OCT Signs of Early Atrophy in Age-Related Macular Degeneration: Interreader Agreement: Classification of Atrophy Meetings Report 6.

PURPOSE: To determine the interreader agreement for incomplete retinal pigment epithelium (RPE) and outer retinal atrophy (iRORA) and complete RPE and outer retinal atrophy (cRORA) and their related features in age-related macular degeneration (AMD). DESIGN: Interreader agreement study. PARTICIPANTS: Twelve readers from 6 reading centers. METHODS: After formal training, readers qualitatively assessed 60 OCT B-scans from 60 eyes with AMD for 9 individual features associated with early atrophy and performed 7 different annotations to quantify the spatial extent of OCT features within regions of interest. The qualitative and quantitative features were used to derive the presence of iRORA and cRORA and also in an exploratory analysis to examine if agreement could be improved using different combinations of features to define OCT atrophy. MAIN OUTCOME MEASURES: Interreader agreement based on Gwet's first-order agreement coefficient (AC1) for qualitatively graded OCT features and classification of iRORA and cRORA, and smallest real difference (SRD) for quantitatively graded OCT features. RESULTS: Substantial or better interreader agreement was observed for all qualitatively graded OCT features associated with atrophy (AC1 = 0.63-0.87), except for RPE attenuation (AC1 = 0.46) and disruption (AC1 = 0.26). The lowest SRD for the quantitatively graded horizontal features was observed for the zone of choroidal hypertransmission (± 190.8 μm). Moderate agreement was found for a 3-category classification of no atrophy, iRORA, and cRORA (AC1 = 0.53). Exploratory analyses suggested a significantly higher level of agreement for a 3-category classification using (1) no atrophy; (2) presence of inner nuclear layer and outer plexiform layer subsidence, or a hyporeflective wedge-shaped band, as a less severe atrophic grade; and (3) the latter plus an additional requirement of choroidal hypertransmission of 250 μm or more for a more severe atrophic grade (AC1 = 0.68; P = 0.013). CONCLUSIONS: Assessment of iRORA and cRORA, and most of their associated features, can be performed relatively consistently and robustly. A refined combination of features to define early atrophy could further improve interreader agreement

Meeting Report: Validation of Toxicogenomics-Based Test Systems: ECVAM–ICCVAM/NICEATM Considerations for Regulatory Use

This is the report of the first workshop “Validation of Toxicogenomics-Based Test Systems” held 11–12 December 2003 in Ispra, Italy. The workshop was hosted by the European Centre for the Validation of Alternative Methods (ECVAM) and organized jointly by ECVAM, the U.S. Interagency Coordinating Committee on the Validation of Alternative Methods (ICCVAM), and the National Toxicology Program (NTP) Interagency Center for the Evaluation of Alternative Toxicological Methods (NICEATM). The primary aim of the workshop was for participants to discuss and define principles applicable to the validation of toxicogenomics platforms as well as validation of specific toxicologic test methods that incorporate toxicogenomics technologies. The workshop was viewed as an opportunity for initiating a dialogue between technologic experts, regulators, and the principal validation bodies and for identifying those factors to which the validation process would be applicable. It was felt that to do so now, as the technology is evolving and associated challenges are identified, would be a basis for the future validation of the technology when it reaches the appropriate stage. Because of the complexity of the issue, different aspects of the validation of toxicogenomics-based test methods were covered. The three focus areas include a) biologic validation of toxicogenomics-based test methods for regulatory decision making, b) technical and bioinformatics aspects related to validation, and c) validation issues as they relate to regulatory acceptance and use of toxicogenomics-based test methods. In this report we summarize the discussions and describe in detail the recommendations for future direction and priorities

The Utility of Continuous Passive Motion After Anterior Cruciate Ligament Reconstruction: A Systematic Review of Comparative Studies

Background: The application of continuous passive motion (CPM) after anterior cruciate ligament reconstruction (ACLR) was popularized in the 1990s, but advancements in the understanding of ACLR rehabilitation have made the application of CPM controversial. Many sports medicine fellowship–trained surgeons report using CPM machines postoperatively. Purpose: To determine the efficacy of CPM use for recovery after ACLR with respect to knee range of motion (ROM), knee swelling, postoperative pain, and postoperative complications. Study Design: Systematic review; Level of evidence, 3. Methods: The PubMed (MEDLINE), EMBASE, Cochrane, Cumulative Index of Nursing, and Allied Health Literature databases were searched from inception to January 1, 2020, for studies with evidence levels 1 to 3 on the use of CPM for ACLR rehabilitation. Included studies were those that comparatively evaluated postoperative outcomes after ACLR between at least 2 groups of patients, with 1 having received CPM rehabilitation and the other not having received CPM. Results: A total of 12 studies from 1989 to 2019 met the inclusion criteria. These studies included 808 patients who underwent ACLR. There was no evidence of CPM improving knee stability, final postoperative ROM, or subjective pain scores. Additionally, CPM did not lead to decreased muscle atrophy or improved International Knee Documentation Committee scores. Regarding pain medication intake during postoperative hospitalization, 2 studies found that the CPM group used less pain medication, 1 study found the CPM group used more pain medication, and 1 study found that there was no difference between the 2 groups. Complications varied widely, with 2 of 12 studies reporting complications that required a return to the operating room. Conclusion: A clinical benefit of postoperative CPM use after ACLR was not identified in this review. While our systematic review identified a number of studies that suggest CPM use may be associated with lower usage of pain medication in hospitalized patients, this cannot be confirmed without further investigation with standardized CPM protocols and larger sample sizes. Routine CPM use after ACLR was not supported by this systematic review

