Designed ankyrin repeat proteins: a new approach to mimic complex antigens for diagnostic purposes?

Inhibitory antibodies directed against coagulation factor VIII (FVIII) can be found in patients with acquired and congenital hemophilia A. Such FVIII-inhibiting antibodies are routinely detected by the functional Bethesda Assay. However, this assay has a low sensitivity and shows a high inter-laboratory variability. Another method to detect antibodies recognizing FVIII is ELISA, but this test does not allow the distinction between inhibitory and non-inhibitory antibodies. Therefore, we aimed at replacing the intricate antigen FVIII by Designed Ankyrin Repeat Proteins (DARPins) mimicking the epitopes of FVIII inhibitors. As a model we used the well-described inhibitory human monoclonal anti-FVIII antibody, Bo2C11, for the selection on DARPin libraries. Two DARPins were selected binding to the antigen-binding site of Bo2C11, which mimic thus a functional epitope on FVIII. These DARPins inhibited the binding of the antibody to its antigen and restored FVIII activity as determined in the Bethesda assay. Furthermore, the specific DARPins were able to recognize the target antibody in human plasma and could therefore be used to test for the presence of Bo2C11-like antibodies in a large set of hemophilia A patients. These data suggest, that our approach might be used to isolate epitopes from different sets of anti-FVIII antibodies in order to develop an ELISA-based screening assay allowing the distinction of inhibitory and non-inhibitory anti-FVIII antibodies according to their antibody signatures.

Efficacy of New Generation Antidepressants: Differences Seem Illusory

Background: Recently, Cipriani and colleagues examined the relative efficacy of 12 new-generation antidepressants on major depression using network meta-analytic methods. They found that some of these medications outperformed others in patient response to treatment. However, several methodological criticisms have been raised about network meta-analysis and Cipriani’s analysis in particular which creates the concern that the stated superiority of some antidepressants relative to others may be unwarranted. Materials and Methods: A Monte Carlo simulation was conducted which involved replicating Cipriani’s network metaanalysis under the null hypothesis (i.e., no true differences between antidepressants). The following simulation strategy was implemented: (1) 1000 simulations were generated under the null hypothesis (i.e., under the assumption that there were no differences among the 12 antidepressants), (2) each of the 1000 simulations were network meta-analyzed, and (3) the total number of false positive results from the network meta-analyses were calculated. Findings: Greater than 7 times out of 10, the network meta-analysis resulted in one or more comparisons that indicated the superiority of at least one antidepressant when no such true differences among them existed. Interpretation: Based on our simulation study, the results indicated that under identical conditions to those of the 117 RCTs with 236 treatment arms contained in Cipriani et al.’s meta-analysis, one or more false claims about the relative efficacy of antidepressants will be made over 70% of the time. As others have shown as well, there is little evidence in these trials that any antidepressant is more effective than another. The tendency of network meta-analyses to generate false positive results should be considered when conducting multiple comparison analyses.

A new method to facilitate valid and consistent grading cardiac events in childhood cancer survivors using medical records

BACKGROUND Cardiac events (CEs) are among the most serious late effects following childhood cancer treatment. To establish accurate risk estimates for the occurrence of CEs it is essential that they are graded in a valid and consistent manner, especially for international studies. We therefore developed a data-extraction form and a set of flowcharts to grade CEs and tested the validity and consistency of this approach in a series of patients. METHODS The Common Terminology Criteria for Adverse Events version 3.0 and 4.0 were used to define the CEs. Forty patients were randomly selected from a cohort of 72 subjects with known CEs that had been graded by a physician for an earlier study. To establish whether the new method was valid for appropriate grading, a non-physician graded the CEs by using the new method. To evaluate consistency of the grading, the same charts were graded again by two other non-physicians, one with receiving brief introduction and one with receiving extensive training on the new method. We calculated weighted Kappa statistics to quantify inter-observer agreement. RESULTS The inter-observer agreement was 0.92 (95% CI 0.80-1.00) for validity, and 0.88 (0.79-0.98) and 0.99 (0.96-1.00) for consistency with the outcome assessors who had the brief introduction and the extensive training, respectively. CONCLUSIONS The newly developed standardized method to grade CEs using data from medical records has shown excellent validity and consistency. The study showed that the method can be correctly applied by researchers without a medical background, provided that they receive adequate training.

Identification of a new genomic hot spot of evolutionary diversification of protein function.

Establishment of phylogenetic relationships remains a challenging task because it is based on computational analysis of genomic hot spots that display species-specific sequence variations. Here, we identify a species-specific thymine-to-guanine sequence variation in the Glrb gene which gives rise to species-specific splice donor sites in the Glrb genes of mouse and bushbaby. The resulting splice insert in the receptor for the inhibitory neurotransmitter glycine (GlyR) conveys synaptic receptor clustering and specific association with a particular synaptic plasticity-related splice variant of the postsynaptic scaffold protein gephyrin. This study identifies a new genomic hot spot which contributes to phylogenetic diversification of protein function and advances our understanding of phylogenetic relationships.

