United States

Abstract Title:
SLCO1B1*5 allele is associated with atorvastatin discontinuation and adverse muscle symptoms in the context of routine care

Background
SLCO1B1 genotype is known to influence patient adherence to statin therapy, in part by increasing the risk for statin-associated musculoskeletal symptoms (SAMS). For simvastatin specifically, the SLCO1B1*5 allele has previously been associated with SAMS. For atorvastatin, prior studies assessing the impact of SLCO1B1*5 on SAMS have yielded inconclusive findings, due to insufficient power.

Methods
This study quantifies the impact of SLCO1B1*5 on atorvastatin discontinuation and SAMS in a large observational cohort using electronic medical record (EMR) data from a single health care system.

Results
In the study cohort (n = 1,627 patients exposed to atorvastatin during the course of routine clinical care), 56% (n = 912 of 1,627 patients) discontinued atorvastatin, and 18% (n = 303 of 1,627 patients) developed SAMS. A univariate analysis revealed that SLCO1B1*5 increased the likelihood that patients would stop atorvastatin during routine care (Odds Ratio 1.2, 95% confidence interval [C.I.]: 1.1 - 1.5, p = 0.04). Further analyses using a multivariate Cox proportional hazards model demonstrated that this same variant was associated with time to atorvastatin discontinuation (Hazard Ratio 1.2, C.I. 1.1 - 1.4, p = 0.004). Additional time-to-event analyses also revealed that SCLO1B1*5 was associated with SAMS (Hazard Ratio 1.4, C.I. 1.1 - 1.7, p = 0.02).

Conclusion
Atorvastatin discontinuation was associated with SAMS (Odds Ratio 1.67, p = 0.0001) in this cohort. It is plausible that SLCO1B1-informed statin therapy with the aim of reducing muscle side effects may lead to improved adherence for this important class of drugs.

2022 AMA Research Challenge

Genetic Variation in SLCO1B1 Increases Risk for Atorvastatin Muscle Side Effects

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Charles Lopresto, DO

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poster

Background: AKI is common following adult orthotopic heart transplantation (OHT) with rates ranging from 40.3% to 72.3%. AKI worsens 12-month survival with a subset of patients requiring kidney replacement therapy (KRT), developing ESRD, worsening CKD, or death. The purpose of our study was to assess the nature of AKI occurring post-adult OHT at the Medical University of South Carolina and to serve as a metric of how to best improve renal outcomes in this cohort of patients.
Methods: We analyzed AKI rates and renal outcomes in a cohort of 120 adult patients undergoing OHT at MUSC from 04/2015 to 04/2021. We investigated AKI incidence, severity, and timing; the effect of hemodilution on AKI I criteria; and KRT indication and initiation in a sub-cohort of AKI patients who required KRT (AKI-D patients). We investigated major adverse kidney events (MAKE) outcomes at 12-months post-OHT. We identified several risk factors for AKI and AKI-D and performed a univariate logistic regression analysis of risk factors.
Results: 90% of patients met AKI criteria within 7 days post-OHT; 10% had no AKI, 48.3% had stage I AKI, 15.8% stage II, and 25.8% stage III. 31% of AKI stage I patients met criteria due to hemodilution. AKI criteria diagnosis was on median day 1 post-OHT. Median initiation of KRT was POD2 for the predominant indication of volume overload. Of AKI-D patients, MAKE criteria was assessed at 12 months post-OHT and showed 74.2% (n=23) of patients had doubling SCr, 16.2% (n=5) were ESRD, and 19.4% (n=6) died. Significant risk factors for AKI included CPB time (OR: 1.007, 95% CI: 1.001-1.013; P=0.015), VIS score (OR: 1.041, 95% CI: 1.011-1.072; P=0.007), preoperative SCr (OR: 5.61, 95% CI: 2.397-13.133; P<0.001), primary graft dysfunction (OR: 8.546, 95% CI: 2.705-26.994; P<0.001), and RV failure (OR: 5.548, 95% CI: 2.263-12.606; P<0.001).
Conclusion: AKI is a common finding post-OHT, however the majority of the AKI in this cohort of patients was AKI stage I. We identified that any AKI was associated with poor renal outcomes such as MAKE-12 months. Timing of all stages of AKI suggests etiologies such as RV failure and graft dysfunction as major risk factors for AKI.

