Faculty Bibliography
Searched for:
school:SOM
Department/Unit:Neurology
Total Results:
23427
Ontogeny and Vulnerabilities of Drug-Tolerant Persisters in HER2+ Breast Cancer
Resistance to targeted therapies is an important clinical problem in HER2-positive (HER2+) breast cancer. "Drug-tolerant persisters" (DTPs), a sub-population of cancer cells that survive via reversible, non-genetic mechanisms, are implicated in resistance to tyrosine kinase inhibitors (TKIs) in other malignancies, but DTPs following HER2 TKI exposure have not been well characterized. We found that HER2 TKIs evoke DTPs with a luminal-like or a mesenchymal-like transcriptome. Lentiviral barcoding/single cell RNA-sequencing reveal that HER2+ breast cancer cells cycle stochastically through a "pre-DTP" state, characterized by a G0-like expression signature and enriched for diapause and/or senescence genes. Trajectory analysis/cell sorting show that pre-DTPs preferentially yield DTPs upon HER2 TKI exposure. Cells with similar transcriptomes are present in HER2+ breast tumors and are associated with poor TKI response. Finally, biochemical experiments indicate that luminal-like DTPs survive via estrogen receptor-dependent induction of SGK3, leading to rewiring of the PI3K/AKT/mTORC1 pathway to enable AKT-independent mTORC1 activation.
PMID: 34911733
ISSN: 2159-8290
CID: 5085072
Perceptions Regarding the SARS-CoV-2 Pandemic's Impact on Neurocritical Care Delivery: Results From a Global Survey
BACKGROUND:The SARS-CoV-2 (COVID-19) pandemic has impacted many facets of critical care delivery. METHODS:An electronic survey was distributed to explore the pandemic's perceived impact on neurocritical care delivery between June 2020 and March 2021. Variables were stratified by World Bank country income level, presence of a dedicated neurocritical care unit (NCCU) and experiencing a COVID-19 patient surge. RESULTS:Respondents from 253 hospitals (78.3% response rate) from 47 countries (45.5% low/middle income countries; 54.5% with a dedicated NCCU; 78.6% experienced a first surge) participated in the study. Independent of country income level, NCCU and surge status, participants reported reductions in NCCU admissions (67%), critical care drug shortages (69%), reduction in ancillary services (43%) and routine diagnostic testing (61%), and temporary cancellation of didactic teaching (44%) and clinical/basic science research (70%). Respondents from low/middle income countries were more likely to report lack of surge preparedness (odds ratio [OR], 3.2; 95% confidence interval [CI], 1.8-5.8) and struggling to return to prepandemic standards of care (OR, 12.2; 95% CI, 4.4-34) compared with respondents from high-income countries. Respondents experiencing a surge were more likely to report conversion of NCCUs and general-mixed intensive care units (ICUs) to a COVID-ICU (OR 3.7; 95% CI, 1.9-7.3), conversion of non-ICU beds to ICU\ beds (OR, 3.4; 95% CI, 1.8-6.5), and deviations in critical care and pharmaceutical practices (OR, 4.2; 95% CI 2.1-8.2). Respondents from hospitals with a dedicated NCCU were less likely to report conversion to a COVID-ICU (OR, 0.5; 95% CI, 0.3-0.9) or conversion of non-ICU to ICU beds (OR, 0.5; 95% CI, 0.3-0.9). CONCLUSION/CONCLUSIONS:This study reports the perceived impact of the COVID-19 pandemic on global neurocritical care delivery, and highlights shortcomings of health care infrastructures and the importance of pandemic preparedness.
PMID: 34882104
ISSN: 1537-1921
CID: 5326642
Sudden unexpected death in epilepsy
PURPOSE OF REVIEW/OBJECTIVE:Sudden unexpected death in epilepsy (SUDEP) is a major contributor to premature mortality in people with epilepsy. This review provides an update on recent findings on the epidemiology of SUDEP, clinical risk factors and potential mechanisms. RECENT FINDINGS/RESULTS:The overall risk rate of SUDEP is approximately 1 per 1000 patients per year in the general epilepsy population and that children and older adults have a similar incidence. Generalized convulsive seizures (GCS), perhaps through their effects on brainstem cardiopulmonary networks, can cause significant postictal respiratory and autonomic dysfunction though other mechanisms likely exist as well. Work in animal models of SUDEP has identified multiple neurotransmitter systems, which may be future targets for pharmacological intervention. There are also chronic functional and structural changes in autonomic function in patients who subsequently die from SUDEP suggesting that some SUDEP risk is dynamic. Modifiable risks for SUDEP include GCS seizure frequency, medication adherence and nighttime supervision. SUMMARY/CONCLUSIONS:Current knowledge of SUDEP risk factors has identified multiple targets for SUDEP prevention today as we await more specific therapeutic targets that are emerging from translational research studies.
