Faculty Bibliography

STUDY DESIGN/METHODS:Retrospective cohort study. OBJECTIVE:Due to proximity of the surgical site to important respiratory structures, patients may undergo delayed extubation after adult cervical deformity (ACD) surgery to manage postoperative airway edema/obstruction. Herein, we evaluate relevant relationships with delayed extubation. SUMMARY OF BACKGROUND DATA/BACKGROUND:Delayed extubation is an underreported perioperative occurrence, with only a few studies conducting case-by-case reviews of prolonged intubation. METHODS:Operative ACD patients with baseline (BL) were grouped based on whether they experienced delayed extubation (DE), or leaving the OR while still intubated, versus those who were extubated successfully in the OR (non-DE). Means comparison and regression analyses identified predictors of delayed extubation and associations with peri-operative complications and outcomes. RESULTS:82 patients met inclusion criteria (mean age 62.4±13.0 y, 52.4% female, Edmonton frailty score: 5.10±2.97, ACFI score: 0.30±0.16, CCI: 1.41±1.73). 14 patients left the OR intubated, and 1(1.2%) required reintubation. DE cohort demonstrated greater Edmonton frailty scores (P=0.017) and smoking histories (P=0.031). Intraoperatively, there was a significant difference EBL (P=0.021) and rate of transfusions (DE: 27.3% v non-DE: 4.8%, P=0.12). Upper instrumented vertebra (UIV) was not associated with DE, while lower LIV increased the likelihood of DE (OR 1.1, P=0.029). Post-operatively, as expected, there was a significant difference in rate of SICU admissions (DE: 90.9% v. non-DE: 49.2%, P=0.01), although no significant differences in LOS. Greater cSVA and MGS correction from baseline was associated with increased likelihood of delayed extubation (OR 1.1, CI 95% 1.05-1.17, P<.001; OR 1.14, CI 95% 1.05-1.24, P=0.003). Furthermore, delayed extubation was a significant predictor of increased VR-Physical Component Scores (P=0.013) at 6W, and DE cohort demonstrated significantly higher VR-PCS and VR-MCS Scores at 6W (P=0.01, both). CONCLUSIONS:Baseline frailty and larger radiographic correction can be associated with delayed extubation, which can impact quality of life perioperatively. Considerations like minimizing intraoperative blood loss and degree of correction could minimize delayed extubation.

Down syndrome (DS), stemming from the triplication of human chromosome 21, results in intellectual disability, with early mid-life onset of Alzheimer's disease (AD) pathology. Early interventions to reduce cognitive impairments and neuropathology are lacking. One modality, maternal choline supplementation (MCS), has shown beneficial effects on behavior and gene expression in neurodevelopmental and neurodegenerative disorders, including trisomic mice. Loss of basal forebrain cholinergic neurons (BFCNs) and other DS/AD relevant hallmarks were observed in a well-established trisomic model (Ts65Dn, Ts). MCS attenuates these endophenotypes with beneficial behavioral effects in trisomic offspring. We postulate MCS ameliorates dysregulated cellular mechanisms within vulnerable BFCNs, with attenuation driven by novel gene expression. Here, choline acetyltransferase immunohistochemical labeling identified BFCNs in the medial septal/ventral diagonal band nuclei of the basal forebrain in Ts and normal disomic (2N) offspring at ~11 months of age from dams exposed to MCS or normal choline during the perinatal period. BFCNs (~500 per mouse) were microisolated and processed for RNA-sequencing. Bioinformatic assessment elucidated differentially expressed genes (DEGs) and pathway alterations in the context of genotype (Ts, 2N) and maternal diet (MCS, normal choline). MCS attenuated select dysregulated DEGs and relevant pathways in aged BFCNs. Trisomic MCS-responsive improvements included pathways such as cognitive impairment and nicotinamide adenine dinucleotide signaling, among others, indicative of increased behavioral and bioenergetic fitness. Although MCS does not eliminate the DS/AD phenotype, early choline delivery provides long-lasting benefits to aged trisomic BFCNs, indicating that MCS prolongs neuronal health in the context of DS/AD.