Assessment of the Nature of Acute Kidney Injury Post Adult Orthotopic Heart Transplantation: A Single Tertiary Referral Center Experience

Factors Affecting Quality of Life in Patients on Hemodialysis: Survey from the Dominican Republic

An Analysis of Demographics and Outcomes of Transfer Patients versus Direct Admits Presenting to a Level 1 Trauma Center with a Traumatic Brain Injury

Evaluation of Risk Factors for Intracranial Hemorrhage in Patients with Left Ventricular Assist Devices using a Machine Learning Model

Background
The accumulation of amyloid proteins in the brain leads to synaptic dysfunction initiated by the binding of toxic oligomeric amyloid to the synapses and causes Alzheimer disease, a neurodegenerative disorder that results in cognitive decline. Treatments aimed at blocking this toxicity must pass through the blood-brain barrier to reach their targets. Brain-derived exosomes, nanosized vesicles released by cells that contain proteins and lipids that play significant roles in neurogenesis and synaptic plasticity, have been proposed as an ideal delivery method due to their ability to cross the blood-brain barrier. While previous studies have focused on more invasive intracranial methods, we investigate whether neuronal stem cell (NSC) exosomes delivered intra-arterially can protect against the toxicity of amyloid oligomers.

Methods
Exosomes isolated from rat hippocampal-derived NSC cultures were labeled with the PKH-26 membrane-permeant cell tracker dye prior to intra-arterial infusion of the internal carotid artery. The brains of experimental rats receiving exosomes and control rats receiving sham surgery were harvested after 4 and 24 hours and analyzed for exosome presence via PKH-26 signal detection with fluorescent microscopy. Localization of exosomes in specific cell types was determined using immunofluorescent staining and changes in gene expression were measured using qPCR.

Results
Fluorescent microscopy revealed exosomes in the cortex of rat brains at both 4 and 24 hours. Localization of both PKH-26 and NeuN, a neuron biomarker, showed exosomes were primarily found in neurons. qPCR demonstrated significant changes in gene expression in the brains of exosome treated rats compared to control rats. Exosome delivery increased gene expression of STAT3, a gene involved in neural survival and regeneration, and STX5, a presynaptic modulator. Furthermore, there was decreased expression of amyloid precursor protein and BACE, an enzyme involved in amyloid beta production and a target for Alzheimer’s disease.

Conclusion
Neuronal stem cell derived exosomes successfully crossed the blood-brain barrier after intra-arterial injection, increased gene expression of proteins involved in neurogenesis in the brain, and decreased gene expression of amyloid precursor proteins implicated in the progression of Alzheimer’s disease. Intra-arterial injection shows promise as a reliable delivery mechanism for Alzheimer’s and other neurodegenerative diseases.

Intra-Arterial Injection of Neural Stem Cell Exosomes to Modulate Gene Expression in Alzheimer’s Disease

Background:
A stroke is an interruption of the blood supply to any part of the brain. Neuroprotection is a therapeutic strategy to extend the window for brain reperfusion by reducing neurological injury. Steroid receptor coactivators (SRCs) are a family of proteins consisting of SRC-1, SRC-2, and SRC-3. Since SRCs are expressed and required in the transcription of 80% of genes, they are thought to have multifactorial neuroprotective effects including intracellular proliferation and regeneration, immune response modulation, and angiogenesis. Our study aims to test whether a novel steroid receptor coactivator, MCB-613, can act as an effective neuroprotective agent.

Methods:
Twenty Sprague Dawley rats underwent middle cerebral artery occlusion, obtained by inserting a 0.41 mm diameter filament into the internal carotid artery and advancing until occlusion. Occlusion time was set for 90 minutes and confirmed by 70% drop from baseline perfusion as measured by laser doppler. MCB-613 or saline was administered through intraperitoneal injection 120 minutes after occlusion. Every 24 hours, the animal underwent behavioral testing using a modified Bederson scale and again received either MCB-613 or saline. After a 4-day survival period, brain tissue was sliced into 2 mm segments following euthanasia and stained with 2,3,5-triphenyltetrazolium to measure infarct volume. Apoptosis was measured by TUNEL and Neuron-Specific Enolase immunostaining, whereas microglia were examined by IBA-1 Fluorescence Intensity. 

