Evolution of Deep Brain Stimulation Techniques for Complication Mitigation.

Complication mitigation in deep brain stimulation has been a topic matter of much discussion in the literature. In this article, we examine how neurosurgeons as individuals and as a field generated and adapted techniques to prevent infection, lead fracture/lead migration, and suboptimal outcomes in both the acute period and longitudinally. The authors performed a MEDLINE search inclusive of articles from 1987 to June 2023 including human studies written in English. Using the Rayyan platform, two reviewers (J.P. and R.M.) performed a title screen. Of the 776 articles, 252 were selected by title screen and 172 from abstract review for full-text evaluation. Ultimately, 124 publications were evaluated. We describe the initial complications and inefficiencies at the advent of deep brain stimulation and detail changes instituted by surgeons that reduced them. Furthermore, we discuss the trend in both undesired short-term and long-term outcomes with emphasis on how surgeons recognized and modified their practice to provide safer and better procedures. This scoping review adds to the literature as a guide to both new neurosurgeons and seasoned neurosurgeons alike to understand better what innovations have been trialed over time as we embark on novel targets and neuromodulatory technologies.

The Evolution of Surgical Technique in Spinal Cord Stimulation: A Scoping Review.

Since the advent of spinal cord stimulation (SCS), its operative technique has consistently advanced. We performed a scoping review of the literature regarding SCS operative techniques to highlight key advancements. To review, summarize, and highlight key changes in SCS implantation techniques since their inception. The authors performed a MEDLINE search inclusive of articles from 1967 to June 2023 including human and modeling studies written in English examining the role of trialing, intraoperative neuromonitoring, and surgical adaptations. Using the Rayyan platform, two reviewers performed a blinded title screen. Of the 960 articles, 197 were included in the title screen, 107 were included in the abstract review, and ultimately 69 articles met inclusion criteria. We examined the utility of trialing and found that historical controls showed significant efficacy, whereas recent results are more equivocal. We discuss the significant improvement in outcomes with intraoperative neuromonitoring for asleep SCS placement. We highlight technique improvements that led to significant reductions in infection, lead migration, and inadequate pain relief. Physicians implanting SCS systems for chronic pain management must continually refine their surgical techniques to keep up with this rapidly evolving therapy. In addition, through collaborative efforts of neuromodulators and industry, SCS is safer and more effective for patients suffering from chronic pain.

Conditioned recurrence-free survival following gross-total resection of nonfunctioning pituitary adenoma: a single-surgeon, single-center retrospective study.

OBJECTIVE: The authors sought to determine the time to recurrence after achieving gross-total resection of nonfunctioning pituitary adenoma (NFPA) in adult patients. The authors also sought to determine the rate of recurrence after increasing years of recurrence-free imaging. METHODS: The authors performed a retrospective chart review of all adult patients who underwent gross-total resection of NFPA between September 2004 and January 2018 by the senior surgeon. The primary outcome of the study was time to recurrence, defined by imaging and/or clinical criteria. RESULTS: The median follow-up time of the 148 patients who met the inclusion criteria was 91 months; 12 of these patients (8.1%) had recurrence. The median time to recurrence was 80 months. The range of time for these recurrences was 36-156 months. The probabilities of remaining recurrence free at 180 months after gross-total resection of NFPA and 12, 36, 60, 84, or 120 months of recurrence-free imaging were 82%, 84%, 86%, 88%, and 93%, respectively. The year-over-year odds of a recurrence increased linearly by 1.07%. There was no difference in recurrence-free imaging when patients were stratified by Knosp grade or tumor subtype. None of the patients with recurrence underwent repeat resection. When identified, patients were managed either conservatively or with radiosurgery. CONCLUSIONS: Increased intervals of recurrence-free imaging were not associated with a decrease in risk of recurrence, which suggests that patients require life-long periodic imaging. If followed with periodic imaging, recurrence can be discovered before clinically symptomatic and successfully treated without repeat surgery.

