Faculty Bibliography

STAT3 is a transcription factor with roles in inflammation and tumorigenicity. A fraction of STAT3 localizes in mitochondria, where it augments tumorigenesis via regulation of mitochondrial functions, including modulation of respiration and redox status. We show a novel mechanism for mitochondrial STAT3 regulation of redox homeostasis in triple negative breast cancer cells. Loss of STAT3 diminished complex I dehydrogenase activity and impaired NAD+ regeneration, leading to impaired expression of glutathione biosynthetic genes and other antioxidant genes. Expressing mitochondrially-restricted STAT3 or replenishment of the cellular NAD pool restored antioxidant gene expression, as did complementation of the NADH dehydrogenase activity by expression of the STAT3-independent yeast dehydrogenase, NDI1. These NAD-regulated processes contributed to malignant phenotypes by promoting clonal cell growth and migration. Proximity interaction and protein pull-down assays identified three components of complex I that associated with mitochondrial STAT3, providing a potential mechanistic basis for how mitochondrial STAT3 affects complex I activity. Our data document a novel mechanism through which mitochondrial STAT3 indirectly controls antioxidant gene regulation through a retrograde NAD+ signal that is modulated by complex I dehydrogenase activity.

To evaluate safety, dose response, and preliminary efficacy of reldesemtiv over 12 weeks in patients with amyotrophic lateral sclerosis (ALS). Methods: Patients (≤2 years since diagnosis) with slow upright vital capacity (SVC) of ≥60% were randomized 1:1:1:1 to reldesemtiv 150, 300, or 450 mg twice daily (bid) or placebo; active treatment was 12 weeks with 4-week follow-up. Primary endpoint was change in percent predicted SVC at 12 weeks; secondary measures included ALS Functional Rating Scale-Revised (ALSFRS-R) and muscle strength mega-score. Results: Patients (N = 458) were enrolled; 85% completed 12-week treatment. The primary analysis failed to reach statistical significance (p = 0.11); secondary endpoints showed no statistically significant effects (ALSFRS-R, p = 0.09; muscle strength mega-score, p = 0.31). Post hoc analyses pooling all active reldesemtiv-treated patients compared against placebo showed trends toward benefit in all endpoints (progression rate for SVC, ALSFRS-R, and muscle strength mega-score (nominal p values of 0.10, 0.01 and 0.20 respectively)). Reldesemtiv was well tolerated, with nausea and fatigue being the most common side effects. A dose-dependent decrease in estimated glomerular filtration rate was noted, and transaminase elevations were seen in approximately 5% of patients. Both hepatic and renal abnormalities trended toward resolution after study drug discontinuation. Conclusions: Although the primary efficacy analysis did not demonstrate statistical significance, there were trends favoring reldesemtiv for all three endpoints, with effect sizes generally regarded as clinically important. Tolerability was good; modest hepatic and renal abnormalities were reversible. The impact of reldesemtiv on patients with ALS should be assessed in a pivotal Phase 3 trial. (ClinicalTrials.gov Identifier: NCT03160898).

Inflammatory peripheral neuropathies can be disabling for any patient. Selecting the most appropriate agent for treatment, especially in the elderly, is no simple task. Several factors should be considered. Herein, we discuss immunotherapeutic options for peripheral nerve diseases and the important considerations required for choosing one in the geriatric population.

INTRODUCTION/BACKGROUND:Body lateropulsion (BLP) is seen in neurological lesions involving the pathways responsible for body position and verticality. We report a case of isolated body lateropulsion (iBLP) as the presentation of lateral medullary infarction and conducted a systematic literature review. METHODS:MEDLINE and EMBASE databases were searched up to December 3, 2020. INCLUSION CRITERIA/METHODS:age ≥ 18, presence of BLP, confirmed stroke on imaging. EXCLUSION CRITERIA/METHODS:age < 18, qualitative reviews, studies with inadequate patient data. Statistical analysis was performed using IBM® SPSS® Statistics 20. RESULTS:A 64-year-old man presented with acute-onset iBLP. Brain MRI demonstrated acute infarction in the right caudolateral medulla. His symptoms progressed with ipsilateral Horner syndrome over the next 24 hours and contralateral hemisensory loss 10 days later. Repeat MRI showed an increase in infarct size. BLP resolved partially at discharge. Systematic review: 418 abstracts were screened; 59 studies were selected reporting 103 patients. Thirty-three patients had iBLP (32%). BLP was ipsilateral to stroke in 70 (68%) and contralateral in 32 (32%). The most common stroke locations were medulla (n = 63, 59%), pons (n = 16, 15%), and cerebellum (n = 16, 15%). Four strokes were cortical, 3 frontal and 1 temporoparietal (3%). The most common etiology was large-artery atherosclerosis (LAA) in 20 patients (32%), followed by small-vessel occlusion in 12 (19%). Seventeen (27%) had large-vessel occlusion (LVO), 12 involving the vertebral artery. Sixty (98%) had some degree of resolution of BLP; complete in 41 (70%). Median time-to-resolution was 14 days (IQR 10-21). There was no relationship between time-to-resolution and age, sex, side of BLP or side of stroke. CONCLUSION/CONCLUSIONS:BLP was commonly seen with medullary infarction and was the isolated finding in one-third. LAA and LVO were the most common etiologies. Recovery of BLP was early and complete in most cases.

