Faculty Bibliography

Background/Purpose: Interferon (IFN)-alpha contributes to susceptibility and severe manifestations in systemic lupus erythematosus (SLE). The PRKG1 rs7897633 variant has been previously identified as the top hit in European ancestry patients with SLE and high IFN-alpha compared to those with low circulating IFN activity. However, the mechanisms by which PRKG1 polymorphisms impact the immune system remain unknown. PRKG1 codes for the cGMP-dependent protein kinase I (PKGI). Activation of PKGI leads to VASP phosphorylation, and the inhibition of RhoA and Rho-associated kinases (ROCK). A subgroup of patients with SLE exhibit higher ROCK activity in circulating immune cells compared to healthy controls. ROCK inhibition decreases IFN-alpha production and ameliorates disease in murine models of lupus. Accordingly, we aimed to assess whether the PRKG1 gene variant was associated with decreased gene expression and activity of PRKG1, hyperactivation of the ROCK pathway, and altered response to type I IFN.
Method(s): We used B lymphoblastoid cell lines (LCL) derived from healthy subjects of European ancestry (Coriell repositories) homozygous (AA or CC) and heterozygous (AC) at the rs7897633 SNP for all experiments. Gene expression of PRKG1, RHOA, and ROCK was assessed by RT-qPCR using gene-specific primers, normalized by GAPDH, and measured by the 2-DELTADELTACT method. IFN score at baseline and after treatment of LCL with increasing doses of IFN-alpha was measured by quantifying 3 canonical IFN-stimulated genes (IFIT1, MX1 and PKR) and summing to generate a score reflecting the degree of IFN-induced gene expression in the cells. Abundance of PKGI and VASP phosphorylation (as a surrogate of PKGI activity) were determined by Western blotting at baseline and after treatment with a PKGI agonist. ROCK2 enzymatic activity was performed by a colorimetric assay (Cell Biolabs). Unstimulated and stimulated cells were compared among PRKG1 genotype categories. Statistically significant differences were determined by Mann Whitney U test or sum-of-squares F test, as appropriate.
Result(s): PRKG1 expression was lower in the homozygous AA genotype as compared with the homozygous CC genotype in LCL (p< 0.05). In contrast, ROCK expression was higher in LCL with the AA rs7897633 genotype (p< 0.05). Compared to LCL with the homozygous AA variant of rs7897633, homozygous CC LCL have greater abundance of PKGI, phosphorylated VASP/total VASP ratio in response to a PKGI agonist (indicating increased PKGI activity), and lower baseline ROCK activity (sum-of-squares F test, p< 0.05). The IFN score was significantly higher in the homozygous CC allele LCL, both at baseline and with increasing doses of IFN-alpha, suggesting increased sensitivity to type I IFN (p< 0.05).
Conclusion(s): PRKG1 AA genotype associates with lower PRKG1 and higher ROCK mRNA expression, decreased PKGI abundance and activity, and greater ROCK baseline activity. In contrast, the rs7897633 CC genotype is associated with increased response to IFNalpha. Overall, these findings suggest an important role of genetic variation at PRKG1 in modulating the RhoA-ROCK pathway and regulating response to type I IFNs in LCL, which may have therapeutic implications in patients with SLE

Background and Objective/UNASSIGNED:Posttraumatic stress disorder (PTSD) is a serious and frequently debilitating psychiatric condition that can occur in people who have experienced traumatic stessors, such as war, violence, sexual assault and other life-threatening events. Treatment of PTSD and traumatic brain injury (TBI) in veterans is challenged by diagnostic complexity, partially due to PTSD and TBI symptom overlap and to the fact that subjective self-report assessments may be influenced by a patient's willingness to share their traumatic experiences and resulting symptoms. Corticotropin-releasing factor (CRF) is one of the main mediators of hypothalamic pituitary adrenal (HPA)-axis responses in stress and anxiety. Methods and Results/UNASSIGNED:We analyzed serum CRF levels in 230 participants including heathy controls (64), and individuals with PTSD (53), TBI (70) or PTSD+TBI (43) by enzyme immunoassay (EIA). Significantly lower CRF levels were found in both the PTSD and PTSD+TBI groups compared to healthy control (PTSD vs Controls: P=0.0014, PTSD + TBI vs Controls: P=0.0011) and chronic TBI participants (PTSD vs TBI: P<0.0001PTSD + TBI vs TBI: P<0.0001) , suggesting a PTSD-related mechanism independent from TBI and associated with CRF reduction. CRF levels negatively correlated with PTSD severity on the CAPS-5 scale in the whole study group. Conclusions/UNASSIGNED:Hyperactivation of the HPA axis has been classically identified in acute stress. However, the recognized enhanced feedback inhibition of the HPA axis in chronic stress supports our findings of lower CRF in PTSD patients. This study suggests that reduced serum CRF in PTSD should be further investigated. Future validation studies will establish if CRF is a possible blood biomarker for PTSD and/or for differentiating PTSD and chronic TBI symptomatology.