INTRODUCTION/BACKGROUND:Underlying causes of Alzheimer's disease (AD) remain unknown, making it imperative to identify molecular mechanisms driving the pathobiology of AD onset and progression. METHODS:Laser capture microdissection was used to isolate layer III pyramidal neurons from post mortem human prefrontal cortex (Brodmann area 9). Single population RNA sequencing was conducted using tissue from subjects with no cognitive impairment (NCI), mild cognitive impairment (MCI), and AD. Differentially expressed genes (DEGs) were compared across groups. RESULTS:DEGs increased from prodromal (MCI vs. NCI) to progression (AD vs. MCI) to frank AD (AD vs. NCI). The majority of DEGs and pathways shared between prodromal and progression exhibited a change in the direction of dysregulation unlike pathways between progression and frank AD. DISCUSSION/CONCLUSIONS:Candidate genes and pathways were identified that demarcate early-stage AD onset from AD progression, providing a roadmap to study cortical cellular vulnerability and key targets for intervention at early stages of AD. HIGHLIGHTS/CONCLUSIONS:Pyramidal neuron differentially expressed genes (DEGs) are directionally divergent between prodromal, progression, and frank Alzheimer's disease (AD). Pyramidal neuron DEGs are directionally convergent between progression and frank AD. Dysfunctional bioenergetic pathways increased dysregulation as the AD spectrum progressed. Immune response pathways were more dysregulated in frank AD than prodromal stages. DEGs, = biological pathways, and interactomes demarcate specific stages across the AD spectrum.

BACKGROUND/OBJECTIVES/OBJECTIVE:Malignant peripheral nerve sheath tumors (MPNSTs) are aggressive malignancies with a challenging prognosis, especially for patients with Neurofibromatosis type 1 (NF1). Their low incidence necessitates comprehensive studies to investigate the survival outcome. METHODS:We conducted a systematic review and meta-analysis, including data from 16 studies and 4265 patients, to explore surgical outcomes and survival rates, focusing on time-related outcomes, including overall survival (OS), progression-free survival (PFS), and recurrence rate. RESULTS:The analysis revealed that the OS rate was 86% [95% CI: 75-97%] at 1 year, decreasing to 60% [95% CI: 45-75%] at 3 years, and further declining to 47% [95% CI: 35-58%] by 5 years. For PFS, the 1-year rate was 61% [95% CI: 25-98%], which remained similar at 62% [95% CI: 35-89%] for 3 and 5 years. In NF1-associated MPNSTs, the 1-year OS was relatively high at 93% [95% CI: 83-100%], but it dropped to 68% [95% CI: 53-84%] at 3 years and further to 50% [95% CI: 31-68%] at 5 years. Additionally, the hazard ratio indicated a 38% lower survival rate in NF1 patients than those with sporadic MPNSTs when data were presented in the same study. Recurrence rates were high, with 56% of patients experiencing a relapse, primarily as local recurrences (70.6%). Mortality was significant, with over 50% of patients dying within an average follow-up period of 33.45 months. CONCLUSIONS:MPNSTs, particularly in NF1 patients, are associated with poor prognosis and high recurrence rates. These results underline the necessity of targeted therapeutic strategies and improved programs for screening, mainly through a multidisciplinary approach to optimize management.

Endoscopic spine surgery (ESS) is growing in popularity worldwide. An expanding body of literature demonstrates rapid functional recovery with reduced morbidity compared to open techniques. Both full endoscopic spine surgery, or uniportal endoscopy, and unilateral biportal endoscopy (UBE) can be employed in conjunction with various navigation and enabling technologies for assistance with localization of anatomic orientation and assessment of the intraoperative target spinal pathology. This review article describes various navigation technologies in ESS, including 2-dimensional (2D) fluoroscopic imaging, 2D fluoroscopic navigation, 3-dimensional C-arm navigation, augmented reality, and spinal robotics. Employment of enabling navigation and emerging technology with the registration of patient-specific anatomy enables clear delineation of anatomic landmarks and facilitation of a successful procedure. Additionally, avoidance of common pitfalls during use of navigation systems in ESS is discussed in this review.