OBJECTIVE:1) to describe the clinical manifestations of functional motor disorders (FMDs) coexisting with other neurological diseases ("comorbid-FMDs"); 2) to compare comorbid-FMDs to FMDs not overlapping with other neurological diseases ("pure FMDs"). METHODS:For this multicenter observational study, we enrolled outpatients with a definite diagnosis of FMDs attending 25 tertiary movement disorders centers in Italy. Each subject with FMDs underwent a detailed clinical assessment including screening for other associated neurological conditions. Groups comparisons (comorbid-FMDs versus pure-FMDs) were performed in order to compare demographical and clinical variables. Logistic regression models were created to estimate adjusted odds ratio (OR; 95% confidence interval) of comorbid-FMDs (dependent variable) in relation to sociodemographic and clinical characteristics (independent variables). RESULTS:Out of 410 FMDs, 21.7% (n=89) of patients had comorbid-FMDs. The most frequent coexisting neurological diseases were migraine, cerebrovascular disease and parkinsonism. In the majority of cases (86.5%) FMDs appeared after the diagnosis of neurological disease. Patients with comorbid-FMDs were older, had more frequent tremor, non-neurological comorbidities, paroxysmal non-epileptic seizures, major depressive disorders, and benzodiazepine intake. Multivariate regression analysis showed that diagnosis of comorbid-FMDs was more likely associated with longer time lag to reach the final diagnosis of FMDs, presence of tremor and non-neurological comorbidities. CONCLUSIONS:Our findings highlight the need of a prompt diagnosis of FMDs, given their relatively high frequency of associated neurological and non-neurological diseases.

The application of pit and fissure sealants is a well-established method to prevent and treat early childhood caries. Resin-based sealants with antibacterial properties provide additional benefits for caries prevention in a cariogenic oral environment. The objective of this study was to evaluate the effect of an antibacterial core-shell AgBr/cationic polymer nanocomposite (AgBr/BHPVP) on the properties of a resin-based pit and fissure sealant. A commercialized pit and fissure sealant without fluoride, Concise (3M, ESPE, USA), was used as the parent material and negative control. Experimental antibacterial sealants were formulated by the addition of AgBr/BHPVP nanoparticles at mass fractions of 0.5, 1.0, and 1.5 wt% to the parent material. A fluoride-releasing sealant, Clinpro (3M, ESPE), was used as the positive control. Bacterial colony-forming unit (CFU) counts, metabolic activity tests, field emission-scanning electron microscopy (FE-SEM), and confocal laser scanning microscopy (CLSM) observations were used to evaluate the antibacterial properties of AgBr/BHPVP-modified sealants against Streptococcus mutans before and after five months of aging. The Vickers microhardness, degree of conversion, and microleakage level of the sealants were also investigated. According to the results of CFU counts and metabolic tests, sealants containing AgBr/BHPVP showed better contact-killing bactericidal activity against S. mutans than the two commercial sealants, irrespective of aging conditions (both P < 0.05). The AgBr/BHPVP-modified sealants also showed a significant inhibitory effect on the planktonic S. mutans around the cured sealant surfaces. In addition, the Vickers microhardness, degree of conversion, and microleakage level of the parent material were not damaged by modification with AgBr/BHPVP (P > 0.05). AgBr/BHPVP-modified pit and fissure sealant with a dual bactericidal mechanism is a promising option for the prevention of pit and fissure caries.

