Interpreting Clinical Reaction Time Change and Recovery After Concussion: A Baseline Versus Norm-Based Cutoff Score Comparison

ContextPreseason testing can be time intensive and cost prohibitive. Therefore, using normative data for postconcussion interpretation in lieu of preseason testing is desirable.ObjectiveTo establish the recovery trajectory for clinical reaction time (RT_clin) and assess the usefulness of changes from baseline (comparison of postconcussion scores with individual baseline scores) and norm-based cutoff scores (comparison of postconcussion scores with a normative mean) for identifying impairments postconcussion.DesignCase-control study.SettingMultisite clinical setting.Patients or Other ParticipantsAn overlapping sample of 99 participants (age = 19.0 ± 1.1 years) evaluated within 6 hours postconcussion, 176 participants (age = 18.9 ± 1.1 years) evaluated at 24 to 48 hours postconcussion, and 214 participants (age = 18.9 ± 1.1 years) evaluated once they were cleared to begin a return-to-play progression were included. Participants with concussion were compared with 942 control participants (age = 19.0 ± 1.0 years) who did not sustain a concussion during the study period but completed preseason baseline testing at 2 points separated by 1 year (years 1 and 2).Main Outcome Measure(s)At each time point, follow-up RT_clin (ie, postconcussion or year 2) was compared with the individual year 1 preseason baseline RT_clin and normative baseline data (ie, sex and sport specific). Receiver operating characteristic curves were calculated to compare the sensitivity and specificity of RT_clin change from baseline and norm-based cutoff scores.ResultsClinical reaction time performance declined within 6 hours (18 milliseconds, 9.2% slower than baseline). The decline persisted at 24 to 48 hours (15 milliseconds, 7.6% slower than baseline), but performance recovered by the time of return-to-play initiation. Within 6 hours, a change from baseline of 16 milliseconds maximized combined sensitivity (52%) and specificity (79%, area under the curve [AUC] = 0.702), whereas a norm-based cutoff score of 19 milliseconds maximized combined sensitivity (46%) and specificity (86%, AUC = 0.700). At 24 to 48 hours, a change from baseline of 2 milliseconds maximized combined sensitivity (64%) and specificity (61%, AUC = 0.666), whereas a norm-based cutoff score of 0 milliseconds maximized combined sensitivity (63%) and specificity (62%, AUC = 0.647).ConclusionsNorm-based cutoff scores can be used for interpreting RT_clin scores postconcussion in collegiate athletes when individual baseline data are not available, although low sensitivity and specificity limit the use of RT_clin as a stand-alone test.     

Genomic copy number determination in cancer cells from single nucleotide polymorphism microarrays based on quantitative genotyping corrected for aneuploidy

Microarrays are frequently used to profile genome-wide copy number (CN) aberrations. While generally robust for detecting CN variants in germline DNA, the methods used to derive CN from signal intensity values have been suboptimal when applied to cancer genomes. The complexity of genomic aberrations in cancer makes it more difficult to discriminate between signal and noise, and measuring CN as a discrete variable does not account for tumor heterogeneity. Furthermore, standard normalization approaches detect CN changes relative to the overall DNA content, which is often not diploid in cancer. We propose an algorithm that uses the degree of allelic imbalance as well as probe intensity, with a correction for aneuploidy, for a quantitative CN assessment and scoring of allelic ratios. This algorithm results in a more precise definition of CN and allelic aberration in the cancer genome, which is essential for translational efforts focused on using these tools for molecular diagnostics and for the discovery of therapeutic targets.     