Exploring protein myristoylation in Toxoplasma gondii

Toxoplasma gondii is an important human and veterinary pathogen and the causative agent of toxoplasmosis, a potentially severe disease especially in immunocompromised or congenitally infected humans. Current therapeutic compounds are not well-tolerated, present increasing resistance, limited efficacy and require long periods of treatment. On this context, searching for new therapeutic targets is crucial to drug discovery. In this sense, recent works suggest that N-myristoyltransferase (NMT), the enzyme responsible for protein myristoylation that is essential in some parasites, could be the target of new anti-parasitic compounds. However, up to date there is no information on NMT and the extent of this modification in T. gondii. In this work, we decided to explore T. gondii genome in search of elements related with the N-myristoylation process. By a bioinformatics approach it was possible to identify a putative T. gondii NMT (TgNMT). This enzyme that is homologous to other parasitic NMTs, presents activity in vitro, is expressed in both intra- and extracellular parasites and interacts with predicted TgNMT substrates. Additionally, NMT activity seems to be important for the lytic cycle of Toxoplasma gondii. In parallel, an in silico myristoylome predicts 157 proteins to be affected by this modification. Myristoylated proteins would be affecting several metabolic functions with some of them being critical for the life cycle of this parasite. Together, these data indicate that TgNMT could be an interesting target of intervention for the treatment of toxoplasmosis.Fil: Alonso, Andrés Mariano. Universidad Nacional de San Martin. Instituto Tecnológico de Chascomús - Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Instituto Tecnológico de Chascomús; Argentina. Universidad Nacional de La Plata. Centro Regional de Estudios Genómicos; ArgentinaFil: Turowski, Valeria Rosana. Universidad Nacional de La Plata. Centro Regional de Estudios Genómicos; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata; ArgentinaFil: Ruiz, Diego Mario. Universidad Nacional de La Plata. Centro Regional de Estudios Genómicos; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata; ArgentinaFil: Orelo, Barbara D.. The Scripps Research Institute; Estados UnidosFil: Moresco, James J.. The Scripps Research Institute; Estados UnidosFil: Yates, John R.. The Scripps Research Institute; Estados UnidosFil: Corvi, Maria Martha. Universidad Nacional de San Martin. Instituto Tecnológico de Chascomús - Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Instituto Tecnológico de Chascomús; Argentin

Validation of Toxicogenomics-Based Test Systems:ECVAM-ICCVAM/NICEATM Considerations for Regulatory Use

This is the report of the first workshop on the Validation of Toxicogenomics-based Test Systems held in Ispra, Italy on 11-12 December 2003. The workshop was hosted by the European Centre for the Validation of Alternative Methods (ECVAM) and organized jointly by ECVAM, the U.S. Interagency Coordinating Committee on the Validation of Alternative Methods (ICCVAM), and the National Toxicology Program (NTP) Interagency Center for the Evaluation of Alternative Toxicological Methods (NICEATM). The primary aim of the workshop was to discuss and define principles applicable to the validation of toxicogenomics platforms as well as validation of specific toxicological test methods that incorporate toxicogenomics technologies. The workshop was viewed as an opportunity for initiating a dialogue between technological experts, regulators, and the principal validation bodies, and for identifying those factors to which the validation process would be applicable. It was felt that to do so now, as the technology is evolving and associated challenges are identified, would serve as the basis for the future validation of the technology when it reached the appropriate stage. Due to the complexity of the issue, different aspects of the validation of toxicogenomics-based test methods were covered. The three focus areas included (a) biological validation of toxicogenomics-based test methods for regulatory decision-making, (b) technical and bioinformatics aspects related to validation, and (c) validation issues as they relate to regulatory acceptance and utilization of toxicogenomics-based test methods. This report summarizes the discussions and details the recommendations for future direction and priorities.JRC.I.2-Validation of biomedical testing method