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In Huntington's disease (HD), aberrant processing of huntingtin (HTT) mRNA produces HTT1a transcripts that encode the pathogenic HTT exon 1 protein. The mechanisms behind HTT1a production are not fully understood. Considering the role of m6A in RNA processing and splicing, we investigated its involvement in HTT1a generation. Here, we show that m6A methylation is increased before the cryptic poly(A) sites (IpA1 and IpA2) within the huntingtin RNA in the striatum of Hdh+/Q111 mice and human HD samples. We further assessed m6A's role in mutant Htt mRNA processing by pharmacological inhibition and knockdown of METTL3, as well as targeted demethylation of Htt intron 1 using a dCas13-ALKBH5 system in HD mouse cells. Our data reveal that Htt1a transcript levels are regulated by both METTL3 and the methylation status of Htt intron 1. They also show that m6A methylation in intron 1 depends on expanded CAG repeats. Our findings highlight a potential role for m6A in aberrant splicing of Htt mRNA. Synopsis: This study unveils that m6A RNA modification contributes to aberrant Htt splicing in Huntington's disease models, promoting the generation of the pathogenic Htt1a variant. Increased m6A methylation levels in Htt1a are detected at early stages in the striatum of Hdh+/Q111 mice. HD mice and human samples reveal m6A methylation in the same intronic DRACH motif located in intron 1 of huntingtin RNA. Pharmacological inhibition and siRNA knockdown of METTL3, as well as targeted demethylation, reduce Htt1a expression in mouse cells. Blocking CAG repeats in exon 1 of Huntingtin RNA with LNA-CTG ASOs reduces m6A RNA methylation in intron 1 in mouse cells. This study unveils that m6A RNA modification contributes to aberrant Htt splicing in Huntington's disease models, promoting the generation of the pathogenic Htt1a variant. [ABSTRACT FROM AUTHOR]

Background: Advancements in non-ionizing methods for quantifying spinal deformities are crucial for assessing and monitoring scoliosis. In this study, we analyzed the observer variability of a newly developed digital tool for quantifying body asymmetry from clinical photographs. Methods: Prospective observational multicenter study. Initially, a digital tool was developed using image analysis software, calculating quantitative measures of body asymmetry. This tool was integrated into an online platform that exports data to a database. The tool calculated 10 parameters, including angles (shoulder height, axilla height, waist height, right and left waistline angles, and their difference) and surfaces of the left and right hemitrunks (shoulders, waists, pelvises, and total). Subsequently, an online training course on the tool was conducted for twelve observers not involved in its development (six research coordinators and six spine surgeons). Finally, 15 standardized back photographs of adolescent idiopathic scoliosis patients were selected from a multicenter image bank, representing various clinical scenarios (different age, gender, curve type, BMI, and pre- and postoperative images). The 12 observers measured the photographs at two different times with a three-week interval. For the second round, the images were randomly mixed. Inter- and intra-observer variabilities of the measurements were analyzed using intraclass correlation coefficients (ICCs), and reliability was measured by the standard error of measurement (SEM). Group comparisons were made using Student's t-test. Results: The mean inter-observer ICC for the ten measurements was 0.981, the mean intra-observer ICC was 0.937, and SEM was 0.3–1.3°. The parameter with the strongest inter- and intra-observer validity was the difference in waistline angles 0.994 and 0.974, respectively, while the highest variability was found with the waist height angle 0.963 and 0.845, respectively. No test–retest differences (p > 0.05) were observed between researchers (0.948 ± 0.04) and surgeons (0.925 ± 0.05). Conclusion: We developed a new digital tool integrated into an online platform demonstrating excellent reliability and inter- and intra-observer variabilities for quantifying body asymmetry in scoliosis patients from a simple clinical photograph. The method could be used for assessing and monitoring scoliosis and body asymmetry without radiation. [ABSTRACT FROM AUTHOR]

Background Context: Mechanical complications (MC) are frequently linked to suboptimal postoperative alignment and represent a primary driver of revision surgery in the context of Adult Spinal Deformity (ASD). However, it's worth noting that even among those deemed "well aligned," the risk of experiencing MCs persists, hinting at the potential influence of factors beyond alignment., Purpose: The aim was to assess the incidence of MCs among well-aligned patients and delving into the relevant risk factors and surgical outcomes that come into play within this specific subgroup., Study Design/setting: A retrospective analysis was conducted using data from a prospective multicenter database dedicated to ASD., Patient Sample: The study focused on patients aged 55 years or older, who had a minimum follow-up period of 2 years, and exhibited a Global Alignment and Proportion (GAP) score of 2 points or less (excluding age) within 6 weeks of their index surgery., Outcome Measures: Mechanical complications such as rod fractures, pseudarthrosis, or junctional kyphosis or failure, METHODS: Patients who developed mechanical complications were identified. Comparative analyses were performed, encompassing both continuous and categorical variables. Furthermore, binary logistic regression tests were employed to pinpoint risk factors, and ROC curves were used to determine the optimal threshold values for these variables., Results: A total of 83 patients met the inclusion criteria for this study, with a mean age of 66 years. On average, they had 10 instrumented levels, and 77% of them had fusion extending to the pelvis. Additionally, 27% of the patients had undergone 3-column osteotomies (3-CO). Among them, 33 patients (40%) experienced at least 1 MC during an average follow-up period of 4 years, which included 14 cases of proximal junctional kyphosis (PJK) and 20 cases of nonunion or rod breakage. 