INTRODUCTION/UNASSIGNED:Individuals with Down syndrome (DS) exhibit neurological deficits throughout life including the development of in Alzheimer's disease (AD) pathology and cognitive impairment. At the cellular level, dysregulation in neuronal gene expression is observed in postmortem human brain and mouse models of DS/AD. To date, RNA-sequencing (RNA-seq) analysis of hippocampal neuronal gene expression including the characterization of discrete circuit-based connectivity in DS remains a major knowledge gap. We postulate that spatially characterized hippocampal neurons display unique gene expression patterns due, in part, to dysfunction of the integrity of intrinsic circuitry. METHODS/UNASSIGNED:We combined laser capture microdissection to microisolate individual neuron populations with single population RNA-seq analysis to determine gene expression analysis of CA1 and CA3 pyramidal neurons and dentate gyrus granule cells located in the hippocampus, a region critical for learning, memory, and synaptic activity. RESULTS/UNASSIGNED:The hippocampus exhibits age-dependent neurodegeneration beginning at ~6 months of age in the Ts65Dn mouse model of DS/AD. Each population of excitatory hippocampal neurons exhibited unique gene expression alterations in Ts65Dn mice. Bioinformatic inquiry revealed unique vulnerabilities and differences with mechanistic implications coinciding with onset of degeneration in this model of DS/AD. CONCLUSIONS/UNASSIGNED:These cell-type specific vulnerabilities may underlie degenerative endophenotypes suggesting precision medicine targeting of individual populations of neurons for rational therapeutic development.

PURPOSE/OBJECTIVE:Stronger Together is a peer mentoring model that seeks to address the severe lack of mental health and psychosocial support for patients with cancer in many low- and middle-income countries (LMICs). This article presents the results of the Stronger Together pilot study among patients with breast and gynecologic cancer in Viet Nam (VN). METHODS:Eligible participants comprised women age 25 years or older with a diagnosis of breast or gynecologic cancers and receiving treatment at four participating hospitals. Participants were asked whether they wanted to proceed with usual care or be matched with a trained and supervised peer mentor (a cancer survivor). Surveys were administered at baseline (0) and 2, 4, and 6 months and assessed depression, anxiety, stress, mental health and physical health components of quality of life (QOL), self-efficacy, and social support. We computed and compared 2-, 4-, and 6-month changes in scores from baseline and conducted difference-in-difference analyses to estimate the intervention effect at 6 months. RESULTS:The sample size included N = 186 participants. Mentees (n = 91) exhibited improvements in depression, anxiety, stress, and mental health QOL across all time points, whereas usual care participants (n = 95) experienced these improvements at later periods (4 and 6 months). Compared with usual care participants, mentees reported greater improvements in depression at 2 and 4 months, mental health QOL at all time points, and self-efficacy and social support at 4 and 6 months. Greater improvements in stress were also seen in the breast cancer subsample. CONCLUSION/CONCLUSIONS:Stronger Together is a promising model to improve mental health and psychosocial outcomes among patients with breast and gynecologic cancer in VN and can help fill gaps in cancer peer support interventions in many LMICs.

Individuals with DS develop Alzheimer's disease (AD) neuropathology, including endosomal-lysosomal system abnormalities and degeneration of basal forebrain cholinergic neurons (BFCNs). We investigated whether maternal choline supplementation (MCS) affects early endosome pathology within BFCNs using the Ts65Dn mouse model of DS/AD. Ts65Dn and disomic (2N) offspring from dams administered MCS were analyzed for endosomal pathology at 3-4 months or 10-12 months. Morphometric analysis of early endosome phenotype was performed on individual BFCNs using Imaris. The effects of MCS on the endosomal interactome were interrogated by relative co-expression (RCE) analysis. MCS effectively reduced age- and genotype-associated increases in early endosome number in Ts65Dn and 2N offspring, and prevented increases in early endosome size in Ts65Dn offspring. RCE revealed a loss of interactome cooperativity among endosome genes in Ts65Dn offspring that was restored by MCS. These findings demonstrate MCS rescues early endosome pathology, a driver of septohippocampal circuit dysfunction. The genotype-independent benefits of MCS on endosomal phenotype indicate translational applicability as an early-life therapy for DS as well as other neurodevelopmental/neurodegenerative disorders involving endosomal pathology.

