Faculty Bibliography

Progressive multifocal leukoencephalopathy (PML) is a subacute CNS inflammatory disease seen primarily among immunocompromised patients. It is caused by the JC virus (JCV), a polyomavirus that otherwise induces an insidious, latent infection in the general population. This reactivated disease is characterized by cognitive and behavioral changes, language disturbances, motor weakness, or visual deficits. Median survival in patients with AIDS is approximately 2-4 months, and mortality is high (around 4% in untreated AIDS). Recent scientific developments indicate that PML can also be associated with the increased utilization of monoclonal antibody (mAb) immunotherapy. In fact, PML has been witnessed with several mAbs, including natalizumab in multiple sclerosis, rituximab for lymphoma or lupus, efalizumab for psoriasis, and ofatumumab in leukemia; this leads us to the risk reassessment of PML due to treatment-induced immunosuppression. The range of clinical presentations of JCV-related disease has transformed over time and can pose significant challenges to the current diagnostic criteria. Most cases with PML suffer from persistent and irreversible neurological conditions, and some with chronic, low-level viral replication in the CNS. With the expanded use of mAbs for various autoimmune and lymphoproliferative disorders, we are now seeing this infection in non-HIV patients on drugs such as natalizumab, rituximab, and other recently approved therapies. This article aims to review the relationship between the incidence of PML and all four mAbs used in the treatment of MS. Currently, at least 18 FDA-approved medications carry label warnings for PML;to this date, no treatment has been convincingly effective.

Although mRNA vaccine responses following previous coronavirus disease 2019 (COVID-19) infection have not been assessed in trials, it has been shown that serological evidence of previous COVID-19 generates strong humoral and cellular responses to one dose of mRNA vaccine. We describe a patient with prior COVID-19 infection who developed acute transient encephalopathy with elevated inflammatory markers within 24 h of her first injection of Moderna COVID-19 vaccine. A 69-year-old cognitively normal woman presented with intermittent inattention, disorientation, left/right confusion, weakness, gait instability, and decreased speech. Head CT, brain MRI and MRA, complete blood count, liver enzymes, hepatitis B serology, ammonia, thyroid function, vitamin B12, and pulse oximetry were normal. Electroencephalography performed 48 h after symptom onset showed diffuse triphasic waves, diffuse theta and delta slowing, and no posterior dominant rhythm. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) IgG was positive and inflammatory markers were elevated. On day 5 post-vaccine, she returned to her baseline, without neurological sequelae. The reported patient likely developed a transient inflammatory encephalopathy associated with an abnormal immunologic reaction to one dose of COVID-19 vaccine, in the setting of remote COVID-19 infection (1 year prior), SARS-CoV-2 IgG-positivity, and multiple comorbidities. Physicians should be alert to possible postvaccination reactogenicity in individuals with SARS-CoV-2 IgG-positivity, including risk of neuro-inflammation.

BACKGROUND AND OBJECTIVES/UNASSIGNED:There have been numerous reports of neurologic manifestations identified in hospitalized patients infected with SARS-CoV-2, the virus that causes COVID-19. Here, we identify the spectrum of associated neurologic symptoms and diagnoses, define the time course of their development, and examine readmission rates and mortality risk posthospitalization in a multiethnic urban cohort. METHODS/UNASSIGNED:We identify the occurrence of new neurologic diagnoses among patients with laboratory-confirmed SARS-CoV-2 infection in New York City. A retrospective cohort study was performed on 532 cases (hospitalized patients with new neurologic diagnoses within 6 weeks of positive SARS-CoV-2 laboratory results between March 1, 2020, and August 31, 2020). We compare demographic and clinical features of the 532 cases with 532 controls (hospitalized COVID-19 patients without neurologic diagnoses) in a case-control study with one-to-one matching and examine hospital-related data and outcomes of death and readmission up to 6 months after acute hospitalization in a secondary case-only analysis. RESULTS/UNASSIGNED:< 0.0001). Of the 394 (74.1%) cases who survived acute hospitalization, more than half (220 of 394, 55.8%) were readmitted within 6 months, with a mortality rate of 23.2% during readmission. DISCUSSION/UNASSIGNED:Hospitalized patients with SARS-CoV-2 and new neurologic diagnoses have significant morbidity and mortality postdischarge. Further research is needed to define the effect of neurologic diagnoses during acute hospitalization on longitudinal post-COVID-19-related symptoms including neurocognitive impairment.