A New Multidisciplinary Home Care Telemedicine System to Monitor Stable Chronic Human Immunodeficiency Virus-Infected Patients: A Randomized Study

BACKGROUND: Antiretroviral therapy has changed the natural history of human immunodeficiency virus (HIV) infection in developed countries, where it has become a chronic disease. This clinical scenario requires a new approach to simplify follow-up appointments and facilitate access to healthcare professionals. METHODOLOGY: We developed a new internet-based home care model covering the entire management of chronic HIV-infected patients. This was called Virtual Hospital. We report the results of a prospective randomised study performed over two years, comparing standard care received by HIV-infected patients with Virtual Hospital care. HIV-infected patients with access to a computer and broadband were randomised to be monitored either through Virtual Hospital (Arm I) or through standard care at the day hospital (Arm II). After one year of follow up, patients switched their care to the other arm. Virtual Hospital offered four main services: Virtual Consultations, Telepharmacy, Virtual Library and Virtual Community. A technical and clinical evaluation of Virtual Hospital was carried out. FINDINGS: Of the 83 randomised patients, 42 were monitored during the first year through Virtual Hospital (Arm I) and 41 through standard care (Arm II). Baseline characteristics of patients were similar in the two arms. The level of technical satisfaction with the virtual system was high: 85% of patients considered that Virtual Hospital improved their access to clinical data and they felt comfortable with the videoconference system. Neither clinical parameters [level of CD4+ T lymphocytes, proportion of patients with an undetectable level of viral load (p = 0.21) and compliance levels >90% (p = 0.58)] nor the evaluation of quality of life or psychological questionnaires changed significantly between the two types of care. CONCLUSIONS: Virtual Hospital is a feasible and safe tool for the multidisciplinary home care of chronic HIV patients. Telemedicine should be considered as an appropriate support service for the management of chronic HIV infection. TRIAL REGISTRATION: Clinical-Trials.gov: NCT01117675.

New York, N.Y., subway and elevated railroad map, 1918 (Raster Image)

This layer is a georeferenced raster image of the historic paper map entitled: Map showing routes & stations on the dual system October, 1918. It was published by State of New York Public Service Commission for the First District in 1918. Scale [ca. 1:46,000]. Covers Manhattan, Queens, Brooklyn, and Bronx, New York, N.Y. The image inside the map neatline is georeferenced to the surface of the earth and fit to the Universal Transverse Mercator (UTM) Zone 18N NAD83 projection. All map collar and inset information is also available as part of the raster image, including any inset maps, profiles, statistical tables, directories, text, illustrations, index maps, legends, or other information associated with the principal map. This map shows features such as subway and elevated railroad lines and stations, drainage, and more. Includes inset: Sub Plan. Includes legend and key. This layer is part of a selection of digitally scanned and georeferenced historic maps from The Harvard Map Collection as part of the Imaging the Urban Environment project. Maps selected for this project represent major urban areas and cities of the world, at various time periods. These maps typically portray both natural and manmade features at a large scale. The selection represents a range of regions, originators, ground condition dates, scales, and purposes.

Report of the Public Service Commission of New Hampshire for the period ending ...

Report year for 1911 ends Nov. 30; for 1912 ends Aug. 31.

To have or to be--take your choice,

"First printing."

Das illustrirte Mississippithal : dargestellt in 80 nach der Natur aufgenommenen Ansichten vom Wasserfalle zu St. Anthony an bis zum Golf von Mexico (eine Entfernung von ungefähr 2300 englischen Meilen) /

Cf. Sabin 40807.

Analytic study no. 7. Public information and education.

National Highway Traffic Safety Administration, Washington, D.C.

Library journal.

Mar. 15 issues for 2009- include section: Movers & shakers, previously issued separately.

The use of computers in literature searching and related reference activities in libraries : papers presented at the 1975 Clinic on Library Applications of Data Processing, April 27-30, 1975 /

Includes bibliographical references.

Candy bibliography, January 1944 to July 1954,

Cover title.

A list of bibliographies useful in developing central library collections.

Mode of access: Internet.

Landmarks of Canada : What art has done for Canadian history; a guide to the J. Ross Robertson historical collection in the Public reference library, Toronto, Canada. This catalogue of the collection covers three thousand seven hundred illustrations and includes originals and reproductions in every form of art of all known pictures in connection with Canadian history from the landing of Wolfe at Louisburg in 1758 to the present time /

Includes brief biographical sketches of the subjects of the portraits in the collection.