Faculty Bibliography

Heart and lung transplant recipients require care provided by clinicians from multiple different specialties, each contributing unique expertise and perspective. The period the patient spends in the intensive care unit is one of the most critical times in the perioperative trajectory. Various organizational models of intensive care exist, including those led by intensivists, surgeons, transplant cardiologists, and pulmonologists. Coordinating timely efficient intensive care is an essential and logistically difficult goal. The present work product of the American Society of Transplantation's Thoracic and Critical Care Community of Practice, Critical Care Task Force outlines operational guidelines and principles that may be applied in different organizational models to optimize the delivery of intensive care for the cardiothoracic organ recipient.

BACKGROUND AND OBJECTIVES:Multiple system atrophy (MSA) is a progressive neurodegenerative disorder caused by the abnormal accumulation of α-synuclein in the nervous system. Clinical features include autonomic and motor dysfunction, which overlap with those of Parkinson disease (PD), particularly at early disease stages. There is an unmet need for accurate diagnostic and prognostic biomarkers for MSA and, specifically, a critical need to distinguish MSA from other synucleinopathies, particularly PD. The purpose of the study was to develop a unique cutaneous pathologic signature of phosphorylated α-synuclein that could distinguish patients with MSA from patients with PD and healthy controls. METHODS:We studied 31 patients with MSA and 54 patients with PD diagnosed according to current clinical consensus criteria. We also included 24 matched controls. All participants underwent neurologic examinations, autonomic testing, and skin biopsies at 3 locations. The density of intraepidermal, sudomotor, and pilomotor nerve fibers was measured. The deposition of phosphorylated α-synuclein was quantified. Results were compared with clinical rating assessments and autonomic function test results. RESULTS:< 0.0001) than patients with PD. These results provided >90% sensitivity and specificity in distinguishing between the 2 disorders. DISCUSSION:α-synuclein is present in the peripheral autonomic nerves of patients with MSA and when combined with synuclein distribution accurately distinguishes MSA from PD. CLASSIFICATION OF EVIDENCE:This study provides Class II evidence that measurement of phosphorylated α-synuclein in skin biopsies can differentiate patients with MSA from those with PD.

The persistent carotid-vertebrobasilar anastomoses are arterial communications between the anterior and posterior circulations due to the persistence of embryological connections. We here present an extremely rare instance of a transclival persistent carotid-vertebrobasilar anastomosis in a 10-month-old infant, which does not fit into any of the traditionally described categories, such as the trigeminal artery, hypoglossal artery, or proatlantal artery.

BACKGROUND:Pediatric patients with multiple sclerosis (POMS) and related disorders, clinically isolated syndrome (CIS), myelin oligodendrocyte glycoprotein antibody disorder (MOGAD), and neuromyelitis optica spectrum disorder (NMOSD), are commonly treated with immunosuppressants. Understanding the impact of SARS-CoV-2 infection in patients may inform treatment decisions. OBJECTIVE:Characterize SARS-CoV-2 infection prevalence and severity among a cohort of patients with POMS and related disorders, as well as the impact of disease-modifying therapies (DMTs). METHODS:POMS and related disorders patients enrolled in a large, prospective registry were screened for COVID-19 during standard-of-care neurology visits. If confirmed positive of having infection, further analysis was undertaken. RESULTS: = 0.016). CONCLUSIONS:B-cell-depleting treatment was associated with a higher risk of COVID-19, higher rates of hospitalization, and ICU admission, suggesting this therapy carries a higher risk of severe infection in POMS and related disorders.

TRIAL DESIGN/METHODS:Current protocols for treatment of acute ischemic stroke with intravenous thrombolytics, such as alteplase (tPA) and tenecteplase (tNK), recommend the completion of a routine non-contrast head CT at 24 hours post treatment to evaluate for hemorrhage prior to the initiation of antiplatelet therapy for secondary stroke prevention. This guideline was instituted because it had been part of the protocol in the NINDS multicenter randomized placebo-controlled trial that showed the benefit of IV thrombolytics within 3 hours of stroke onset. Recent observational studies indicate that the repeat (stability) head CT rarely alters clinical management, in the absence of neurological worsening or evidence of clinical signs of hemorrhagic conversion, such as seizures, severe headache, or novel acute deficits. A solitary CT carries with it a non-negligible dose of radiation with additive cost to the medical system at large. METHODS:We aimed to identify, with a randomized, blinded outcome assessment trial, if a routine head CT at 24 hours, in the absence of clinical indication, negatively influences clinical outcomes. We enrolled 58 patients, and evaluated differences between groups with t-tests. We also evaluated differences between outcomes (90 day modified Rankin Scale, mRS and change in National Institutes of Health Stroke Scale, NIHSS) from pretreatment to discharge using multivariable logistic regression, including age, baseline NIHSS, and group as independent variables. RESULTS:We found no added benefit of routine CT on either outcome measure. CONCLUSION/CONCLUSIONS:It is likely safe to forgo follow up imaging after thrombolysis in the absence of clinical decompensation.

