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Direct electrical stimulation has been used for decades as a gold standard clinical tool to map cognitive function in neurosurgery patients 1-8 . However, the molecular impact of electrical stimulation in the human brain is unknown. Here, using state-of-the-art transcriptomic and epigenomic sequencing techniques, we define the molecular changes in bulk tissue and at the single-cell level in the human cerebral cortex following direct electrical stimulation of the anterior temporal lobe in patients undergoing neurosurgery. Direct electrical stimulation surprisingly had a robust and consistent impact on the expression of genes related to microglia-specific cytokine activity, an effect that was replicated in mice. Using a newly developed deep learning computational tool, we further demonstrate cell type-specific molecular activation, which underscores the effects of electrical stimulation on gene expression in microglia. Taken together, this work challenges the notion that the immediate impact of electrical stimulation commonly used in the clinic has a primary effect on neuronal gene expression and reveals that microglia robustly respond to electrical stimulation, thus enabling these non-neuronal cells to sculpt and shape the activity of neuronal circuits in the human brain.

Objective: Primary rod fracture after surgery for adult spinal deformity (ASD) is a leading cause of revision, with recent prospective multicenter fracture rates reported at 11%-14% by 2 years. Consequently, the addition of supplemental rods has been explored to reduce fractures. Here the authors describe their experience with a novel iliac accessory rod technique in which each accessory rod anchors to an independent iliac bolt caudally via lateral connector, and attaches to the primary rod rostrally via side-to-side connector., Methods: This retrospective, single-center case series included patients who underwent thoracolumbar/lumbar fusion for ASD between March 2019 and August 2023. Data on baseline demographics, radiographic parameters, surgical characteristics, complications, rod fracture, and revision rates were collected. Paired, 2-tailed t-tests were used to compare pre- and postoperative radiographic outcomes. Rod fracture rates were compared to prior investigations via chi-square goodness of fit testing. The technique for iliac accessory rod placement is described., Results: The study consisted of 82 patients (mean age 66 years, 51% female, 26% with prior fusion) with a median follow-up of 2 years (IQR 28-104 weeks). A total of 50 patients (61%) had ≥ 2-year follow-up. Each surgery involved an average of 4 posterior column osteotomies and 8 segments. Iliac accessory rods were cobalt chromium and were placed bilaterally in 87% of constructs. Postoperative alignment improved significantly in the following parameters: maximum coronal Cobb angle, fractional curve, sagittal vertical axis, lumbar lordosis, thoracic kyphosis, and pelvic incidence to lumbar lordosis mismatch (p < 0.001 for all comparisons). Of 50 patients with ≥ 2-year follow-up, rod fracture occurred in 1 (2.0%), which was incidentally found and required no intervention. The present rod fracture rate was significantly lower than the authors' historically reported institutional rate of 21% for traditional dual-rod constructs, and the 11%-14% reported in recent prospective multicenter studies that used traditional and supplemental rod constructs (p < 0.05 for all comparisons). Reoperation occurred in 12 patients (14.6%); 7 (8.5%) for proximal junctional kyphosis and 5 (6.1%) for wound complication., Conclusions: Here the authors describe their experience with a novel iliac accessory rod technique to prevent rod fracture in patients undergoing surgery for ASD. The 2-year rod fracture rate (2.0%) in this study is significantly lower than the authors' historical dual-rod fracture rate, and other prospective multicenter investigations. Future studies with longer follow-up are needed to determine the durability of this technique.

