Huntington's disease (HD) is a fatal neurodegenerative disease caused by expansion of CAG repeats in the Huntingtin gene (). Neither its pathogenic mechanisms nor the normal functions of HTT are well understood. To model HD in humans, we engineered a genetic allelic series of isogenic human embryonic stem cell (hESC) lines with graded increases in CAG repeat length. Neural differentiation of these lines unveiled a novel developmental HD phenotype: the appearance of giant multinucleated telencephalic neurons at an abundance directly proportional to CAG repeat length, generated by a chromosomal instability and failed cytokinesis over multiple rounds of DNA replication. We conclude that disrupted neurogenesis during development is an important, unrecognized aspect of HD pathogenesis. To address the function of normal HTT protein we generated and lines. Surprisingly, the same phenotype emerged in but not lines. We conclude that HD is a developmental disorder characterized by chromosomal instability that impairs neurogenesis, and that HD represents a genetic dominant-negative loss of function, contrary to the prevalent gain-of-toxic-function hypothesis. The consequences of developmental alterations should be considered as a new target for HD therapies.

Objectives: To propose a previous implant fractures (PIFs) classification system with good interobserver reliability. Design: Retrospective classification. Setting: Four academic medical centers. Patients/Participants: A retrospective review of PIFs treated at 4 academic medical centers over 10 years was performed. Data collected included initial implant and PIF radiographs. There were 103 PIFs in 96 patients during the study period. Seventy-three (70.9%) were about plate/screw (PS) constructs and 30 (29.1%) were about intramedullary (IM) devices. Intervention: Assignment of PIF classification. Main Outcome Measurements: PIFs were classified based on initial implant (PS or IM) and fracture location with respect to the initial implant (proximal or distal to the implant, at the tip of the construct, or within the construct). Reliability of this scheme was assessed among 5 observers using Fleiss' kappa tests. Results: Of PIFs about plate/screw constructs, 26.0% were proximal/distal to the implant (classification: PS1), 57.5% involved bone between the most proximal/distal screw and the same end of the plate (classification: PS2), and 16.4% involved only bone between the most proximal and distal screws (classification: PS3). Of PIFs about IM, 43.3% were distal to the device (classification: IM1), 46.7% involved bone between the most proximal/distal locking bolt and the same end of the device (classification: IM2), and 10.0% involved only bone between locking bolts (classification: IM3). Interobserver reliability for the classification system was excellent between observers, κ = 0.839, P < 0.0005. Conclusions: The proposed system offers a simple method to classify and describe fractures that occur about a previously implanted fracture device. Development of a classification system will allow for comparison of treatment modalities between injury types.

Study Design: Retrospective cohort. Objective: The objective of this study was to assess the effectiveness of the O-arm as an intraoperative imaging tool by comparing accuracy of pedicle screw placement to freehand technique. Methods: The study comprised a total of 1161 screws placed within the cervical (n = 187) thoracic (n = 657), or lumbar (n = 317) spinal level. A pedicle breach was determined by any measurable displacement of the screw outside of the pedicle cortex in any plane on postoperative images. Each pedicle screw was subsequently classified by its placement relative to the targeted pedicle. Statistical analysis was then performed to determine the frequency and type of pedicle screw mispositioning that occurred using the O-arm versus freehand technique. Results: A total of 155 cases (O-arm 84, freehand 71) involved the placement of 454 pedicle screws in the O-arm group and 707 pedicle screws in the freehand group. A pedicle breach occurred in 89 (12.6%) screws in the freehand group and 55 (12.1%) in the O-arm group ( P = .811). Spinal level operated upon did not influence pedicle screw accuracy between groups ( P > .05). Three screws required revision surgery between the 2 groups (O-arm 1, freehand 2, P > .05). The most frequent breach type was a lateral pedicle breach (O-arm 22/454, 4.8%; freehand 54/707, 7.6%), without a significant difference between groups ( P > .05). Conclusions: The use of the O-arm coupled with navigation does not assure improved transpedicular screw placement accuracy when compared with the freehand technique.

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Tranexamic acid (TXA) has been shown to reduce blood loss and postoperative transfusions in total knee arthroplasty (TKA). There is no consensus on the ideal dosing regimen in the literature, although there is a growing body of literature stating there is little benefit to additional doses. Our study compared one versus two doses of TXA in primary TKA and its effect on postoperative transfusion rate. We retrospectively reviewed patients undergoing primary TKA at our two high-volume arthroplasty centers between 2013 and 2016. Patients were included if they underwent unilateral primary TKA, and received one or two doses of intravenous TXA. Patients receiving therapeutic anticoagulation were excluded. Our primary outcome was postoperative transfusion rate. Secondary outcomes included blood loss, length of stay, rate of deep vein thrombosis or pulmonary embolism (DVT/PE), readmission and reoperation.A total of 1,191 patients were included: 891 received one dose and 300 received two doses. There was no significant difference in rate of transfusion, deep vein thrombosis or pulmonary embolism (DVT/PE), blood volume loss, and reoperation. There was a significantly higher risk of readmission (6.7 vs. 2.4%, odds ratio [OR] 2.96, p < 0.001) and reoperation (2.0 vs. 0.6%, OR 3.61, p = 0.024) in patients receiving two doses. These findings were similar with subgroup analysis of patients receiving only aspirin prophylaxis.In unilateral TKA, there is no difference in transfusion rate with one or two doses of perioperative TXA. There was no increased risk of thromboembolic events between groups, although the two-dose group had a higher rate of readmission and reoperation. Given the added cost without clear benefit, these findings may support administration of one rather than two doses of TXA during primary TKA.