Bone-anchored annular closure device leading to histiocytic-inflammation-induced neuropathy with resolution after removal: a case report.

PURPOSE: To determine and report the underlying cause of local inflammation causing recurrent neuropathy and multiple operations in a patient with a Barricaid® device. METHODS: After removal of this patient's Barricaid® device, we sent local inflammatory tissue to pathology for histochemical analysis. Upon discovery of giant cells formation with polarizable foreign bodies, we performed a literature review regarding the Barricaid® device and its elements. RESULTS: After two previous operations and three trials of conservative management, the presented patient underwent an L5/S1 TLIF with removal of her previously installed Barricaid® device. There were no signs of device instability/failure nor were there obvious signs of infection. Inflamed tissue proximal to the Barricaid® device was discovered, debrided, and sample sent to pathology. Removal of the Barricaid® device led to subsequent and durable relief of her symptoms. During review of this case, we discovered the polyethylene terephthalate (PET) weave used in the Barricaid® device is known to induce foreign body reactions, and this precise finding was seen in the majority of animal data submitted to the FDA for the device's acceptance. CONCLUSION: Given the constellation of this patient's symptoms, imaging, intraoperative, and pathology findings, previously published reports, and pre-approval data submitted to the FDA, we conclude that the inflammatory response to the PET weave in this patient's Barricaid® device was the ultimate cause of her continued neuropathy despite multiple prior surgical interventions.

Ancestry-inclusive dog genomics challenges popular breed stereotypes.

Behavioral genetics in dogs has focused on modern breeds, which are isolated subgroups with distinctive physical and, purportedly, behavioral characteristics. We interrogated breed stereotypes by surveying owners of 18,385 purebred and mixed-breed dogs and genotyping 2155 dogs. Most behavioral traits are heritable [heritability (h2) > 25%], and admixture patterns in mixed-breed dogs reveal breed propensities. Breed explains just 9% of behavioral variation in individuals. Genome-wide association analyses identify 11 loci that are significantly associated with behavior, and characteristic breed behaviors exhibit genetic complexity. Behavioral loci are not unusually differentiated in breeds, but breed propensities align, albeit weakly, with ancestral function. We propose that behaviors perceived as characteristic of modern breeds derive from thousands of years of polygenic adaptation that predates breed formation, with modern breeds distinguished primarily by aesthetic traits.

Posterior Polyethylene Tethers Reduce Occurrence of Proximal Junctional Kyphosis After Multilevel Spinal Instrumentation for Adult Spinal Deformity: A Retrospective Analysis.

BACKGROUND: Proximal junctional kyphosis (PJK) is a common postoperative complication after adult spinal deformity (ASD) surgery and may manifest with neurological decline, worsening spinal deformity, and spinal instability, which warrant reoperation. Rates of PJK may be as high as 69.4% after ASD surgery. OBJECTIVE: To evaluate the efficacy of junctional tethers for PJK prophylaxis after multilevel instrumented surgery for ASD with minimum 2-yr follow-up. METHODS: Single-center retrospective analysis of adult patients (age ≥18 yr) who underwent ASD surgery with index operations performed between November 2010 and June 2016 and achieved minimum 2-yr follow-up. Patients with ASD were subdivided into 3 treatment cohorts based on institutional protocol: no tether (NT), polyethylene tether-only (TO), and tether with crosslink (TC). PJK was defined as a proximal junctional angle (PJA) >10° and 10° greater than the corresponding preoperative measurement. Patient demographics, operative details, standard radiographic scoliosis measurements (including PJA and assessment of PJK), and complications were analyzed. RESULTS: Of 184 patients, 146 (79.3%) achieved minimum 2-yr follow-up (mean = 45 mo; mean age = 67 yr; 67.8% women). PJK rates reported for the NT, TO, and TC cohorts were 60.7% (37/61), 35.7% (15/42), and 23.3% (10/43), respectively. PJK rates among TC patients were significantly lower than NT (P = .01601). CONCLUSION: Junctional tethers with crosslink significantly reduced the incidence of PJK and revisions for PJK among ASD patients treated with long-segment posterior instrumented fusions who achieved minimum 2-yr follow-up.