Triple negative breast cancer (TNBC) represents a subtype of breast cancer that does not express the three major prognostic receptors of human epidermal growth factor receptor 2 (HER2), progesterone (PR), and estrogen (ER). This limits treatment options and results in a high rate of mortality. We have reported previously on the efficacy of a water-soluble, cationic organometallic compound ( Ru-IM ) in a TNBC mouse xenograft model with impressive tumor reduction and targeted tumor drug accumulation. Ru-IM inhibits cancer hallmarks such as migration, angiogenesis, and invasion in TNBC cells by a mechanism that generates apoptotic cell death. Ru-IM displays little interaction with DNA and appears to act by a P53-independent pathway. We report here on the mitochondrial alterations caused by Ru-IM treatment and detail the inhibitory properties of Ru-IM in the PI3K/AKT/mTOR pathway in MDA-MB-231 cells. Lastly, we describe the results of an efficacy study of the TNBC xenografted mouse model with Ru-IM and Olaparib monotherapy and combinatory treatments. We find 59% tumor shrinkage with Ru-IM and 65% with the combination. Histopathological analysis confirmed no test-article-related toxicity. Immunohistochemical analysis indicated an inhibition of the angiogenic marker CD31 and increased levels of apoptotic cleaved caspase 3 marker, along with a slight inhibition of p-mTOR. Taken together, the effects of Ru-IM in vitro show similar trends and translation in vivo . Our investigation underscores the therapeutic potential of Ru-IM in addressing the challenges posed by TNBC as evidenced by its robust efficacy in inhibiting key cancer hallmarks, substantial tumor reduction, and minimal systemic toxicity., Competing Interests: The authors declare the following competing financial interest(s): The authors declare the following financial interests/personal relationships which may be considered as potential competing interests. Maria Contel has patent #US Patent 9555049 issued to Maria Contel, Isabel Marzo, Malgorzata Frik and Benelita T. Elie. Mark Bazett and Brian J Park are employees and/or stock holders of Bold Therapeutics Inc., (© 2024 American Chemical Society.)

Objective: The ability to utilize the T1 slope is often limited by poor visibility on cervical radiographs. The C7 slope has been proposed as a reliable substitute but may have similar limitations of visibility. Herein, the authors propose a novel method that takes advantage of the superior visibility on CT to accurately substitute for the radiographic T1 slope and compare the accuracy of this method with previously reported substitutes., Methods: Lateral neutral standing cervical radiographs and cervical CT scans were examined. When the T1 slope was clearly visible on radiographs, the C3-7 slopes and T1 slope were measured. In CT method 1, a direct method, the T1 slope was measured from the upper endplate of T1 to the bottom edge of the CT image, assuming the edge was parallel to the horizontal plane. In CT method 2, an overlaying method, the T1 slope was calculated by superimposing the C7 slope angle measured on a radiograph onto the CT scan and measuring the angle formed by the upper endplate of T1 and the superimposed horizontal line of the C7 slope. A Pearson correlation with linear regression modeling was performed for potential substitutes for the actual T1 slope., Results: Among 160 patients with available noninstrumented lateral neutral cervical radiographs, the T1 slope was visible in only 54 patients (33.8%). A total of 52 patients met the inclusion criteria for final analysis. The Pearson correlation coefficients between the T1 slope and the C3-7 slopes, CT method 1, and CT method 2 were 0.243 (p = 0.083), 0.292 (p = 0.035), 0.609 (p < 0.001), 0.806 (p < 0.001), 0.898 (p < 0.001), 0.426 (p = 0.002), and 0.942 (p < 0.001), respectively. Linear regression modeling showed R2 = 0.807 for the correlation between C7 slope and T1 slope and R2 = 0.888 for the correlation between T1 slope with the CT method 2 and actual T1 slope., Conclusions: The C7 slope can be a reliable predictor of the T1 slope and is more accurate than more rostral cervical slopes. However, this study disclosed that the novel CT method 2, an overlaying method, was the most reliable estimate of true T1 slope with a greater positive correlation than C7 slope. When CT studies are available in patients with an invisible T1 slope on cervical radiographs, CT method 2 should be used as a substitute for the T1 slope.

Head and neck squamous cell carcinomas (SCCHN) arise in the mucosa of the upper aerodigestive tract at multiple anatomic sites. While tobacco and alcohol exposure remain the primary risk factors for this malignancy, infection with the human papilloma virus is emerging as a major contributing factor to cancers that arise primarily in the oropharynx. Despite therapeutic advances, survival has remained relatively unchanged over the past few decades. Increased understand of the cellular and molecular biology of these cancers will improve our understanding of this malignancy and facilitate the development of more effective therapeutic strategies. Alterations that have been studied to date include genetic and epigenetic changes. While the epidermal growth factor receptor (EGFR) is the only established molecular therapeutic target, other proteins and pathways are under active investigation to determine their contribution to SCCHN carcinogenesis and progression.