Impact energy absorption of three mouthguard materials in three environments

Abstract – The objective of this study was to compare the impact energy absorption of three mouthguard materials in three environments. Thirty specimens with 12.7 cm × 12.7 cm × 4 mm dimensions were prepared for each material: ethylene vinyl acetate (EVA, T&S Dental and Plastics), Pro‐form? (Dental Resources Inc), and PolyShok? (Sportsguard Laboratories). Ten specimens of each material were conditioned for 1 h at 37°C in three environments: dry (ambient) condition, deionized water and artificial saliva. Specimens were impacted at 20 mph by a 0.5‐inch diameter indenter containing a force transducer (Dynatup Model 9250 HV, Instron Corp), based upon ASTM Standard D3763. Energy absorption was determined from the area under the force–time curve during impact (approximately 5 or 7 ms depending on the material). Groups were compared using anova and the Tukey test. Energy absorption values, normalized to specimen thickness (mean ± SD in J mm^?1), were: (i) Dry: EVA 4.73 ± 0.27, Pro‐form? 3.55 ± 0.25, PolyShok? 6.32 ± 0.24; (ii) DI water: EVA 4.82 ± 0.40, Pro‐form? 3.78 ± 0.33, PolyShok? 5.87 ± 0.38; (iii) Artificial saliva: EVA 5.63 ± 0.49, Pro‐form? 4.01 ± 0.54, PolyShok? 6.37 ± 0.55. PolyShok? was the most energy‐absorbent material in all three environments. EVA was significantly more impact resistant than Pro‐form? in all three environments. EVA and Pro‐form? performed significantly better after saliva conditioning than dry or water conditioned, but PolyShok? did not show any difference in energy absorption when conditioned in any of the three environments. Characteristic deformation patterns from impact loading were observed with an SEM for each material. The superior energy absorption for PolyShok? is attributed to the polyurethane additive.     

SIX2 and BMP4 mutations associate with anomalous kidney development

Renal hypodysplasia (RHD) is characterized by reduced kidney size and/or maldevelopment of the renal tissue following abnormal organogenesis. Mutations in renal developmental genes have been identified in a subset of affected individuals. Here, we report the first mutations in BMP4 and SIX2 identified in patients with RHD. We detected 3 BMP4 mutations in 5 RHD patients, and 3 SIX2 mutations in 5 different RHD patients. Overexpression assays in zebrafish demonstrated that these mutations affect the function of Bmp4 and Six2 in vivo. Overexpression of zebrafish six2.1 and bmp4 resulted in dorsalization and ventralization, respectively, suggesting opposing roles in mesendoderm formation. When mutant constructs containing the identified human mutations were overexpressed instead, these effects were attenuated. Morpholino knockdown of bmp4 and six2.1 affected glomerulogenesis, suggesting specific roles for these genes in the formation of the pronephros. In summary, these studies implicate conserved roles for Six2 and Bmp4 in the development of the renal system. Defects in these proteins could affect kidney development at multiple stages, leading to the congenital anomalies observed in patients with RHD.     

Molecular basis of cross-species reactivities of human versus porcine CTLA-4

The binding motif of human CTLA-4 is well known to be MYPPPY and for porcine CTLA-4 the binding motif is LYPPPY. Is this single amino acid difference of methionine (M) versus leucine (L) critical for the CTLA-4 binding? Recently, we have reported that the recombinant soluble porcine CTLA-4 was incapable of binding to human CD80. In this study we mutated L to M in the binding motif of the soluble porcine CTLA-4 and mutated M to L in the binding motif of the soluble human CTLA-4. We then analyzed how these mutations affected the binding affinity of the mutants to both porcine and human CD80⁺ cells. The soluble porcine CTLA-4-L97M mutant partially lost its binding affinity to porcine CD80 compared to the wild-type and conferred very weak binding ability to human CD80. These results indicate that the L in the binding motif of porcine CTLA-4 is important for determining its binding ability to porcine CD80. Wild-type soluble human CTLA-4 binds to both human and porcine CD80 with comparable affinity, however, the soluble human CTLA-4-M97L mutant almost lost its binding ability to human CD80 and increased its binding ability to porcine CD80. These results indicate that M in the human CTLA-4 binding motif is extremely critical for its binding to human CD80. Those data suggest that the human CTLA-4 based recombinant protein drugs such as human CTLA-4-Ig can be used and/or tested in a porcine model. Conversely, the use of porcine CTLA-4 based recombinant protein drugs such as porcine CTLA-4-Ig is restricted to swine models. The difference in binding specificity of CTLA-4 observed in this study may be useful for studies such as pig to nonhuman primate xeno-transplantation. Porcine CTLA-4- and human CTLA-4-M97L mutant-based recombinant protein drugs can be used to specifically block the direct presentation by donor antigen presenting cells in pig to nonhuman primate xeno-transplantation. Human CTLA-4-M97L mutant-based recombinant protein drugs will be more ideal as it is without immunogenicity to human being.