cutaneous Mast Cell Tumors
Variation in nuclear size and shape is an important criterion of malignancy
for many tumor types; however, categorical estimates by pathologists have poor
reproducibility. Measurements of nuclear characteristics (morphometry) can
improve reproducibility, but manual methods are time consuming. In this study,
we evaluated fully automated morphometry using a deep learning-based algorithm
in 96 canine cutaneous mast cell tumors with information on patient survival.
Algorithmic morphometry was compared with karyomegaly estimates by 11
pathologists, manual nuclear morphometry of 12 cells by 9 pathologists, and the
mitotic count as a benchmark. The prognostic value of automated morphometry was
high with an area under the ROC curve regarding the tumor-specific survival of
0.943 (95% CI: 0.889 - 0.996) for the standard deviation (SD) of nuclear area,
which was higher than manual morphometry of all pathologists combined (0.868,
95% CI: 0.737 - 0.991) and the mitotic count (0.885, 95% CI: 0.765 - 1.00). At
the proposed thresholds, the hazard ratio for algorithmic morphometry (SD of
nuclear area ) was 18.3 (95% CI: 5.0 - 67.1), for manual
morphometry (SD of nuclear area ) 9.0 (95% CI: 6.0 - 13.4),
for karyomegaly estimates 7.6 (95% CI: 5.7 - 10.1), and for the mitotic count
30.5 (95% CI: 7.8 - 118.0). Inter-rater reproducibility for karyomegaly
estimates was fair ( = 0.226) with highly variable
sensitivity/specificity values for the individual pathologists. Reproducibility
for manual morphometry (SD of nuclear area) was good (ICC = 0.654). This study
supports the use of algorithmic morphometry as a prognostic test to overcome
the limitations of estimates and manual measurements
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