Results:
Behavioral results demonstrate that subjects treated with MCB-613 suffered significantly less neurologic impairment for the 4-day survival period (p<0.01; MCB-613=1.3, Control=2.7). Additionally, subjects treated with MCB-613 experienced a greater than 50% reduction in infarct (p<0.001; mean infarct area difference: 0.016). Histologic analysis revealed decreased neuronal apoptosis, increased microglia with an M2 (ameboid) pro-reparative phenotype, upregulated Nrf2 pathway in astrocytes mitigating oxidative damage, and decreased inflammatory reaction.

Conclusion:
Our study suggests that MCB-613 has the potential as a neuroprotectant for acute ischemic stroke, confirming previous 1-day survival studies that showed decreased neurological impairment (p<0.01; MCB-613=1.8, Control=3.8). Preliminary results show that 7-day survival subjects treated with MCB-613 also suffered significantly less neurologic impairment (p<0.01; MCB-613=2.4, Control=3.4). Further histologic analysis is needed to uncover the specific mechanism of action for MCB-613 as a steroid receptor coactivator.

Intraperitoneal Infusion of MCB-613 as a Novel Neuroprotectant in a Murine Stroke Model

Background: Postoperative surgical site hematoma (SSH) following lumbosacral surgery carries significant morbidity and increased length of stay (LOS). Intravenous tranexamic acid (ivTXA) was shown to reduce the SSH rate. Topical TXA (tTXA) could potentially benefit patients with contraindications to ivTXA. However, this has not been widely studied.
Objectives: We sought to demonstrate that a quality improvement (QI) protocol using tTXA with/without ivTXA in patients undergoing elective open and minimally invasive lumbosacral surgery could decrease the SSH rate and LOS with no increase in associated complications.
Methods: A retrospective chart review for July 2018-June 2019 demonstrated our pre-implementation baseline SSH rate. Interdisciplinary meetings were conducted to develop standardized institutional measures and perioperative tTXA administration protocol. The primary outcome was SSH necessitating evacuation. The secondary outcome was LOS and TXA-related complications. The post-implementation data were collected prospectively from July 2020-October 2020. Univariate analysis was used to compare pre-implementation and post-implementation cohorts. We considered p-value <.05 significant. 

Results: Comparing consecutive lumbosacral surgical patients in pre- (219 patients) and post-implementation (258 patients), the post-implementation group demonstrated a significantly reduced rate of SSH requiring evacuation (.38% vs. 3.3%, p<.001), a significantly increased tTXA utilization (86.0% vs. 9.6%, p<.001), a significantly lower incidence of SSH (.45% vs.4.8%, p=.037), and a significantly decreased LOS (3.4 ± 2.5 vs. 3.1 ± 2.7, p=.003). There were no complications attributable to TXA use.

Conclusions: Our QI project successfully increased compliance with the use of tTXA. Post-implementation rate of SSH requiring evacuation and LOS was significantly lowered with no associated complications.

Preventing Surgical Site Hematoma using Topical with or without Intravenous Tranexamic Acid in Lumbosacral Surgery: A Quality Improvement Project

With the rise in Technological advances and availability of handheld inexpensive ultrasound devices, we investigated the feasibility of cranial ultrasound image acquisition in a moving ambulance using a handheld device. We concluded that cranial ultrasound image acquisition using handheld ultrasound is feasible in a moving ambulance providing reasonable quality images of visualized landmarks with a very quick turnaround time required for TeleGuidance™ & remote image interpretation by a physician in a 4G network with variable signal strength. This experience is the basis of an ongoing clinical trial for using cranial ultrasound for the detection of intracranial hemorrhage in prehospital settings.