Background: To describe preliminary results of a multi-center, randomized, blinded, placebo-controlled, pilot trial of shunt surgery in INPH.
Method(s): Five sites randomized 18 patients scheduled for ventriculoperitoneal shunting based on CSF-drainage response. Patients were randomized to a Codman Certas Plus valve with SiphonGuard at either setting 4 (Active, N=9) or setting 8/virtual off (Placebo, N=9). Patients and assessors were blinded to the shunt setting. Outcomes included 10-meter gait velocity, cognitive function, and bladder activity scores. The prespecified primary analysis compared changes in 4-month gait velocity in the Active versus Placebo groups. After the 4 months follow up, all shunts were opened, i.e., adjusted to setting 4 whereafter patients underwent 8 and 12-month post-surgical assessment. At the 8-month follow-up, the Placebo group had had an open shunt for 4 months and the Active group for 8 months.
Result(s): At 4-months, gait velocity increased by 0.28+/-0.28m/s in the Active Group and 0.04+/-0.17m/s in the Placebo Group (p=0.071). Overactive Bladder (OAB-q) scores improved in the Active versus Placebo groups (p=0.007). At 8 months, Placebo gait velocity increased by 0.36+/-0.27m/s and was comparable to the Active Group (0.40+/-0.20m/s p=0.56).
Conclusion(s): This study shows a trend suggesting gait velocity improves more at an Active shunt setting than a Placebo shunt setting and demonstrates the feasibility of a placebo-controlled trial in iNPH

Attention-deficit hyperactivity disorder (ADHD) affects multiple cognitive domains, including impaired attention, hyperactivity, and increased impulsivity. According to the CDC, 9.4% of children between 2 and 17 years old have been diagnosed with ADHD. Neurotransmitters such as noradrenaline and dopamine have been suggested as crucial players in the pathophysiology of ADHD and are often targets of modern medication. Adenosine receptors types A1 and A2a in the brain are inhibited by caffeine: a stimulant known to augment attention by increasing cholinergic and dopaminergic transmission. The cognitive function of attention is also enhanced by the amino acid: L-theanine. The mechanism of action is that it behaves like a glutamate reuptake inhibitor while also acting in the hippocampus as a competitive low-affinity glutamate receptor antagonist. It's also shown to have a neuroprotective effect by its action on the gamma aminobutyric acid (GABA)-A receptors. Our systematic review investigates the literature and clinical trials on the cognitive-enhancing effects of caffeine and L-theanine.

BACKGROUND:The initial limited supply of COVID-19 vaccine in the U.S. presented significant allocation, distribution, and delivery challenges. Information that can assist health officials, hospital administrators and other decision makers with readily identifying who and where to target vaccine resources and efforts can improve public health response. OBJECTIVE:The objective of this project was to develop a publicly available geographical information system (GIS) web mapping tool that would assist North Carolina health officials readily identify high-risk, high priority population groups and facilities in the immunization decision making process. METHODS:Publicly available data were used to identify 14 key health and socio-demographic variables and 5 differing themes (social and economic status; minority status and language; housing situation; at risk population; and health status). Vaccine priority population index (VPI) scores were created by calculating a percentile rank for each variable over each N.C. Census tract. All Census tracts (N = 2,195) values were ranked from lowest to highest (0.0 to 1.0) with a non-zero population and mapped using ArcGIS. RESULTS:The VPI tool was made publicly available (https://enchealth.org/) during the pandemic to readily assist with identifying high risk population priority areas in N.C. for the planning, distribution, and delivery of COVID-19 vaccine. DISCUSSION/CONCLUSIONS:While health officials may have benefitted by using the VPI tool during the pandemic, a more formal evaluation process is needed to fully assess its usefulness, functionality, and limitations. CONCLUSION/CONCLUSIONS:When considering COVID-19 immunization efforts, the VPI tool can serve as an added component in the decision-making process.

