Faculty Bibliography

BACKGROUND:Improving confidence in and uptake of the COVID-19 vaccines and boosters among long-term care workers (LTCWs) is a crucial public health goal, given their role in the care of the elderly and people at risk. While difficult to reach with workplace communication interventions, most LTCWs regularly use social media and smartphones. Various social media interventions have improved attitudes and uptake for other vaccines and hold promise for the LTCW population. OBJECTIVE:e aimed to develop a curated social web app (interactive website) to increase COVID-19 vaccine confidence (three-arm randomized trial underway). METHODS:Following user-centric design and participatory research approaches, we undertook three steps: 1) content identification, 2) platform development, and 3) community building. A LTCW and stakeholder advisory group provided iterative input. For content identification, we identified topics of concern about COVID-19 vaccines via desktop research (published literature, public opinion polls and social media monitoring), refined by interviewing and polling LTCWs. We also conducted a national online panel survey. We curated and fact-checked posts from popular social media platforms that addressed the identified concerns. During platform development, we solicited preferences for design and functionality via interviews and user experience (UX) testing with LTCWs. We also identified best practices for online community building, like comment moderation. RESULTS:In the interviews (n=9), we found three themes: LTCWs 1) are proud of their work but feel undervalued; 2) have varying levels of trust in COVID-19 related information, and 3) would welcome a curated COVID-19 resource that is easy to understand and use. Desktop research, LTCW interviews and our national online panel survey (n=592) found participants are interested in information about COVID-19 in general, vaccine benefits, vaccine risks, and vaccine development. Content identification resulted in 434 posts addressing these topic areas, with 209 uploaded to the final web app. Our LTCW poll (n=8) revealed preferences for personal stories and video content. The platform we developed is an accessible WordPress-based social media web app, refined through formal (n=3) and informal UX testing. Users can sort posts by topic or subtopic and react to or comment on them. To build an online community, we recruited three LTCW 'community ambassadors' and instructed them to encourage discussion, acknowledge concerns and offer factual information on COVID-19 vaccines. We also set 'community standards' for the web app. CONCLUSIONS:An iterative, user-centric, participatory approach led to the launch of an accessible social media web app with curated content for COVID-19 vaccines targeting LTCWs in the U.S. Through our trial, we will determine if this approach successfully improves vaccine confidence. If so, a similar social media resource could be used to develop curated social media interventions in other populations and with other public health goals. CLINICALTRIAL/BACKGROUND:This effort is part of a broader clinical trial; ClinicalTrials.gov NCT05168800.

BACKGROUND:ALS). METHODS:ALS in a 2:1 ratio to receive eight doses of tofersen (100 mg) or placebo over a period of 24 weeks. The primary end point was the change from baseline to week 28 in the total score on the ALS Functional Rating Scale-Revised (ALSFRS-R; range, 0 to 48, with higher scores indicating better function) among participants predicted to have faster-progressing disease. Secondary end points included changes in the total concentration of SOD1 protein in cerebrospinal fluid (CSF), in the concentration of neurofilament light chains in plasma, in slow vital capacity, and in handheld dynamometry in 16 muscles. A combined analysis of the randomized component of the trial and its open-label extension at 52 weeks compared the results in participants who started tofersen at trial entry (early-start cohort) with those in participants who switched from placebo to the drug at week 28 (delayed-start cohort). RESULTS:A total of 72 participants received tofersen (39 predicted to have faster progression), and 36 received placebo (21 predicted to have faster progression). Tofersen led to greater reductions in concentrations of SOD1 in CSF and of neurofilament light chains in plasma than placebo. In the faster-progression subgroup (primary analysis), the change to week 28 in the ALSFRS-R score was -6.98 with tofersen and -8.14 with placebo (difference, 1.2 points; 95% confidence interval [CI], -3.2 to 5.5; P = 0.97). Results for secondary clinical end points did not differ significantly between the two groups. A total of 95 participants (88%) entered the open-label extension. At 52 weeks, the change in the ALSFRS-R score was -6.0 in the early-start cohort and -9.5 in the delayed-start cohort (difference, 3.5 points; 95% CI, 0.4 to 6.7); non-multiplicity-adjusted differences favoring early-start tofersen were seen for other end points. Lumbar puncture-related adverse events were common. Neurologic serious adverse events occurred in 7% of tofersen recipients. CONCLUSIONS:ALS, tofersen reduced concentrations of SOD1 in CSF and of neurofilament light chains in plasma over 28 weeks but did not improve clinical end points and was associated with adverse events. The potential effects of earlier as compared with delayed initiation of tofersen are being further evaluated in the extension phase. (Funded by Biogen; VALOR and OLE ClinicalTrials.gov numbers, NCT02623699 and NCT03070119; EudraCT numbers, 2015-004098-33 and 2016-003225-41.).

