Neuropathological findings and in vivo imaging correlates of the red nucleus compared to those of the substantia nigra pars compacta in parkinsonisms.

INTRODUCTION: The substantia nigra pars compacta (SNc) is the key pathologic locus in neurodegenerative parkinsonian disorders. Recently, in vivo susceptibility MRI metrics were associated with postmortem glial cell density and tau burden in the SNc of parkinsonism subjects. This study investigated the red nucleus (RN), another iron-rich region adjacent to the SNc and a potential site of higher functionality in parkinsonisms. METHODS: In vivo MRI and postmortem data were obtained from 34 parkinsonism subjects and 3 controls. Neuron density, glial cell density, and percentages of area occupied by α-synuclein and tau were quantified using digitized midbrain slides. R2* and quantitative susceptibility mapping (QSM) metrics in the RN and SNc were derived from multi-gradient echo images. Histopathology data were compared between the RN and SNc using paired t-tests. MRI-histology associations were analyzed using partial Pearson correlations. RESULTS: The RN had greater neuron (t23 = 3.169, P = 0.004) and glial cell densities (t23 = 2.407, P = 0.025) than the SNc, whereas the SNc had greater α-synuclein (t28 = 4.614, P < 0.0001) and tau burden (t24 = 4.513, P = 0.0001). In both the RN (R2*: r = 0.47, P = 0.043; QSM: r = 0.52, P = 0.024) and SNc (R2*: r = 0.57, P = 0.01; QSM: r = 0.58, P = 0.009), MRI values were associated with glial cell density but not neuron density or α-synuclein (Ps > 0.092). QSM associated with tau burden (r = 0.49, P = 0.038) in the SNc, but not the RN. CONCLUSIONS: The RN is resilient to parkinsonian-related pathological processes compared to the SNc, and susceptibility MRI captured glial cell density in both regions. These findings help to further our understanding of the underlying pathophysiological processes in parkinsonisms.

Susceptibility Magnetic Resonance Imaging Correlates with Glial Density and Tau in the Substantia Nigra Pars Compacta.

BACKGROUND: Susceptibility magnetic resonance imaging (MRI) is sensitive to iron-related changes in the substantia nigra pars compacta (SNc), the key pathologic locus of parkinsonisms. It is unclear, however, if iron deposition in the SNc is associated with its neurodegeneration. OBJECTIVE: The objective of this study was to test whether susceptibility MRI metrics in parkinsonisms are associated with SNc neuropathologic features of dopaminergic neuron loss, gliosis, and α-synuclein and tau burden. METHODS: This retrospective study included 27 subjects with both in vivo MRI and postmortem data. Multigradient echo imaging was used to derive the apparent transverse relaxation rate (R2*) and quantitative susceptibility mapping (QSM) in the SNc. Archived midbrain slides that were stained with hematoxylin and eosin, anti-α-synuclein, and anti-tau were digitized to quantify neuromelanin-positive neuron density, glial density, and the percentages of area occupied by positive α-synuclein and tau staining. MRI-histology associations were examined using Pearson correlations and regression. RESULTS: Twenty-four subjects had postmortem parkinsonism diagnoses (Lewy body disorder, progressive supranuclear palsy, multiple system atrophy, and corticobasal degeneration), two had only Alzheimer's neuropathology, and one exhibited only mild atrophy. Among all subjects, both R2* and QSM were associated with glial density (r ≥ 0.67; P < 0.001) and log-transformed tau burden (r ≥ 0.53; P ≤ 0.007). Multiple linear regression identified glial density and log-transformed tau as determinants for both MRI metrics (R2 ≥ 0.580; P < 0.0001). Neither MRI metric was associated with neuron density or α-synuclein burden. CONCLUSIONS: R2* and QSM are associated with both glial density and tau burden, key neuropathologic features in the parkinsonism SNc. © 2023 International Parkinson and Movement Disorder Society.

Dynamics of Nigral Iron Accumulation in Parkinson's Disease: From Diagnosis to Late Stage.