INTRODUCTION:Huntington's disease is a neurodegenerative disease that is characterized by motor dysfunction, behavioral/psychiatric symptoms, and cognitive impairment. Because of the lack of availability of curative or disease modifying treatments, much of clinical practice in HD care to date has focused on symptomatic treatment. Recent work has created optimism surrounding possible emerging disease modifying therapeutics. HD is a developing therapeutic field with diverse and promising emerging therapies. AREAS COVERED:A PubMed literature review was completed to discover pertinent reviews and analyses. ClinicalTrials.gov was referenced to find updated information about ongoing and planned trials. Lastly, because of the rapidly evolving nature of HD treatments, drug manufacturer websites and press releases were reviewed to provide current information surrounding recently reported trial results. EXPERT OPINION:Recent setbacks involving antisense oligonucleotide research should not diminish enthusiasm and hope for the many other novel therapies currently being pursued. We remain optimistic about the many promising emerging therapies for HD, and we expect that growing knowledge about the pathophysiology of the underlying disease and constant advances in biotechnology will lead to therapies that have a meaningful impact in the lives of patients, their families, and those who care for them.

We reviewed data on the American diet from 1800 to 2019. Methods: We examined food availability and estimated consumption data from 1800 to 2019 using historical sources from the federal government and additional public data sources. Results: Processed and ultra-processed foods increased from <5 to >60% of foods. Large increases occurred for sugar, white and whole wheat flour, rice, poultry, eggs, vegetable oils, dairy products, and fresh vegetables. Saturated fats from animal sources declined while polyunsaturated fats from vegetable oils rose. Non-communicable diseases (NCDs) rose over the twentieth century in parallel with increased consumption of processed foods, including sugar, refined flour and rice, and vegetable oils. Saturated fats from animal sources were inversely correlated with the prevalence of NCDs. Conclusions: As observed from the food availability data, processed and ultra-processed foods dramatically increased over the past two centuries, especially sugar, white flour, white rice, vegetable oils, and ready-to-eat meals. These changes paralleled the rising incidence of NCDs, while animal fat consumption was inversely correlated.

Background: MOG antibody disorder (MOGAD) is associated with diverse clinical phenotypes, including recurrent and bilateral optic neuritis, acute disseminated encephalomyelitis, and longitudinally extensive transverse myelitis with a predilection for the conus medullaris. Spinal nerve root involvement in this disease has rarely been described.
Objective(s): To describe a case of MOG antibody disorder with an unusual radiographic presentation.
Method(s): A case is described and review of the literature was performed.
Result(s): A 53-year-old previously healthy man presented to our hospital with three weeks of numbness and pain involving his right arm, bilateral lower extremities, and perineum. Neurologic exam was notable for decreased sensation in his right hand and left leg, hyperreflexia in bilateral lower extremities, and an extensor plantar response on the left. MRI spine was notable for multifocal short-segment T2 hyperintense lesions consistent with demyelination. There was also contrast enhancement of the cauda equina nerve roots and focal lobular enhancement of the left S1 nerve root. MRI brain showed several small T2 hyperintense brainstem lesions. He was started on pulse dose intravenous steroids while undergoing extensive work-up for inflammatory, infectious, and neoplastic causes. Serology was notable for mildly elevated ACE. CSF showed elevated protein. Given these laboratory and radiographic findings, an inflammatory etiology such as neurosarcoidosis was initially felt to be most likely. CT chest was negative for evidence of pulmonary sarcoid. He demonstrated clinical improvement with steroids and was discharged on a slow taper. MOG antibody in the serum (by cell-based assay) resulted positive at 1:100, suggestive of demyelination in the setting of MOGAD. The patient opted for monthly IV immunoglobulin (IVIG) maintenance therapy and has been clinically stable. Repeat MRI two months later showed stable areas of spinal nerve root enhancement and decrease in some of the cord lesions.
Conclusion(s): Our case demonstrates that MOGAD should be a diagnostic consideration when MRI shows spinal nerve root enhancement in the appropriate clinical context, especially with the additional presence of CNS lesions that are typical of demyelination. MOGAD can manifest clinically and radiographically in both the central and peripheral nervous system