A Systematic Review of the Cost-Utility of Spinal Cord Stimulation for Persistent Low Back Pain in Patients With Failed Back Surgery Syndrome.

STUDY DESIGN: Systematic Review. OBJECTIVES: To review the literature surrounding the cost-effectiveness of implanting spinal cord stimulators for failed back surgery syndrome. METHODS: A systematic review was conducted inclusive of all publications in the Medline database and Cochrane CENTRAL trials register within the last 10 years (English language only) assessing the cost-effectiveness of Spinal Cord Stimulator device implantation (SCSdi) in patients with previous lumbar fusion surgery. RESULTS: The majority of reviewed publications that analyzed cost-effectiveness of SCSdi compared to conventional medical management (CMM) or re-operation in patients with failed back surgery syndrome (FBSS) showed an overall increase in direct medical costs; these increased costs were found in nearly all cases to be offset by significant improvements in patient quality of life. The cost required to achieve these increases in quality adjusted life years (QALY) falls well below $25 000/QALY, a conservative estimate of willingness to pay. CONCLUSIONS: The data suggest that SCSdi provides both superior outcomes and a lower incremental cost: effectiveness ratio (ICER) compared to CMM and/or re-operation in patients with FBSS. These findings are in spite of the fact that the majority of studies reviewed were agnostic to the type of device or innervation utilized in SCSdi. Newer devices utilizing burst or higher frequency stimulation have demonstrated their superiority over traditional SCSdi via randomized clinical trials and may provide lower ICERs.

A single-center retrospective analysis of 3- or 4-level anterior cervical discectomy and fusion: surgical outcomes in 66 patients.

OBJECTIVE: Anterior cervical discectomy and fusion (ACDF) is a safe and effective intervention to treat cervical spine pathology. Although these were originally performed as single-level procedures, multilevel ACDF has been performed for patients with extensive degenerative disc disease. To date, there is a paucity of data regarding outcomes related to ACDFs of 3 or more levels. The purpose of this study was to compare surgical outcomes of 3- and 4-level ACDF procedures. METHODS: The authors performed a retrospective chart review of patients who underwent 3- and 4-level ACDF at the University of Virginia Health System between January 2010 and December 2017. In patients meeting the inclusion/exclusion criteria, demographics, fusion rates, time to fusion, and reoperation rates were evaluated. Fusion was determined by < 1 mm of change in interspinous distance between individual fused vertebrae on lateral flexion/extension radiographs and lack of radiolucency between the grafts and vertebral bodies. Any procedure requiring a surgical revision was considered a failure. RESULTS: Sixty-six patients (47 with 3-level and 19 with 4-level ACDFs) met the inclusion/exclusion criteria of having at least one lateral flexion/extension radiograph series ≥ 12 months after surgery. Seventy percent of 3-level patients and 68% of 4-level patients had ≥ 24 months of follow-up. Ninety-four percent of 3-level patients and 100% of 4-level patients achieved radiographic fusion for at least 1 surgical level. Eighty-eight percent and 82% of 3- and 4-level patients achieved fusion at C3-4; 85% and 89% of 3- and 4-level patients achieved fusion at C4-5; 68% and 89% of 3- and 4-level patients achieved fusion at C5-6; 44% and 42% of 3- and 4-level patients achieved fusion at C6-7; and no patients achieved fusion at C7-T1. Time to fusion was not significantly different between levels. Revision was required in 6.4% of patients with 3-level and in 16% of patients with 4-level ACDF. The mean time to revision was 46.2 and 45.4 months for 3- and 4-level ACDF, respectively. The most common reason for revision was worsening of initial symptoms. CONCLUSIONS: The authors' experience with long-segment anterior cervical fusions shows their fusion rates exceeding most of the reported fusion rates for similar procedures in the literature, with rates similar to those reported for short-segment ACDFs. Three-level and 4-level ACDF procedures are viable options for cervical spine pathology, and the authors' analysis demonstrates an equivalent rate of fusion and time to fusion between 3- and 4-level surgeries.