BACKGROUND: Higher nigral iron has been reported in Parkinson's disease (PD). OBJECTIVE: The aim is to understand the dynamics of nigral iron accumulation in PD and its association with drug treatment. METHODS: Susceptibility magnetic resonance imaging data were obtained from 79 controls and 18 drug-naive (PDDN ) and 87 drug-treated (PDDT ) PD patients. Regional brain iron in basal ganglia and cerebellar structures was estimated using quantitative susceptibility mapping. Nigral iron was compared between PDDN and PDDT subgroups defined by disease duration (early [PDE, <2 years], middle [PDM, 2-6 years], and later [PDL, >6 years]). Associations with both disease duration and types of antiparkinson drugs were explored using regression analysis. RESULTS: Compared to controls, PDDN had lower iron in the substantia nigra (P = 0.018), caudate nucleus (P = 0.038), and globus pallidus (P = 0.01) but not in the putamen or red nucleus. In contrast, PDDT had higher iron in the nigra (P < 0.001) but not in other regions, compared to either controls or PDDN . Iron in the nigra increased with disease duration (PDE > PDDN [P = 0.001], PDM > PDE [P = 0.045]) except for PDM versus PDL (P = 0.226). Levodopa usage was associated with higher (P = 0.013) nigral iron, whereas lower nigral iron was correlated with selegiline usage (P = 0.030). CONCLUSION: Nigral iron is lower before the start of dopaminergic medication and then increases throughout the disease until it plateaus at late stages, suggesting increased iron may not be an etiological factor. Interestingly, PD medications may have differential associations with iron accumulation that need further investigation. © 2022 International Parkinson and Movement Disorder Society.

Higher R2* in the Red Nucleus Is Associated With Lead Exposure in an Asymptomatic Welder Cohort.

Lead is a nonessential metal and may be a coexposure in welding fumes. Preclinical data indicate lead may affect iron regulation. The current study investigated blood lead concentrations and their association with brain iron accumulation in workers with chronic welding fume exposure, with a focus on iron-rich subcortical regions of the cerebellum and basal ganglia. Occupational exposure, whole blood metal, and brain MRI data were obtained from 29 controls and 42 welders. R2* (1/T2*) and R1 (T1 relaxation rate) values were used to estimate brain iron and manganese content, respectively. Blood metals and brain R2* (in the red nucleus [RN], dentate nucleus, caudate, putamen, globus pallidus, and substantia nigra) were compared between groups. Associations between brain R2* values and exposure metrics were tested within each group, and analyses were adjusted for potential confounders. Welders had significantly higher levels of whole blood lead, manganese, iron, and copper. Welders also had higher R2* RN (p = .002), but not R1. A 2nd-order polynomial modeled the association between R2* RN and a long-term welding exposure metric. In welders, but not controls, R2* RN was associated positively with whole blood lead (r = 0.54, p = .003), and negatively with whole blood manganese (r = -0.43, p = .02). Higher blood Pb and lower blood Mn independently accounted for variance in high RN R2*. Together, these data suggest that higher RN R2* values may mark lead exposure in welders. Because lead is a known neurotoxicant, additional studies are warranted to confirm this finding, and ascertain its scientific and public/occupational health implications.

An operationally implementable model for predicting the effects of an infectious disease on a comprehensive regional healthcare system.

An operationally implementable predictive model has been developed to forecast the number of COVID-19 infections in the patient population, hospital floor and ICU censuses, ventilator and related supply chain demand. The model is intended for clinical, operational, financial and supply chain leaders and executives of a comprehensive healthcare system responsible for making decisions that depend on epidemiological contingencies. This paper describes the model that was implemented at NorthShore University HealthSystem and is applicable to any communicable disease whose risk of reinfection for the duration of the pandemic is negligible.

Emergency department bounceback characteristics for patients diagnosed with COVID-19.

BACKGROUND: The global healthcare burden of COVID-19 continues to rise. There is currently limited information regarding the disease progression and the need for hospitalizations in patients who present to the Emergency Department (ED) with minimal or no symptoms. OBJECTIVES: This study identifies bounceback rates and timeframes for patients who return to the ED due to COVID-19 after initial discharge on the date of testing. METHODS: Using the NorthShore University Health System's (NSUHS) Enterprise Data Warehouse (EDW), we conducted a retrospective cohort analysis of patients who were tested positive for COVID-19 and were discharged home on the date of testing. A one-month follow-up period was included to ensure the capture of disease progression. RESULTS: Of 1883 positive cases with initially mild symptoms, 14.6% returned to the ED for complaints related to COVID-19. 56.9% of the mildly symptomatic bounceback patients were discharged on the return visit while 39.5% were admitted to the floor and 3.6% to the ICU. Of the 1120 positive cases with no initial symptoms, only four returned to the ED (0.26%) and only one patient was admitted. Median initial testing occurred on day 3 (2-5.6) of illness, and median ED bounceback occurred on day 9 (6.3-12.7). Our statistical model was unable to identify risk factors for ED bouncebacks. CONCLUSION: COVID-19 patients diagnosed with mild symptoms on initial presentation have a 14.6% rate of bounceback due to progression of illness.