IMPORTANCE/UNASSIGNED:Increasing numbers of unaffected individuals could benefit from genetic evaluation for inherited cancer susceptibility. Automated conversational agents (ie, chatbots) are being developed for cancer genetics contexts; however, randomized comparisons with standard of care (SOC) are needed. OBJECTIVE/UNASSIGNED:To examine whether chatbot and SOC approaches are equivalent in completion of pretest cancer genetic services and genetic testing. DESIGN, SETTING, AND PARTICIPANTS/UNASSIGNED:This equivalence trial (Broadening the Reach, Impact, and Delivery of Genetic Services [BRIDGE] randomized clinical trial) was conducted between August 15, 2020, and August 31, 2023, at 2 US health care systems (University of Utah Health and NYU Langone Health). Participants were aged 25 to 60 years, had had a primary care visit in the previous 3 years, were eligible for cancer genetic evaluation, were English or Spanish speaking, had no prior cancer diagnosis other than nonmelanoma skin cancer, had no prior cancer genetic counseling or testing, and had an electronic patient portal account. INTERVENTION/UNASSIGNED:Participants were randomized 1:1 at the patient level to the study groups at each site. In the chatbot intervention group, patients were invited in a patient portal outreach message to complete a pretest genetics education chat. In the enhanced SOC control group, patients were invited to complete an SOC pretest appointment with a certified genetic counselor. MAIN OUTCOMES AND MEASURES/UNASSIGNED:Primary outcomes were completion of pretest cancer genetic services (ie, pretest genetics education chat or pretest genetic counseling appointment) and completion of genetic testing. Equivalence hypothesis testing was used to compare the study groups. RESULTS/UNASSIGNED:This study included 3073 patients (1554 in the chatbot group and 1519 in the enhanced SOC control group). Their mean (SD) age at outreach was 43.8 (9.9) years, and most (2233 of 3063 [72.9%]) were women. A total of 204 patients (7.3%) were Black, 317 (11.4%) were Latinx, and 2094 (75.0%) were White. The estimated percentage point difference for completion of pretest cancer genetic services between groups was 2.0 (95% CI, -1.1 to 5.0). The estimated percentage point difference for completion of genetic testing was -1.3 (95% CI, -3.7 to 1.1). Analyses suggested equivalence in the primary outcomes. CONCLUSIONS AND RELEVANCE/UNASSIGNED:The findings of the BRIDGE equivalence trial support the use of chatbot approaches to offer cancer genetic services. Chatbot tools can be a key component of sustainable and scalable population health management strategies to enhance access to cancer genetic services. TRIAL REGISTRATION/UNASSIGNED:ClinicalTrials.gov Identifier: NCT03985852.

We elucidated the molecular fingerprint of vulnerable excitatory neurons within select cortical lamina of individuals with Down syndrome (DS) for mechanistic understanding and therapeutic potential that also informs Alzheimer's disease (AD) pathophysiology. Frontal cortex (BA9) layer III (L3) and layer V (L5) pyramidal neurons were microisolated from postmortem human DS and age- and sex-matched controls (CTR) to interrogate differentially expressed genes (DEGs) and key biological pathways relevant to neurodegenerative programs. We identified > 2300 DEGs exhibiting convergent dysregulation of gene expression in both L3 and L5 pyramidal neurons in individuals with DS versus CTR subjects. DEGs included over 100 triplicated human chromosome 21 genes in L3 and L5 neurons, demonstrating a trisomic neuronal karyotype in both laminae. In addition, thousands of other DEGs were identified, indicating gene dysregulation is not limited to trisomic genes in the aged DS brain, which we postulate is relevant to AD pathobiology. Convergent L3 and L5 DEGs highlighted pertinent biological pathways and identified key pathway-associated targets likely underlying corticocortical neurodegeneration and related cognitive decline in individuals with DS. Select key DEGs were interrogated as potential hub genes driving dysregulation, namely the triplicated DEGs amyloid precursor protein (APP) and superoxide dismutase 1 (SOD1), along with key signaling DEGs including mitogen activated protein kinase 1 and 3 (MAPK1, MAPK3) and calcium calmodulin dependent protein kinase II alpha (CAMK2A), among others. Hub DEGs determined from multiple pathway analyses identified potential therapeutic candidates for amelioration of cortical neuron dysfunction and cognitive decline in DS with translational relevance to AD.