Quality-of-life trajectories after stereotactic radiosurgery for brain metastases.

OBJECTIVE: Quality of life (QOL) is an important endpoint measure of cancer treatment. The authors' goal was to evaluate QOL trajectories and prognostic value in cancer patients treated with stereotactic radiosurgery (SRS) for brain metastases. METHODS: Patients who underwent Gamma Knife radiosurgery (GKRS) between January 2016 and November 2019 were prospectively evaluated for QOL using the EQ-5D-3L questionnaire before SRS and at follow-up visits. Only patients who had pre-SRS and at least 1 post-SRS QOL assessment were considered. RESULTS: Fifty-four cancer patients underwent 109 GKRS procedures. The first post-SRS visit was at a median of 2.59 months (range 0.13-21.08 months), and the last post-SRS visit was at 14.72 months (range 2.52-45.21 months) after SRS. There was no statistically significant change in the EQ-5D index score (p = 0.539) at the first compared with last post-SRS visit. The proportion of patients reporting some problems on the EQ-5D dimension of self-care increased during the course of follow-up from 9% (pre-SRS visit) to 18% (last post-SRS visit; p = 0.03). The proportion of patients reporting problems on the EQ-5D dimensions of mobility, usual activities, pain/discomfort, and anxiety/depression remained stable during the course of follow-up (p ≥ 0.106). After adjusting for clinical variables, a higher recursive partitioning analysis (RPA) class (i.e., worse prognostic category) was independently associated with greater odds for EQ-5D index score deterioration (p = 0.050). Upfront whole-brain radiation therapy predicted deterioration of the EQ-5D self-care (p = 0.03) and usual activities (p = 0.024) dimensions, while a greater number of lesions predicted deterioration of the EQ-5D anxiety/depression dimension (p = 0.008). A lower pre-SRS EQ-5D index was associated with shorter survival independently from clinical and demographic variables (OR 18.956, 95% CI 2.793-128.64; p = 0.003). CONCLUSIONS: QOL is largely preserved in brain metastasis patients treated with SRS. Higher RPA class, upfront whole-brain radiation therapy, and greater intracranial disease burden are independent predictors of post-SRS QOL deterioration. Worse pre-SRS QOL predicts shorter survival. Assessment of QOL is recommended in brain metastasis patients managed with SRS.

Muscle-Specific FXR1 Isoforms in Squamous Cell Cancer.

The RNA-binding protein fragile-X mental retardation autosomal 1 (FXR1) is upregulated in head and neck squamous cell carcinomas (HNSCCs) and expressed as at least seven isoforms in humans. Only two of these isoforms are capable of binding to RNA containing G-quadruplex structures. We suggest that these unique isoforms play a role in the pathogenesis of HNSCC.

Combining Citizen Science and Genomics to Investigate Tick, Pathogen, and Commensal Microbiome at Single-Tick Resolution.