In the natural environment, we often form stable perceptual experiences from ambiguous and fleeting sensory inputs. Which neural activity underlies the content of perception and which neural activity supports perceptual stability remains an open question. We used a bistable perception paradigm involving ambiguous images to behaviorally dissociate perceptual content from perceptual stability, and magnetoencephalography to measure whole-brain neural dynamics in humans. Combining multivariate decoding and neural state-space analyses, we found frequency-band-specific neural signatures that underlie the content of perception and promote perceptual stability, respectively. Across different types of images, non-oscillatory neural activity in the slow cortical potential (<5 Hz) range supported the content of perception. Perceptual stability was additionally influenced by the amplitude of alpha and beta oscillations. In addition, neural activity underlying perceptual memory, which supports perceptual stability when sensory input is temporally removed from view, also encodes elapsed time. Together, these results reveal distinct neural mechanisms that support the content versus stability of visual perception.

BACKGROUND:Transcranial direct current stimulation (tDCS) is a safe and well-tolerated noninvasive technique used for cortical excitability modulation. tDCS has been extensively investigated for its clinical applications; however further understanding of its underlying in-vivo physiological mechanisms remains a fundamental focus of current research. OBJECTIVES/OBJECTIVE:) using simultaneous MRI in healthy adults to provide a reference frame for its neurobiological mechanisms. METHODS:at three time points: pre-, during- and post- 15 minutes of 2.0 mA tDCS on left anodal dorsolateral prefrontal cortex. RESULTS:significantly increased by 5.9 % during-tDCS (175.68 ± 30.78 µmol/100g/min) compared to pre-tDCS (165.84 ± 25.32 µmol/100g/min; p = 0.0015), maintaining increased levels in post-tDCS (176.86 ± 28.58 µmol/100g/min). CONCLUSIONS:changes due to tDCS in healthy adults that may be incorporated in clinical studies to evaluate its therapeutic potential.

Stress contributes to the development of many human diseases, including cancer. Based on the source of stress, it can be divided into external stress, such as environmental carcinogens, chemicals, and radiation, and internal stress, like endoplasmic reticulum (ER) stress, hypoxia, and oxidative stress. Nuclear Protein 1 (NUPR1, p8 or Com-1) is a small, highly basic transcriptional regulator that participates in regulating a variety of cellular processes including DNA repair, ER stress, oxidative stress response, cell cycle, autophagy, apoptosis, ferroptosis and chromatin remodeling. A large number of studies have reported that NUPR1 expression can be stimulated rapidly in response to various stresses. Thus, NUPR1 is also known as a stress-response gene. Since the role of NUPR1 in breast cancer was identified in 1999, an increasing number of studies sought to reveal its function in cancer. High expression of NUPR1 has been identified in oral squamous cell carcinoma, breast cancer, lung cancer, multiple myeloma, liver cancer and renal cancer. In this review, we summarize current studies of NUPR1 in response to multiple external stressors and internal stressors, and its role in mediating stressors to cause different cell signaling responses. In addition, this review discusses the function of NUPR1 in carcinogenesis, tumorigenesis, metastasis, and cancer therapy. Thus, this review gives a comprehensive insight into the role of NUPR1 in mediating signals from stress to different cell responses, and this process plays a role in the development of cancer.

BACKGROUND AND OBJECTIVES/OBJECTIVE:Recent studies have suggested that inter-eye differences (IEDs) in peripapillary retinal nerve fiber layer (pRNFL) or ganglion cell+inner plexiform (GCIPL) thickness by spectral-domain optical coherence tomography (SD-OCT) may identify people with a history of unilateral optic neuritis (ON). However, this requires further validation. Machine learning classification may be useful for validating thresholds for OCT IEDs and for examining added utility for visual function tests, such as low-contrast letter acuity (LCLA), in the diagnosis of people with multiple sclerosis (PwMS) and for unilateral ON history. METHODS:Participants were from 11 sites within the International Multiple Sclerosis Visual System (IMSVISUAL) consortium. pRNFL and GCIPL thicknesses were measured using SD-OCT. A composite score combining OCT and visual measures was compared individual measurements to determine the best model to distinguish PwMS from controls. These methods were also used to distinguish those with history of ON among PwMS. ROC curve analysis was performed on a training dataset (2/3 of cohort), then applied to a testing dataset (1/3 of cohort). Support vector machine (SVM) analysis was used to assess whether machine learning models improved diagnostic capability of OCT. RESULTS:Among 1,568 PwMS and 552 controls, variable selection models identified GCIPL IED, average GCIPL thickness (both eyes), and binocular 2.5% LCLA as most important for classifying PwMS vs. controls. This composite score performed best, with AUC=0.89 (95% CI 0.85, 0.93), sensitivity=81% and specificity=80%. The composite score ROC curve performed better than any of the individual measures from the model (p<0.0001). GCIPL IED remained the best single discriminator of unilateral ON history among PwMS (AUC=0.77, 95% CI 0.71,0.83, sensitivity=68%, specificity=77%). SVM analysis performed comparably to standard logistic regression models. CONCLUSIONS:A composite score combining visual structure and function improved the capacity of SD-OCT to distinguish PwMS from controls. GCIPL IED best distinguished those with history of unilateral ON. SVM performed as well as standard statistical models for these classifications. CLASSIFICATION OF EVIDENCE/METHODS:The study provides Class III evidence that SD-OCT accurately distinguishes multiple sclerosis from normal controls as compared to clinical criteria.