G-Quadruplexes as pathogenic drivers in neurodegenerative disorders.

G-quadruplexes (G4s), higher-order DNA and RNA secondary structures featuring guanine-rich nucleic acid sequences with various conformations, are widely distributed in the human genome. These structural motifs are known to participate in basic cellular processes, including transcription, splicing, and translation, and their functions related to health and disease are becoming increasingly recognized. In this review, we summarize the landscape of G4s involved in major neurodegenerative disorders, describing the genes that contain G4-forming sequences and proteins that have high affinity for G4-containing elements. The functions of G4s are diverse, with potentially protective or deleterious effects in the pathogenic cascades of various neurological diseases. While the studies of the functions of G4s in vivo, including those involved in pathophysiology, are still in their early stages, we will nevertheless discuss the evidence pointing to their biological relevance. A better understanding of this unique structural element in the biological context is important for unveiling its potential roles in the pathogenesis of diseases such as neurodegeneration and for designing new diagnostic and therapeutic strategies.

HFE H63D Limits Nigral Vulnerability to Paraquat in Agricultural Workers.

Paraquat is an herbicide whose use is associated with Parkinson's disease (PD), a neurodegenerative disorder marked by neuron loss in the substantia nigra pars compacta (SNc). We recently observed that the murine homolog to the human H63D variant of the homeostatic iron regulator (HFE) may decrease paraquat-associated nigral neurotoxicity in mice. The present study examined the potential influence of H63D on paraquat-associated neurotoxicity in humans. Twenty-eight paraquat-exposed workers were identified from exposure histories and compared with 41 unexposed controls. HFE genotypes, and serum iron and transferrin were measured from blood samples. MRI was used to assess the SNc transverse relaxation rate (R2*), a marker for iron, and diffusion tensor imaging scalars of fractional anisotropy (FA) and mean diffusivity, markers of microstructural integrity. Twenty-seven subjects (9 exposed and 18 controls) were H63D heterozygous. After adjusting for age and use of other PD-associated pesticides and solvents, serum iron and transferrin were higher in exposed H63D carriers than in unexposed carriers and HFE wildtypes. SNc R2* was lower in exposed H63D carriers than in unexposed carriers, whereas SNc FA was lower in exposed HFE wildtypes than in either unexposed HFE wildtypes or exposed H63D carriers. Serum iron and SNc FA measures correlated positively among exposed, but not unexposed, subjects. These data suggest that H63D heterozygosity is associated with lower neurotoxicity presumptively linked to paraquat. Future studies with larger cohorts are warranted to replicate these findings and examine potential underlying mechanisms, especially given the high prevalence of the H63D allele in humans.

Tryptophan Metabolites Are Associated With Symptoms and Nigral Pathology in Parkinson's Disease.

BACKGROUND: The objective of this study was to determine whether neurotoxic kynurenine metabolites, induced by inflammation, in plasma and cerebrospinal fluid (CSF) are associated with symptom severity and nigral pathology in Parkinson's disease (PD). METHODS: Clinical and MRI data were obtained from 97 PD and 89 controls. We used ultra-performance liquid chromatography to quantify kynurenine metabolites and high-sensitivity multiplex assays to quantify inflammation in plasma and CSF. We evaluated group-wise differences as well as associations between the biomarkers, motor and nonmotor symptoms, and nigral R2* (MRI metric reflecting iron content). RESULTS: PD subjects had >100% higher 3-hydroxykynurenine and 14% lower 3-hydroxyanthranilic acid in plasma. The 3-HK in plasma was closely associated with both symptom severity and disease duration. PD subjects also had 23% lower kynurenic acid in the CSF. Higher CSF levels of the excitotoxin quinolinic acid were associated with more severe symptoms, whereas lower levels of the neuroprotective kynurenic acid were linked to olfactory deficits. An elevated quinolinic acid/picolinic acid ratio in the CSF correlated with higher R2* values in the substantia nigra in the entire cohort. Plasma C-reactive protein and serum amyloid alpha were associated with signs of increased kynurenine pathway activity in the CSF of PD patients, but not in controls. CONCLUSIONS: In PD, the kynurenine pathway metabolite levels are altered in both the periphery and the central nervous system, and these changes are associated with symptom severity. Replication studies are warranted in other cohorts, and these can also explore if kynurenine metabolites might be PD biomarkers and/or are involved in PD pathogenesis. © 2020 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Resident Supervision and Patient Care: A Comparative Time Study in a Community-Academic Versus a Community Emergency Department.