Background: Fatigue is among the most frequent and disabling symptoms in RMS patients.
Objective(s): To measure multiple sclerosis (MS) fatigue and its impact on daily life in a real-world population using a survey including the relapsing MS (RMS)-specific Fatigue Symptoms and Impacts Questionnaire-Relapsing Multiple Sclerosis (FSIQ-RMS).
Method(s): This is an ongoing noninterventional prospective study of RMS patients recruited across the USA via an online survey. Participants completed questionnaires including disease history, disease status, sleep, social and emotional functioning, and the FSIQ-RMS, administered daily for 7 days. The FSIQ-RMS measures self-reported fatigue, and scores range from 0-100 (higher score = greater severity). The impact of fatigue on several aspects of patient's life was rated from 0 (no impact) to 10 (very high impact).
Result(s): A total of 300 RMS participants completed the 7-day assessment: mean age: 43.0 yrs; 88% women; mean diagnosis age: 32 yrs. Fatigue was reported as the symptom with the greatest impact on daily functioning. Participants with lower disability rated fatigue as the most impactful symptom on daily life. Fatigue was rated as severe, with a mean score: 57.3 for the FSIQ-RMS symptom domain; 3 impact sub-domain scores were 42.3, 43.4 and 50.1 (physical, cognitive/emotional, and coping). Fatigue severity did not vary among patients receiving high efficacy disease modifying therapy (DMT) vs other DMTs (44% [n=111] vs 56% [n=143], with score of 57.8?}17.6 vs 55.9?}19.8). Impact of ability to perform daily activities was rated as the highest (6.9/10) in terms of impact on patient's life. Because of MS, 44% of participants did not work. Among those who were working currently (48%), the impact of fatigue on professional life was rated as 4.5/10. Nearly half of the participants (49% of 300) discussed fatigue at each visit with their neurologists and 35% discussed at most visits, with 'impact of fatigue on quality of life' being the most discussed topic (65% of 289). Participants used different approaches to manage their fatigue including avoided heat exposure (77%), took breaks (65%), managed their energy (59%), took non-medicinal products (58%); however, only 6% (of 293) were totally satisfied with these strategies.
Conclusion(s): In this survey including the novel RMS specific FSIQ-RMS, fatigue occurred in most MS participants and adversely influenced patient's daily functioning and life. Fatigue remains a major concern for those with MS

PURPOSE/OBJECTIVE:Neurologic determination of death (NDD) is legally accepted as death in Canada but remains susceptible to misunderstandings. In some cases, families request continued organ support after NDD. Conflicts can escalate to formal legal challenges, causing emotional, financial, and moral distress for all involved. We describe prevalence, characteristics, and common experiences with requests for continued organ support following NDD in Canada. METHODS:Mixed-methods design combining anonymous online survey with semi-structured interviews of Canadian critical care physicians (448 practitioners, adult and pediatric). RESULTS:One hundred and six physicians responded to the survey and 12 participated in an interview. Fifty-two percent (55/106) of respondents had encountered a request for continued organ support after NDD within two years, 47% (26/55) of which involved threat of legal action. Requests for continued support following NDD ranged from appeals for time for family to gather before ventilator removal to disagreement with the concept of NDD. Common responses to requests included: consultation with an additional physician (54%), consultation with spiritual services (41%), and delay of one to three days for NDD acceptance (49%). Respondents with prior experience were less likely to recommend ancillary tests (P = 0.004) or consultation with bioethics services (P = 0.004). Qualitative analysis revealed perceptions that requests for continued organ support were driven by mistrust, tensions surrounding decision-making, and cultural differences rather than a lack of specific information about NDD. CONCLUSIONS:Family requests for continued somatic support following NDD were encountered by half our sample of Canadian critical care physicians. Mitigation strategies require attention to the multifaceted social contexts surrounding these complex scenarios.