BACKGROUND:We summarize the history of individuals with Sturge-Weber syndrome (SWS) to inform clinical trial design and identify variations in care. METHODS:We performed retrospective chart review of individuals with SWS from centers in New York City. We characterized data quality using a novel scoring system. For 13 clinical concepts, we evaluated if data were present and if they were of high quality. RESULTS:We included 26 individuals with SWS (58% female; median age at initial visit 7 years; absolute range 1 month to 56 years]). Twenty-two had nevus flammeus, 13 glaucoma, four homonymous hemianopia, and 15 hemiparesis. Nineteen of 21 had at least one confirmed seizure with a known first seizure date, all before 24 months. Most (18 of 26, 69%) epilepsy was controlled. A plurality (10 of 23, 43%) had either normal cognitive function or mild cognitive delays. Aspirin use varied by site (P = 0.02)-at four sites, use was 0% (zero of three), 0% (zero of four), 80% (four of five), and 64% (nine of 14). Data were present for more than 75% of cases for 11 of 13 clinical concepts (missing: age of diagnosis, age of glaucoma onset). There were gaps in level of detail for motor impairments, glaucoma severity, seizure history, cognition, and medication history. CONCLUSIONS:Clinical charts have important gaps in the level of detail around core SWS clinical features, limiting value for some natural history studies. Any clinical trial in SWS designed to prevent epilepsy should begin in the first year of life. Variations in use of aspirin suggest de facto clinical equipoise and warrant a comparative effectiveness study.

Propagation of tau pathology via the seeding of naive tau aggregation underlies the progression of Alzheimer's disease (AD) and related tauopathies. Individuals with Down syndrome (DS) develop tau pathology at the fourth decade of life, but tau seeding activity in DS brain has not yet been determined. To measure tau seeding activity, we developed capture assay and seeded-tau aggregation assay with truncated tau_151-391. By using brain extracts from AD and related tauopathies, we validated these two methods and found that the brain extracts from AD and related tauopathies, but not from controls and the diseases in which tau was not hyperphosphorylated, captured in vitro and seeded 3R-tau_151-391 and 4R-tau_151-391 to aggregate in cultured cells similarly. Captured tau_151-391 levels were strongly correlated with the seeded-tau_151-391 aggregation. Employing these two newly developed assays, we analyzed tau seeding activity in the temporal (TC), frontal (FC), and occipital cortex (OC); corpus callosum (CC); and cerebellar cortex (CBC) of DS and control brains. We found that the extracts of TC, FC, or OC, but not the CC or CBC of DS or the corresponding brain regions of control cases, captured tau_151-391. Levels of the captured tau_151-391 by brain extracts were positively correlated with their levels of phosphorylated tau. Extracts of cerebral cortex and CC, but not CBC of DS with a similar tau level, induced more tau_151-391 aggregation than did the corresponding samples from the control cases. Thus, higher tau seeding activity associated with tau hyperphosphorylation was found in the TC, FC, and OC of DS compared with the corresponding control regions as well as with the CBC and CC of DS. Of note, these two assays are sensitive, specific, and repeatable at a low cost and provide a platform for measuring tau seeding activity and for drug screening that targets tau propagation.

Memory and its care were significant sociocultural and scientific topics in early modern Spain. While a major interest in memory was related to its rhetorical implications, medical treatises discussing memory, cognitive impairment, and its treatment began to appear in the 16^th- and 17^th-century. Among these treatises, Disputationes phylosophicæ ac medicæ super libros Aristotelis de memoria, et reminiscentia (Philosophical and medical arguments on Aristotle's "De memoria et reminiscentia"), published in 1629 by the physician Juan Gutiérrez de Godoy, is unique in that it is entirely devoted to the medical aspects of memory. While many of its concepts are now superseded, the treatise is valuable to understand the views on memory and cognitive impairment in 17^th-century Spain and their sources, as Gutiérrez quoted many classical, medieval, and contemporary scholars and physicians. The book, written in Latin, is exclusively devoted to memory from a physiological and medical point of view, with chapters on the classification of memory loss, a description of its causes (including old age, something not widely recognized before), and several chapters on its prevention and treatment, with a fascinating emphasis on confectio anacardina, or anacardium, an intranasal concoction made with the "marking nut", the fruit of the Semecarpus anacardium tree (also known as Malacca bean), with alleged memory-enhancing properties. We review Gutiérrez's Disputationes phylosophicæ, putting it into the wider intellectual and social context in the Europe of its time, and discuss the relevance and purported neuropharmacological effects of anacardina.