OBJECTIVE: The objective was to compare attending emergency physician (EP) time spent on direct and indirect patient care activities in emergency departments (EDs) with and without emergency medicine (EM) residents. METHODS: We performed an observational, time-motion study on 25 EPs who worked in a community-academic ED and a nonacademic community ED. Two observations of each EP were performed at each site. Average time spent per 240-minute observation on main-category activities are illustrated in percentages. We report descriptive statistics (median and interquartile ranges) for the number of minutes EPs spent per subcategory activity, in total and per patient. We performed a Wilcoxon two-sample test to assess differences between time spent across two EDs. RESULTS: The 25 observed EPs executed 34,358 tasks in the two EDs. At the community-academic ED, EPs spent 14.2% of their time supervising EM residents. Supervision activities included data presentation, medical decision making, and treatment. The time spent on supervision was offset by a decrease in time spent by EPs on indirect patient care (specifically communication and electronic health record work) at the community academic ED compared to the nonacademic community ED. There was no statistical difference with respect to direct patient care time expenditure between the two EDs. There was a nonstatistically significant difference in attending patient load between sites. CONCLUSIONS: EPs in our study spent 14.2% of their time (8.5 minutes/hour) supervising residents. The time spent supervising residents was largely offset by time savings related to indirect patient care activities rather than compromising direct patient care.

TGF-ß Initiates ß-Catenin-Mediated CTGF Secretory Pathway in Old Bovine Nucleus Pulposus Cells: A Potential Mechanism for Intervertebral Disc Degeneration.

We have recently demonstrated that overexpression of Smurf2 under the control of type II collagen alpha 1 (Col2a1) promoter induces an intervertebral disc degeneration phenotype in Col2a1-Smurf2 transgenic mice. The chondrocyte-like cells that express type II collagen and Smurf2 in the transgenic mouse discs are prone to degenerate. However, how the chondrocyte-like cells contribute to disc degeneration is not known. Here, we utilized primary old bovine nucleus pulposus (NP) cells as substitutes for the chondrocyte-like cells in Col2a1-Smurf2 transgenic mouse discs to identify mechanism. We found that 35% of the cells were senescent; TGF-ß treatment of the cells induced a rapid moderate accumulation of ß-catenin, which interacted with connective tissue growth factor (CTGF/CCN2) in the cytoplasm and recruited it to the membrane for secretion. The TGF-ß-initiated ß-catenin-mediated CTGF secretory cascade did not occur in primary young bovine NP cells; however, when Smurf2 was overexpressed in young bovine NP cells, the cells became senescent and allowed this cascade to occur. These results suggest that Smurf2-induced disc degeneration in Col2a1-Smurf2 transgenic mice occurs through activation of CTGF secretory pathway in senescent disc cells.

Multimodal MRI evaluation of parkinsonian limbic pathologies.