15 patients (18%) required revision surgery specifically for MC. In univariable analyses, patients who developed MC were characterized by higher body weight, poorer baseline general health (as indicated by worse SF-36 scores), and less favorable preoperative coronal and sagittal alignment. They also had longer hospital stays, a greater number of instrumented levels, and achieved less favorable postoperative coronal and sagittal alignment. Interestingly, factors such as 3-column osteotomies, postoperative bracing, and the addition of an anterior approach did not significantly alter the risk of MC in well-aligned adult spinal deformity (ASD) patients. Binary regression models revealed that independent risk factors for MC included the residual coronal lumbosacral curve, the number of instrumented levels, and Relative Spinopelvic Alignment (RSA). ROC curves identified an optimal threshold of a residual lumbosacral curve of ≤4° and RSA of ≤3°. Moreover, the rate of MCs showed a stepwise increase within the GAP-Proportioned group, with rates of 31% for GAP=0, 54% for GAP=1, and 75% for GAP=2, with RSA emerging as the most influential parameter. Lastly, patients with MC exhibited poorer functional and radiological outcomes at their last follow-up assessment., Conclusions: The rate of MCs remains elevated in sagittally "well-aligned" ASD patients that can be attributed to suboptimal residual sagittal and coronal malalignment, which in turn leads to poorer functional outcomes. This study reaffirms the multifaceted nature of MCs and underscores the significance of achieving impeccable postoperative alignment, particularly in the presence of additional risk factors such as extensive surgical correction, a high lever arm (involving instrumented vertebrae), excessive body weight, and frailty (as indicated by SF-36 scores)., Competing Interests: Declarations of Competing Interests The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Study Design: Retrospective analysis of a prospective multicenter Adult Spinal Deformity (ASD) registry., Objective: Assess whether spinal alignment deteriorates post-surgery in absence of mechanical complications and evaluate the long-term outcomes of ASD surgery over a five-year period., Summary of Background Data: ASD is prevalent among older adults, leading to significant pain and disability. Surgical intervention, although increasingly popular, is associated with complications, high costs, and uncertain long-term outcomes beyond two years. Mechanical failure and alignment loss often necessitate revision surgeries, but the natural progression of spinal alignment post-surgery without complications remains unclear., Methods: Clinical and radiological data were analyzed from surgical patients in a multicenter ASD registry who maintained alignment within the instrumented region and completed a 5-year follow-up. The study evaluated patient demographics, surgical details, radiological parameters, and quality of life (QoL) outcomes. Sub-analyses were conducted to compare patients with different initial postoperative alignments and fixation levels., Results: The study included 79 patients (83.5% women, average age 61.9 years) with a mean of 10.7 fused levels. Of these, 29.1% underwent three-column osteotomies (3CO), and 88.6% had a posterior-only approach. While 65% showed favorable alignment at 6 weeks post-surgery, there was a progressive deterioration in global sagittal alignment (Global Tilt/RSA) and thoracic kyphosis over five years (P<0.05), along with increased pelvic compensation (PT SS/RPV). These changes did not correlate with worsening Health-Related Quality of Life outcomes (P>0.05). Older age was linked to greater progression in T2-T12 kyphosis, and osteoporosis was associated with increased SVA and RPV. Optimal immediate postoperative sagittal alignment did not prevent this "aging effect.", Conclusions: ASD surgery and achieving ideal postoperative alignment do not prevent the ongoing "aging" of the non-instrumented spine. Both thoracic and global sagittal alignments deteriorate over time. Although no functional decline has been observed, the implications of these changes for surgical planning remain uncertain., Competing Interests: Conflict of Interests: The European Spine Study Group receives funding support from DePuy Synthes and Medtronic., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Objective: To determine whether maternofetal transfer of NMDA receptor (NMDAR) antibodies has pathogenic effects on the fetus and offspring, we developed a model of placental transfer of antibodies., Methods: Pregnant C57BL/6J mice were administered via tail vein patients' or controls' immunoglobulin G (IgG) on days 14-16 of gestation, when the placenta is able to transport IgG and the immature fetal blood-brain barrier is less restrictive to IgG crossing. Immunohistochemical and DiOlistic (gene gun delivery of fluorescent dye) staining, confocal microscopy, standardized developmental and behavioral tasks, and hippocampal long-term potentiation were used to determine the antibody effects., Results: In brains of fetuses, patients' IgG, but not controls' IgG, bound to NMDAR, causing a decrease in NMDAR clusters and cortical plate thickness. No increase in neonatal mortality was observed, but offspring exposed in utero to patients' IgG had reduced levels of cell-surface and synaptic NMDAR, increased dendritic arborization, decreased density of mature (mushroom-shaped) spines, microglial activation, and thinning of brain cortical layers II-IV with cellular compaction. These animals also had a delay in innate reflexes and eye opening and during follow-up showed depressive-like behavior, deficits in nest building, poor motor coordination, and impaired social-spatial memory and hippocampal plasticity. Remarkably, all these paradigms progressively improved (becoming similar to those of controls) during follow-up until adulthood., Conclusions: In this model, placental transfer of patients' NMDAR antibodies caused severe but reversible synaptic and neurodevelopmental alterations. Reversible antibody effects may contribute to the infrequent and limited number of complications described in children of patients who develop anti-NMDAR encephalitis during pregnancy., (Copyright © 2020 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)