OBJECTIVE:Blacks have the highest incidence and mortality rates for prostate cancer (PCa) in the U.S. Black PCa patients (PCaP) also report high psychological distress. Identifying culturally specific coping strategies that lower distress among Black PCaP could help improve psychological interventions for this group. African-centered coping (strategies unique to the structure of Black personality and the African-centered worldview) have been identified. We hypothesized that these coping strategies and resilience would be associated with lower psychological distress (anxiety and depression) in Black PCaP. METHODS:Black PCaP (N = 95) completed a survey assessing African-centered coping strategies, resilience, anxiety, and depression. Multiple regression was employed to examine African-centered coping strategies and resilience as predictors of psychological distress. RESULTS:Participants were aged M = 67 ± 9 years and 52% had late-stage PCa. Twenty percent met criteria for clinically significant anxiety, and 17% for depression. African-centered coping strategies were not associated with lower anxiety or depression, while resilience was associated with decreased anxiety (r = -0.45, p < 0.001) and depression (r = -0.54, p < 0.001). Mediation analyses did not support an indirect association among African-centered coping strategies, resilience, and anxiety and depression. CONCLUSIONS:Contrary to hypotheses, African-centered coping strategies were not associated with psychological distress. However, as predicted, greater resilience was associated with lower anxiety and depression. These findings support the relevancy of resilience in Blacks' psychological adjustment to PCa. It might be worthwhile to explore African-centered coping strategies that help Black PCaP cope with distress.

OBJECTIVES/OBJECTIVE:To assess differences in career longevity, as a potential marker of athlete well-being, before and after the 1995 implementation of the Women's Tennis Association (WTA) Age Eligibility Rule (AER) and Player Development Programmes (PDP), which focused on organisational, physical and psychosocial education, skill building and support for adolescent athletes (≤17 years). METHODS:Career longevity data were collected through 2019 on adolescent players who began professional tournament play between 1970 and 2014 and reached a WTA singles ranking of 1-150 for a minimum of 1 week during their careers. Players were separated into pre-AER/PDP and post-AER/PDP groups, consisting of those who played their first professional events (FPE) before or after 1 January 1995. Measures of career longevity included career duration and premature retirement. RESULTS:Eight-hundred and eleven players were included in this study (51% pre-AER/PDP). The median career duration was 14.2 years for the post-AER/PDP group compared with 12.1 years for the pre-AER/PDP group (p<0.001). Moreover, post-AER/PDP players had higher probabilities of 10-year and 15-year careers compared with pre-AER/PDP players. After adjusting for age at FPE, athletes in the pre-AER/PDP group had an increased risk of shorter career duration (HR 1.55; 95% CI 1.31 to 1.83) and increased odds of premature retirement (OR 5.39; 95% CI 2.28 to 12.75) than athletes in the post-AER/PDP group. CONCLUSIONS:Adolescent athletes participating on the WTA after the combined AER/PDP initiative had longer career durations, higher probabilities of 10-year and 15-year careers, and decreased risk of premature retirement compared with those participating prior to AER/PDP. Organisational practices that encompass both education and competition regulation can positively affect career longevity related to improving athlete well-being.

Most pediatric central nervous system (CNS) tumors are located in eloquent anatomic areas, making surgical resection and, in some cases, even biopsy risky or impossible. This diagnostic predicament coupled with the move toward molecular classification for diagnosis has exposed an urgent need to develop a minimally invasive means to obtain diagnostic information. In non-CNS solid tumors, the detection of circulating tumor DNA (ctDNA) in plasma and other bodily fluids has been incorporated into routine practice and clinical trial design for selection of molecular targeted therapy and longitudinal monitoring. For primary CNS tumors, however, detection of ctDNA in plasma has been challenging. This is likely related at least in part to anatomic factors such as the blood-brain barrier. Due to the proximity of primary CNS tumors to the cerebrospinal fluid (CSF) space, our group and others have turned to CSF as a rich alternative source of ctDNA. Although multiple studies at this time have demonstrated the feasibility of CSF ctDNA detection across multiple types of pediatric CNS tumors, the optimal role and utility of CSF ctDNA in the clinical setting has not been established. This review discusses the work-to-date on CSF ctDNA liquid biopsy in pediatric CNS tumors and the associated technical challenges, and reviews the promising opportunities that lie ahead for integration of CSF ctDNA liquid biopsy into clinical care and clinical trial design.