Previous multimodal magnetic resonance imaging (MRI) studies of parkinsonian syndromes have focused primarily on motor-related basal ganglia structures. The present study investigated MRI changes in nonmotor-related limbic structures in 35 Parkinson's disease, 16 multiple system atrophy parkinsonian subtype, 17 progressive supranuclear palsy, and 37 control subjects. Mean diffusivity (MD), fractional anisotropy, transverse relaxation rate (R2*), quantitative susceptibility mapping, and volume measurements were obtained from the amygdala, hippocampus, and nucleus accumbens (NAc) to examine differences between groups and to test for associations with clinical scores. Compared with controls, Parkinson's disease subjects had lower NAc volume; multiple system atrophy parkinsonian subtype subjects had higher NAc transverse relaxation rate; and progressive supranuclear palsy subjects had higher amygdala and hippocampus MD and lower hippocampus fractional anisotropy (p's ≤ 0.008). Among parkinsonian subjects, amygdala and hippocampus MD associated positively with Unified Parkinson's Disease Rating Scale nonmotor and activities of daily living scores (p's ≤ 0.005). Together, these findings support the inclusion of limbic structures in future MRI studies of parkinsonian syndromes.

The Effect of an Electronic Dynamic Cognitive Aid Versus a Static Cognitive Aid on the Management of a Simulated Crisis: A Randomized Controlled Trial.

The aim of this study was to assess the effect of a dynamic electronic cognitive aid with embedded clinical decision support (dCA) versus a static cognitive aid (sCA) tool. Anesthesia residents in clinical anesthesia years 2 and 3 were recruited to participate. Each subject was randomized to one of two groups and performed an identical simulated clinical scenario. The primary outcome was task checklist performance with a secondary outcome of performance using the Anesthesia Non-technical skills (ANTS) scoring system. 34 residents were recruited to participate in the study. 19 residents were randomized to the sCA group and 15 to the dCA group. Overall inter-rater agreement for total checklist, malignant hyperthermia, hyperkalemia and ventricular fibrillation was 98.9%, 97.8%, 99.5% and 99.5% respectively with similar Kappa coefficient. Inter-rater agreement for ANTS partial ratings, however, was only 53.5% with a similar Kappa of 0.15. Mean performance was statistically higher in the dCA group versus the sCA group for total check list performance (15.70 ± 1.93 vs 12.95 ± 2.16, p < 0.0001). The difference in performance between dCA and sCA is most notable in dose-dependent related checklist items (4.60 ± 1.3 vs 1.89 ± 1.23, p < 0.0001), while the performance score for dose-independent checklist items was similar between the two groups (p = 0.8908). ANTS ratings did not differ between groups. In conclusion, we evaluated the use of a sCA versus a dCA with embedded decision support in a simulated environment. The dCA group was found to perform more checklist items correctly.Clinical Trial Registration: Clinicaltrials.gov study #: NCT02440607.

A Multicenter Collaboration for Simulation-Based Assessment of ACGME Milestones in Emergency Medicine.

STATEMENT: In 2014, the six allopathic emergency medicine (EM) residency programs in Chicago established an annual, citywide, simulation-based assessment of all postgraduate year 2 EM residents. The cases and corresponding assessment tools were designed by the simulation directors from each of the participating sites. All assessment tools include critical actions that map directly to numerous EM milestones in 11 different subcompetencies. The 2-hour assessments provide opportunities for residents to lead resuscitations of critically ill patients and demonstrate procedural skills, using mannequins and task trainers respectively. More than 80 residents participate annually and their assessment experiences are essentially identical across testing sites. The assessments are completed electronically and comparative performance data are immediately available to program directors.

NKCC1 up-regulation contributes to early post-traumatic seizures and increased post-traumatic seizure susceptibility.

Traumatic brain injury (TBI) is not only a leading cause for morbidity and mortality in young adults (Bruns and Hauser, Epilepsia 44(Suppl 10):210, 2003), but also a leading cause of seizures. Understanding the seizure-inducing mechanisms of TBI is of the utmost importance, because these seizures are often resistant to traditional first- and second-line anti-seizure treatments. The early post-traumatic seizures, in turn, are a contributing factor to ongoing neuropathology, and it is critically important to control these seizures. Many of the available anti-seizure drugs target gamma-aminobutyric acid (GABAA) receptors. The inhibitory activity of GABAA receptor activation depends on low intracellular Cl-, which is achieved by the opposing regulation of Na+-K+-Cl- cotransporter 1 (NKCC1) and K+-Cl--cotransporter 2 (KCC2). Up-regulation of NKCC1 in neurons has been shown to be involved in neonatal seizures and in ammonia toxicity-induced seizures. Here, we report that TBI-induced up-regulation of NKCC1 and increased intracellular Cl- concentration. Genetic deletion of NKCC1 or pharmacological inhibition of NKCC1 with bumetanide suppresses TBI-induced seizures. TGFß expression was also increased after TBI and competitive antagonism of TGFß reduced NKKC1 expression, ameliorated reactive astrocytosis, and inhibited seizures. Thus, TGFß might be an important pathway involved in NKCC1 up-regulation after TBI. Our findings identify neuronal up-regulation of NKCC1 and its mediation by TGFß, as a potential and important mechanism in the early post-traumatic seizures, and demonstrate the therapeutic potential of blocking this pathway.