Introduction: Alzheimer"™s disease (AD) and Lewy body disease (LBD) are the two most common neurodegenerative dementias and can occur in combination (AD+LBD). Due to overlapping biomarkers and symptoms, clinical differentiation of these subtypes could be difficult. However, it is unclear how the magnitude of diagnostic uncertainty varies across dementia spectra and demographic variables. We aimed to compare clinical diagnosis and post-mortem autopsy-confirmed pathological results to assess the clinical subtype diagnosis quality across these factors. Methods: We studied data of 1,920 participants recorded by the National Alzheimer"™s Coordinating Center from 2005 to 2019. Selection criteria included autopsy-based neuropathological assessments for AD and LBD, and the initial visit with Clinical Dementia Rating (CDR) stage of normal, mild cognitive impairment, or mild dementia. Longitudinally, we analyzed the first visit at each subsequent CDR stage. This analysis included positive predictive values, specificity, sensitivity and false negative rates of clinical diagnosis, as well as disparities by sex, race, age, and education. If autopsy-confirmed AD and/or LBD was missed in the clinic, the alternative clinical diagnosis was analyzed. Findings: In our findings, clinical diagnosis of AD+LBD had poor sensitivities. Over 61% of participants with autopsy-confirmed AD+LBD were diagnosed clinically as AD. Clinical diagnosis of AD had a low sensitivity at the early dementia stage and low specificities at all stages. Among participants diagnosed as AD in the clinic, over 32% had concurrent LBD neuropathology at autopsy. Among participants diagnosed as LBD, 32% to 54% revealed concurrent autopsy-confirmed AD pathology. When three subtypes were missed by clinicians, "No cognitive impairment" and "primary progressive aphasia or behavioral variant frontotemporal dementia" were the leading primary etiologic clinical diagnoses. With increasing dementia stages, the clinical diagnosis accuracy of black participants became significantly worse than other races, and diagnosis quality significantly improved for males but not females. Discussion: These findings demonstrate that clinical diagnosis of AD, LBD, and AD+LBD are inaccurate and suffer from significant disparities on race and sex. They provide important implications for clinical management, anticipatory guidance, trial enrollment and applicability of potential therapies for AD, and promote research into better biomarker-based assessment of LBD pathology.

INTRODUCTION:Deep brain stimulation (DBS) is an effective treatment for Parkinson's disease (PD), but its efficacy is tied to DBS programming, which is often time consuming and burdensome for patients, caregivers, and clinicians. Our aim is to test whether the Mobile Application for PD DBS (MAP DBS), a clinical decision support system, can improve programming. METHODS:We conducted an open-label, 1:1 randomized, controlled, multicenter clinical trial comparing six months of SOC standard of care (SOC) to six months of MAP DBS-aided programming. We enrolled patients between 30 and 80 years old who received DBS to treat idiopathic PD at six expert centers across the United States. The primary outcome was time spent DBS programming and secondary outcomes measured changes in motor symptoms, caregiver strain and medication requirements. RESULTS:We found a significant reduction in initial visit time (SOC: 43.8 ± 28.9 min n = 37, MAP DBS: 27.4 ± 13.0 min n = 35, p = 0.001). We did not find a significant difference in total programming time between the groups over the 6-month study duration. MAP DBS-aided patients experienced a significantly larger reduction in UPDRS III on-medication scores (-7.0 ± 7.9) compared to SOC (-2.7 ± 6.9, p = 0.01) at six months. CONCLUSION:MAP DBS was well tolerated and improves key aspects of DBS programming time and clinical efficacy.