OBJECTIVE:We sought to investigate the patient experience of telemedicine for headache care during the coronavirus disease 2019 (COVID-19) pandemic. BACKGROUND:The use of telemedicine has rapidly expanded and evolved since the beginning of the COVID-19 pandemic. Telemedicine eliminates the physical and geographic barriers to health care, preserves personal protective equipment, and prevents the spread of COVID-19 by allowing encounters to happen in a socially distanced way. However, few studies have assessed the patient perspective of telemedicine for headache care. METHODS:The American Migraine Foundation (AMF) designed a standardized electronic questionnaire to assess the patient experience of telemedicine for headache care between March and September 2020 to help inform future quality improvement as part of its patient advocacy initiative. The date parameters were identified as the emergence of severe acute respiratory syndrome coronavirus 2 disease and the declaration of a national emergency in the United States. The questionnaire was distributed electronically to more than 100,000 members of the AMF community through social media platforms and the AMF email database. RESULTS:A total of 1172 patients responded to our electronic questionnaire, with 1098 complete responses. The majority, 1081/1153 (93.8%) patients, had a previous headache diagnosis prior to the telemedicine encounter. A total of 648/1127 (57.5%) patients reported that they had used telemedicine for headache care during the study period. Among those who participated in telehealth visits, 553/647 (85.5%) patients used it for follow-up visits; 94/647 (14.5%) patients used it for new patient visits. During the telemedicine encounters, 282/645 (43.7%) patients were evaluated by headache specialists, 222/645 (34.4%) patients by general neurologists, 198/645 (30.7%) patients by primary care providers, 73/645 (11.3%) patients by headache nurse practitioners, and 21/645 (3.2%) patients by headache nurses. Only 47/633 (7.4%) patients received a new headache diagnosis from telemedicine evaluation, whereas the other 586/633 (92.6%) patients did not have a change in their diagnoses. During these visits, a new treatment was prescribed for 358/636 (52.3%) patients, whereas 278/636 (43.7%) patients did not have changes made to their treatment plan. The number (%) of patients who rated the telemedicine headache care experience as "very good," "good," "fair," "poor," and "other" were 396/638 (62.1%), 132/638 (20.7%), 67/638 (10.5%), 23/638 (3.6%), and 20/638 (3.1%), respectively. Detailed reasons for "other" are listed in the manuscript. Most patients, 573/638 (89.8%), indicated that they would prefer to continue to use telemedicine for their headache care, 45/638 (7.1%) patients would not, and 20/638 (3.1%) patients were unsure. CONCLUSIONS:Our study evaluating the patient perspective demonstrated that telemedicine facilitated headache care for many patients during the COVID-19 pandemic, resulting in high patient satisfaction rates, and a desire to continue to use telemedicine for future headache care among those who completed the online survey.

Adoption of middle meningeal artery embolization in the management of chronic subdural hematomas has led to a renewed interest in dural vascular anatomy. The readily identifiable major dural arteries and potential hazards associated with their embolization are well described. Less emphasized are several levels of intrinsic dural angioarchitecture, despite their more direct relationship to dural based diseases, such as subdural hematoma and dural fistula. Fortunately, microvascular aspects of dural anatomy, previously limited to ex vivo investigations, are becoming increasingly accessible to in vivo visualization, setting the stage for synthesis of the old and the new, and providing a rationale for the endovascular approach to subdural collections in particular. In contrast with traditional anatomical didactics, where descriptions advance from larger trunks to smaller pedicles, we present a strategic approach that proceeds from a fundamental understanding of the dural microvasculature and its relationship to larger vessels.

Peripheral neuropathy is one of the most prevalent neurologic conditions encountered by neurologists and nonneurologists. Geriatricians and primary care physicians often face the task of screening patients for early neuropathy when they have underlying conditions such as diabetes mellitus and evaluating patients who report new symptoms that suggest neuropathy. An understanding about different forms of neuropathies based on anatomic pattern and type of nerve fiber involvement and ability to perform basic neurologic examination reliably can help determine how to pursue further investigations and identify those patients who are likely to benefit from early specialist referral.

OBJECTIVE:To analyze electronic diary (e-diary) use in a phase 2, randomized, controlled clinical trial (OPUS; NCT03283371) of natalizumab in adult participants with drug-resistant focal epilepsy. METHODS:We developed an e-diary, which incorporated an episodic seizure diary and a daily diary reminder, for use as the primary source to record participants' daily seizure activity in the OPUS phase 2 clinical trial. Participants and/or their designated caregivers made e-diary entries by selecting seizure descriptions generated in the participants' and/or caregivers' own words at the time of screening. Seizures and seizure-free days were reported for the current day and for up to 5 and 4 retrospective days, respectively. A record of seizure symptoms entered within the prior 5-day period was displayed on accessing the diary. Changes were not permitted in the e-diary once a seizure record was saved unless a data change request was made. A paper backup diary was available. RESULTS:E-diary entries (N = 15,176) from the 6-week baseline period and subsequent 24-week placebo-controlled period were analyzed for 66 adults who were randomized and dosed in the OPUS trial. The overall e-diary compliance, defined as the total number of days with any entry out of the total number of days in the baseline and placebo-controlled periods for all participants combined, was 83.6%. Caregivers made 190 (1.3%) e-diary entries. Day-of-event e-diary entries totaled 11,248 (74.1%). At least one paper backup diary was used by 36 (54.5%) participants. SIGNIFICANCE:Our data highlight that good e-diary compliance can be achieved across participants in randomized clinical trials in adult focal epilepsy. In addition to identifying and addressing any barriers that may prevent a minority of participants from achieving good e-diary compliance, consideration of e-diary elements, such as recall period and reporting of seizure-free days, will facilitate the most accurate data capture in epilepsy clinical trials.