Mastery Learning of Video Laryngoscopy Using the Glidescope in the Emergency Department.

INTRODUCTION: According to the Accreditation Council for Graduate Medical Education emergency medicine requirements established before the popularity of video laryngoscopy (VL) use, 35 intubations are necessary for graduation. Our study aimed to establish a mastery-learning model for a skill set very different (VL) from direct laryngoscopy (DL) and to determine the number of attempts needed to achieve mastery with VL. METHODS: With the use of a randomized, controlled crossover study design, two learner groups underwent baseline testing intubating a mannequin using VL. Afterward, the intervention group received a mastery training intervention. After training, learners were required to repeat the procedure until achievement of 100% on the checklist for two consecutive attempts was achieved. After 3 months, both groups returned for retesting, and the control group received the same mastery training as the intervention group. Both groups returned for final testing after another 3 months. RESULTS: The intervention arm had an improvement in performance versus the control arm at 3 months of total time (P < 0.05). Both groups had an improvement within their groups' checklist scores at 3 months after training (P < 0.05), and within the intervention arm, this effect was sustained at 6 months (P < 0.05). There was no significant difference in the mean required attempts to demonstrate mastery (overall, 2.5; intervention, 2.75; control 2.25; P = 0.28). CONCLUSIONS: Simulation-based mastery-learning produces skill enhancement with VL that is resistant to decay across 6 months. Furthermore, although a small number of attempts are needed to achieve mastery, clinical experience did not substitute as a proxy for skill acquisition. This mastery-learning model provides skill sets that are not otherwise obtained in the clinical curriculum in a 3-month period.

Outpatient Advance Care Planning Internal Medicine Resident Curriculum: Valuing Our Patients' Wishes.

BACKGROUND: Although many studies have illustrated the discomfort that resident physicians feel when discussing end-of-life (EOL) issues with their patients, fewer studies have addressed interventions to directly increase medical resident proficiency and comfort in conducting these discussions and for translating these beliefs into a formal advance care plan. OBJECTIVES: We report on an innovative curriculum conducted at The University of Chicago (NorthShore) internal medicine residency to improve residents' proficiency and comfort in leading outpatient advance care planning (ACP) discussions. METHODS: Four educational components were executed. First, residents completed an on-line module introducing ACP and guiding residents to complete their own ACP. Second, residents attended a didactic "How To" lecture given by physicians with expertise in ACP that emphasized ACP communication tools and a video demonstration. Third, residents completed a video-recorded simulation-based ACP discussion with a standardized patient. Finally, residents conducted an ACP outpatient encounter with one of their continuity clinic patients. Expert preceptors directly observed, evaluated, and provided feedback to residents during both patient encounters. Residents were surveyed before and immediately after the curriculum using a nine-variable questionnaire, which assessed the resident's training and comfort with ACP. RESULTS: Sixteen second year residents completed the curriculum and surveys. Precurriculum and post-curriculum mean change on a Likert scale of 1 (uncomfortable) to 5 (very comfortable) was compared using paired t-tests. Results demonstrated statistically significant improvements in the following comfort level variables: eliciting understanding of health and prognosis (pre 3.63 vs. post 4.38, p = 0.035), discussing EOL care based on patient values (pre 3.50 vs. post 4.38, p = 0.008), specifically discussing EOL care based on patient values in the outpatient setting (pre 2.75 vs. post 4.31, p = 0.001) and initiating an advance directive and medical power of attorney (pre 2.56 vs. post 4.19, p < 0.001). CONCLUSION: A multimodality curriculum including self-directed learning, lectures, and practice with simulated and actual outpatients with active reflection and feedback is effective in improving resident comfort level and formal training in ACP. Further research is needed to understand whether these interventions will translate into an increased frequency of discussions with patients about ACP after residency training.