Introduction: Previous case-control studies of sudden unexpected death in epilepsy (SUDEP) patients failed to identify ECG features (peri-ictal heart rate, heart rate variability, corrected QT interval, postictal heart rate recovery, and cardiac rhythm) predictive of SUDEP risk. This implied a need to derive novel metrics to assess SUDEP risk from ECG. Methods: We applied Single Spectrum Analysis and Independent Component Analysis (SSA-ICA) to remove artifact from ECG recordings. Then cross-frequency phase-phase coupling (PPC) was applied to a 20-s mid-seizure window and a contour of −3 dB coupling strength was determined. The contour centroid polar coordinates, amplitude (alpha) and angle (theta), were calculated. Association of alpha and theta with SUDEP was assessed and a logistic classifier for alpha was constructed. Results: Alpha was higher in SUDEP patients, compared to non-SUDEP patients (p < 0.001). Theta showed no significant difference between patient populations. The receiver operating characteristic (ROC) of a logistic classifier for alpha resulted in an area under the ROC curve (AUC) of 94% and correctly classified two test SUDEP patients. Discussion: This study develops a novel metric alpha, which highlights non-linear interactions between two rhythms in the ECG, and is predictive of SUDEP risk.

OBJECTIVE:Interventions for carotid occlusions are infrequently undertaken and the outcomes are poorly defined. We sought to study patients undergoing urgent carotid revascularization for symptomatic occlusions. METHODS:The Society for Vascular Surgery Vascular Quality Initiative database was queried from 2003 to 2020 to identify patients with carotid occlusions undergoing carotid endarterectomy (CEA). Only symptomatic patients undergoing urgent interventions within 24 hours of presentation were included. Patients were identified based on CT and MRI imaging. This cohort was compared to symptomatic patients undergoing urgent intervention for severe stenosis (≥80%). Primary endpoints were perioperative stroke, death, myocardial infarction (MI) and composite outcomes as defined by the SVS reporting guidelines. Patient characteristics were analyzed to determine predictors of perioperative mortality and neurological events. RESULTS:inhibitor (32.0%), aspirin (77.9%) and renin-angiotensin inhibitor (43.7%) preoperatively. When compared to patients undergoing urgent endarterectomy for severe stenosis (≥80%), those with symptomatic occlusion were well matched with regards to risk factors, but the severe stenosis cohort appeared better medically managed and less likely to present with cortical stroke symptoms. Perioperative outcomes were significantly worse for the carotid occlusion cohort, primarily driven by higher perioperative mortality (2.8% vs 0.9%, P<.001). The composite endpoint of stroke/death/MI was also significantly worse in the occlusion cohort (7.7% vs 4.9%, P=.014). On multivariate analysis, carotid occlusion was associated with increased mortality (OR, 3.028; 95% CI, 1.362-6.730; P=.007) and composite outcome of stroke, death, or MI (OR, 1.790; 95% CI, 1.135-2.822, P=.012). CONCLUSIONS:Revascularization for symptomatic carotid occlusion constitutes approximately 2% of carotid interventions captured in the VQI, affirming the rarity of this undertaking. These patients have acceptable rates of perioperative neurologic events but are at an elevated risk of overall perioperative adverse events, primarily driven by higher mortality, compared to those with severe stenosis. Carotid occlusion appears to be the most significant risk factor for the composite endpoint of perioperative stroke, death, or MI. While intervention for a symptomatic carotid occlusion may be performed with acceptable rate of perioperative complications, judicious patient selection is warranted in this high-risk cohort.

Heterozygous pathogenic variants in POLR1A, which encodes the largest subunit of RNA Polymerase I, were previously identified as the cause of acrofacial dysostosis, Cincinnati-type. The predominant phenotypes observed in the cohort of 3 individuals were craniofacial anomalies reminiscent of Treacher Collins syndrome. We subsequently identified 17 additional individuals with 12 unique heterozygous variants in POLR1A and observed numerous additional phenotypes including neurodevelopmental abnormalities and structural cardiac defects, in combination with highly prevalent craniofacial anomalies and variable limb defects. To understand the pathogenesis of this pleiotropy, we modeled an allelic series of POLR1A variants in vitro and in vivo. In vitro assessments demonstrate variable effects of individual pathogenic variants on ribosomal RNA synthesis and nucleolar morphology, which supports the possibility of variant-specific phenotypic effects in affected individuals. To further explore variant-specific effects in vivo, we used CRISPR-Cas9 gene editing to recapitulate two human variants in mice. Additionally, spatiotemporal requirements for Polr1a in developmental lineages contributing to congenital anomalies in affected individuals were examined via conditional mutagenesis in neural crest cells (face and heart), the second heart field (cardiac outflow tract and right ventricle), and forebrain precursors in mice. Consistent with its ubiquitous role in the essential function of ribosome biogenesis, we observed that loss of Polr1a in any of these lineages causes cell-autonomous apoptosis resulting in embryonic malformations. Altogether, our work greatly expands the phenotype of human POLR1A-related disorders and demonstrates variant-specific effects that provide insights into the underlying pathogenesis of ribosomopathies.