The prevalence of tickborne diseases worldwide is increasing virtually unchecked due to the lack of effective control strategies. The transmission dynamics of tickborne pathogens are influenced by the tick microbiome, tick co-infection with other pathogens, and environmental features. Understanding this complex system could lead to new strategies for pathogen control, but will require large-scale, high-resolution data. Here, we introduce Project Acari, a citizen science-based project to assay, at single-tick resolution, species, pathogen infection status, microbiome profile, and environmental conditions of tens of thousands of ticks collected from numerous sites across the United States. In the first phase of the project, we collected more than 2,400 ticks wild-caught by citizen scientists and developed high-throughput methods to process and sequence them individually. Applying these methods to 192 Ixodes scapularis ticks collected in a region with a high incidence of Lyme disease, we found that 62% were colonized by Borrelia burgdorferi, the Lyme disease pathogen. In contrast to previous reports, we did not find an association between the microbiome diversity of a tick and its probability of carrying B. burgdorferi. However, we did find undescribed associations between B. burgdorferi carriage and the presence of specific microbial taxa within individual ticks. Our findings underscore the power of coupling citizen science with high-throughput processing to reveal pathogen dynamics. Our approach can be extended for massively parallel screening of individual ticks, offering a powerful tool to elucidate the ecology of tickborne disease and to guide pathogen-control initiatives.

Inhibitors of the protein disulfide isomerase family for the treatment of multiple myeloma.

Multiple Myeloma (MM) is highly sensitive to disruptions in cellular protein homeostasis. Proteasome inhibitors (PIs) are initially effective in the treatment of MM, although cures are not achievable and the emergence of resistance limits the durability of responses. New therapies are needed for refractory patients, and those that combat resistance to standard of care agents would be particularly valuable. Screening of multiple chemical libraries for PI re-sensitizing compounds identified E61 as a potent enhancer of multiple PIs and MM specific activity. Using a tandem approach of click chemistry and peptide mass fingerprinting, we identified multiple protein disulfide isomerase (PDI) family members as the primary molecular targets of E61. PDIs mediate oxidative protein folding, and E61 treatment induced robust ER and oxidative stress responses as well as the accumulation of ubiquitinylated proteins. A chemical optimization program led to a new structural class of indene (exemplified by lead E64FC26), which are highly potent pan-style inhibitors of PDIs. In mice with MM, E64FC26 improved survival and enhanced the activity of bortezomib without any adverse effects. This work demonstrates the potential of E64FC26 as an early drug candidate and the strategy of targeting multiple PDI isoforms for the treatment of refractory MM and beyond.

Advances and Challenges of HDAC Inhibitors in Cancer Therapeutics.

Since the identification and cloning of human histone deacetylases (HDACs) and the rapid approval of vorinostat (Zolinza®) for the treatment of cutaneous T-cell lymphoma, the field of HDAC biology has met many initial successes. However, many challenges remain due to the complexity involved in the lysine posttranslational modifications, epigenetic transcription regulation, and nonepigenetic cellular signaling cascades. In this chapter, we will: review the discovery of the first HDAC inhibitor and present discussion regarding the future of next-generation HDAC inhibitors, give an overview of different classes of HDACs and their differences in lysine deacylation activity, discuss different classes of HDAC inhibitors and their HDAC isozyme preferences, and review HDAC inhibitors' preclinical studies, their clinical trials, their pharmacokinetic challenges, and future direction. We will also discuss the likely reason for the failure of multiple HDAC inhibitor clinical trials in malignancies other than lymphoma and multiple myeloma. In addition, the potential molecular mechanism(s) that may play a key role in the efficacy and therapeutic response rate in the clinic and the likely patient population for HDAC therapy will be discussed.

Comparison of the Deacylase and Deacetylase Activity of Zinc-Dependent HDACs.

The acetylation status of lysine residues on histone proteins has long been attributed to a balance struck between the catalytic activity of histone acetyl transferases and histone deacetylases (HDAC). HDACs were identified as the sole removers of acetyl post-translational modifications (PTM) of histone lysine residues. Studies into the biological role of HDACs have also elucidated their role as removers of acetyl PTMs from lysine residues of nonhistone proteins. These findings, coupled with high-resolution mass spectrometry studies that revealed the presence of acyl-group PTMs on lysine residues of nonhistone proteins, brought forth the possibility of HDACs acting as removers of both acyl- and acetyl-based PTMs. We posited that HDACs fulfill this dual role and sought to investigate their specificity. Utilizing a fluorescence-based assay and biologically relevant acyl-substrates, the selectivities of zinc-dependent HDACs toward these acyl-based PTMs were identified. These findings were further validated using cellular models and molecular biology techniques. As a proof of principal, an HDAC3 selective inhibitor was designed using HDAC3's substrate preference. This resulting inhibitor demonstrates nanomolar activity and >30 fold selectivity toward HDAC3 compared to the other class I HDACs. This inhibitor is capable of increasing p65 acetylation, attenuating NF-κB activation, and thereby preventing downstream nitric oxide signaling. Additionally, this selective HDAC3 inhibition allows for control of HMGB-1 secretion from activated macrophages without altering the acetylation status of histones or tubulin.