Cranial ultrasound image acquisition and remote physician interpretation in a moving ambulance-simulated test to assess feasibility for pre-hospital EMS applications 

Background
Dementia and its impact on the aging population is a growing public health concern. Alzheimer’s Disease (AD) is the most common form of neurodegenerative disease and is primarily characterized by a decline in cognitive function that affects a person’s day-to-day activities. The development and diagnosis of AD occurs in stages, beginning with cognitive symptoms in the preclinical stage and progressing to mild cognitive impairment (MCI) then mild, moderate, or severe AD. This study is designed to categorize subjects within the Alzheimer’s Disease Neuroimaging Initiative database to discover alternative indicators for the development and diagnosis of AD. 
Methods
981 AD patients were extracted from the ADNI database and had a cortical SUVr ≥ 1.2, measured using PET imaging utilizing the AV45 biomarker. This indicated a patient as Aβ+, meeting the requirements for AD diagnosis. Subjects were analyzed via one-way MANOVAs examining the impacts of head trauma, smoking, and marital status on the onset of cognitive symptoms, MCI, and AD symptoms. 
Results
In congruence with the literature, results indicate that TBI+ patients report earlier onset of MCI (F (1, 114) = 5.660, p < .05). Additionally, results yield that patients who smoke develop AD symptoms later (F(1,23) = 9.211, p < .01) and patients who are divorced develop cognitive impairment earlier (F (4,813) = 2.750, p <.05). 
Conclusion
Although the stages of AD are well-described, its diagnosis presents a challenge, particularly in early stages, as its symptoms are often attributed to the consequences of aging. These results support previous research describing TBI effects on the development of AD and may provide diagnostic insight regarding the development of AD. Future research should focus on improving the diagnostic criteria for AD, providing guidance to researchers and physicians on the development and implementation of early interventions.

Demographic Categorization of Subjects within the Alzheimer’s Disease Neuroimaging Initiative Database

Background: Automating the process of obtaining data through natural language processing (NLP) can be useful in extracting salient information from unstructured radiology reports. However, to ensure rigorous quality control, scalable gold-standard protocols for manual verification of automatic data are essential. Our aim was to develop a standardized pipeline for the verification of large vessel occlusion (LVO) locations in head CT angiograms (CTAs) determined by an NLP algorithm. Our developed pipeline can be applied to other variables that require manual verification for quality control of retrospective datasets. 

Methods: Our initial dataset included 866 patients with 4184 radiology reports; from this we extracted 489 patients with 513 CTA reports, who presented to two tertiary-care institutions with acute large ischemic stroke (>1/2 middle cerebral artery territory) from 2006-2021. We constructed a rule-based system for feature detection using regular expressions and spaCy, a Python NLP integration with advanced sentence parsing and negation to automatically indicate location of LVO. Thereafter, we developed a pipeline for gold-standard verification including manual review of all reports and documentation of feedback with root-cause analysis to understand automatic errors. Secondary review of selected reports by an attending neurologist was also performed, allowing for correction of errors from initial manual review.

Results: We found that the automated NLP algorithm had an accuracy of 78.8% in terms of LVO designation, after initial manual review of CTA reports. Secondary MD review was performed on 60/513 (11.7%) reports with 7/60 (11.7%) reports found to have errors from the initial manual review. After complete review, the frequencies of LVO locations were found to be 38.4% internal carotid artery (ICA)/tandem, 56.9% M1, 36.3% M2, 4.3% M3/M4, 15.0% anterior cerebral artery (ACA), and 0.4% indeterminate location. The most common reason for NLP error included the inability to interpret radiographic findings in the context of surrounding text. For example, the algorithm would misclassify reports with modifiers including “small” or “incomplete,” indicating the lack of complete occlusion.

Conclusion: While tailored rule-based NLP methods can expedite radiology report review for stroke patients, they may err. Therefore, protocolized manual review of radiology reports is necessary, especially for reports with ambiguous language.

Genetic Variation in SLCO1B1 Increases Risk for Atorvastatin Muscle Side Effects

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Assessment of the Nature of Acute Kidney Injury Post Adult Orthotopic Heart Transplantation: A Single Tertiary Referral Center Experience

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