Liquid biopsy has emerged as a novel noninvasive tool in cancer diagnostics. While significant strides have been made in other malignancies using liquid biopsy for diagnosis, disease monitoring, and treatment selection, development of these assays has been more challenging for brain tumors. Recently, research in primary and metastatic brain tumors has begun to harness the potential utility of liquid biopsy-particularly using circulating tumor DNA (ctDNA). Initial studies to identify ctDNA in plasma of brain tumor patients have shown feasibility, but the yield of ctDNA is far below that for other malignancies. Attention has therefore turned to the cerebrospinal fluid (CSF) as a more robust source of ctDNA. This review discusses the unique considerations in liquid biopsy for glioma and places them in the context of the work to date. We address the utility of CSF liquid biopsy for diagnosis, longitudinal monitoring, tracking tumor evolution, clinical trial eligibility, and prognostication. We discuss the differences in assay requirements for each clinical application to best optimize factors such as efficacy, cost, and speed. Ultimately, CSF liquid biopsy has the potential to transform how we manage primary brain tumor patients.

Precise photochemical control, using two-photon excitation (2PE), of the timing and location of activation of glutamate is useful for studying the molecular and cellular physiology of the brain. Antenna-based light harvesting strategies represent a general method to increase the sensitivity to 2PE of otherwise insensitive photoremovable protecting groups (PPGs). This was applied to the most commonly used form of "caged" glutamate, MNI-Glu. Computational investigation showed that a four- or six-carbon linker attached between the 4-position of thioxanthone (THX) and the 4-position of the 5-methyl derivative of MNI-Glu (MMNI-Glu) would position the antenna and PPG close to one another to enable Dexter energy transfer. Nine THX-MMNI-Glu conjugates were prepared and their photochemical properties determined. Installation of the THX antenna resulted in a red shift of the absorption (λ_max = 385-405 nm) along with increased quantum yield compared to the parent compound MNI-Glu (λ_max = 347 nm). The THX-MMNI-Glu conjugate with a four-carbon linker and attachment to the 4-position of THX underwent photolysis via 1PE at 405 and 430 nm and via 2PE at 770 and 860 nm, yielding glutamate. The two-photon uncaging action cross section (δ_u) was 0.11 and 0.29 GM at 770 and 860, respectively, which was greater than for MNI-Glu (0.06 and 0.072 GM at 720 and 770 nm, respectively). The THX sensitizer harvested the light via 2PE and transferred its resulting triplet energy to MMNI-Glu. Release of glutamate through 2PE at 860 nm from the compound (100 μM) activated iGluSnFR, a genetically encoded, fluorescent glutamate sensor, on the surface of cells in culture, portending its usefulness in studies of neurophysiology in acute brain slice.

BACKGROUND:The diagnosis of multiple sclerosis (MS) requires demyelinating events that are disseminated in time and space. Peripapillary retinal nerve fiber layer (pRNFL) thickness as measured by optical coherence tomography (OCT) distinguishes eyes with a prior history of acute optic neuritis (ON) and may provide evidence to support a demyelinating attack. OBJECTIVE:To investigate whether a deep learning (DL)-based network can distinguish between eyes with prior ON and healthy control (HC) eyes using peripapillary ring scans. METHODS:We included 1033 OCT scans from 415 healthy eyes (213 HC subjects) and 510 peripapillary ring scans from 164 eyes with prior acute ON (140 patients with MS). Data were split into 70% training, 15% validation, and 15% test data. We included 102 OCT scans from 80 healthy eyes (40 HC) and 61 scans from 40 ON eyes (31 MS patients) from an independent second center. Receiver operating characteristic curve analyses with area under the curve (AUC) were used to investigate performance. RESULTS:We used a dilated residual convolutional neural network for the classification. The final network had an accuracy of 0.85 and an AUC of 0.86, whereas pRNFL only had an AUC of 0.77 in recognizing ON eyes. Using data from a second center, the network achieved an accuracy of 0.77 and an AUC of 0.90 compared to pRNFL, which had an AUC of 0.84. INTERPRETATION:DL-based disease classification of prior ON is feasible and has the potential to outperform thickness-based classification of eyes with and without history of prior ON.