Development of Allosteric Hydrazide-Containing Class I Histone Deacetylase Inhibitors for Use in Acute Myeloid Leukemia.

One of the biggest hurdles yet to be overcome for the continued improvement of histone deacetylase (HDAC) inhibitors is finding alternative motifs equipotent to the classic and ubiquitously used hydroxamic acid. The N-hydroxyl group of this motif is highly subject to sulfation/glucoronidation-based inactivation in humans; compounds containing this motif require much higher dosing in clinic to achieve therapeutic concentrations. With the goal of developing a second generation of HDAC inhibitors lacking this hydroxamate, we designed a series of potent and selective class I HDAC inhibitors using a hydrazide motif. These inhibitors are impervious to glucuronidation and demonstrate allosteric inhibition. In vitro and ex vivo characterization of our lead analogues' efficacy, selectivity, and toxicity profiles demonstrate that they possess low nanomolar activity against models of acute myeloid leukemia (AML) and are at least 100-fold more selective for AML than solid immortalized cells such as HEK293 or human peripheral blood mononuclear cells.

Silver-catalyzed direct thiolation of quinones by activation of aryl disulfides to synthesize quinonyl aryl thioethers.

A silver-catalyzed coupling reaction of quinones with aryl disulfides for the synthesis of quinonyl aryl thioethers is described. In the presence of AgOAc (0.2 equiv)/dppp (0.24 equiv) as the catalyst, (NH4)2S2O8 (3.0 equiv) as the oxidant, and Bu4NBF4 (1.0 equiv) as the additive, the reaction is simple, provides high yield (up to 88% yield), and possesses a broad substrate scope. The reaction is believed to proceed via direct activation of disulfides evidenced by observation of a metathesis reaction between two different disulfides placed together under the reaction conditions and (13)C NMR spectroscopy analysis.

Isolating the delay component of impulsive choice in adolescent rats.

Impulsive choice-the preference for small immediate rewards over larger delayed rewards-has been linked to various psychological conditions ranging from behavioral disorders to addiction. These links highlight the critical need to dissect the various components of this multifaceted behavioral trait. Delay discounting tasks allow researchers to study an important factor of this behavior: how the subjective value of a rewards changes over a delay period. However, existing methods of delay discounting include a confound of different reward sizes within the procedure. Here we present a new approach of using a single constant reward size to assess delay discounting. A complementary approach could hold delay constant and assess the utility of changing quantities of a reward. Isolating these behavioral components can advance our ability to explore the behavioral complexity of impulsive choice. We present in detail the methods for isolating delay, and further capitalize on this method by pairing it with a standard peak interval task to test whether individual variation in delay discounting can be explained by differences in perception of time in male and female adolescent rats. We find that rats that were more precise in discriminating time intervals were also less impulsive in their choice. Our data suggest that differences in timing and delay discounting are not causally related, but instead are more likely influenced by a common factor. Further, the mean-level change in our measure between post-natal day 28 and 42 suggests this test may be capturing a developmental change in this factor. In summary, this new method of isolating individual components of impulsive choice (delay or quantity) can be efficiently applied in either adolescent or adult animal models and may help elucidate the mechanisms underlying impulsivity and its links to psychological disorders.