PMID: 35102124
ISSN: 1473-6551
CID: 5182232
New insights into the genetic etiology of Alzheimer's disease and related dementias
Characterization of the genetic landscape of Alzheimer's disease (AD) and related dementias (ADD) provides a unique opportunity for a better understanding of the associated pathophysiological processes. We performed a two-stage genome-wide association study totaling 111,326 clinically diagnosed/'proxy' AD cases and 677,663 controls. We found 75 risk loci, of which 42 were new at the time of analysis. Pathway enrichment analyses confirmed the involvement of amyloid/tau pathways and highlighted microglia implication. Gene prioritization in the new loci identified 31 genes that were suggestive of new genetically associated processes, including the tumor necrosis factor alpha pathway through the linear ubiquitin chain assembly complex. We also built a new genetic risk score associated with the risk of future AD/dementia or progression from mild cognitive impairment to AD/dementia. The improvement in prediction led to a 1.6- to 1.9-fold increase in AD risk from the lowest to the highest decile, in addition to effects of age and the APOE ε4 allele.
PMCID:9005347
PMID: 35379992
ISSN: 1546-1718
CID: 5213092
The ConTraSt database for analysing and comparing empirical studies of consciousness theories
Understanding how consciousness arises from neural activity remains one of the biggest challenges for neuroscience. Numerous theories have been proposed in recent years, each gaining independent empirical support. Currently, there is no comprehensive, quantitative and theory-neutral overview of the field that enables an evaluation of how theoretical frameworks interact with empirical research. We provide a bird's eye view of studies that interpreted their findings in light of at least one of four leading neuroscientific theories of consciousness (N = 412 experiments), asking how methodological choices of the researchers might affect the final conclusions. We found that supporting a specific theory can be predicted solely from methodological choices, irrespective of findings. Furthermore, most studies interpret their findings post hoc, rather than a priori testing critical predictions of the theories. Our results highlight challenges for the field and provide researchers with an open-access website ( https://ContrastDB.tau.ac.il ) to further analyse trends in the neuroscience of consciousness.
PMID: 35190711
ISSN: 2397-3374
CID: 5175042
Acute ischaemic stroke associated with SARS-CoV-2 infection in North America
BACKGROUND:To analyse the clinical characteristics of COVID-19 with acute ischaemic stroke (AIS) and identify factors predicting functional outcome. METHODS:Multicentre retrospective cohort study of COVID-19 patients with AIS who presented to 30 stroke centres in the USA and Canada between 14 March and 30 August 2020. The primary endpoint was poor functional outcome, defined as a modified Rankin Scale (mRS) of 5 or 6 at discharge. Secondary endpoints include favourable outcome (mRS ≤2) and mortality at discharge, ordinal mRS (shift analysis), symptomatic intracranial haemorrhage (sICH) and occurrence of in-hospital complications. RESULTS:A total of 230 COVID-19 patients with AIS were included. 67.0% (154/230) were older than 60 years, while 33.0% (76/230) were younger. Median (IQR) National Institutes of Health Stroke Scale (NIHSS) at presentation was 12.0 (17.0) and 42.8% (89/208) presented with large vessel occlusion (LVO). Approximately 50.2% (102/203) of the patients had poor outcomes with an observed mortality rate of 38.8% (35/219). Age >60 years (aOR: 4.60, 95% CI 1.89 to 12.15, p=0.001), diabetes mellitus (aOR: 2.53, 95% CI 1.14 to 5.79, p=0.025), increased NIHSS at admission (aOR: 1.10, 95% CI 1.05 to 1.16, p<0.001), LVO (aOR: 3.02, 95% CI 1.27 to 7.44, p=0.014) and no IV tPA (aOR: 2.76, 95% CI 1.06 to 7.64, p=0.043) were significantly associated with poor functional outcome. CONCLUSION/CONCLUSIONS:There may be a relationship between COVID-19 associated AIS and severe disability or death. We identified several factors that predict worse outcomes, and these outcomes were more frequent compared with global averages. We found that elevated neutrophil-to-lymphocyte ratio, rather than D-dimer, predicted both morbidity and mortality.
PMCID:8804309
PMID: 35078916
ISSN: 1468-330x
CID: 5154472
Early Neurorehabilitation and Recovery from Disorders of Consciousness After Severe COVID-19
BACKGROUND:Early neurorehabilitation improves outcomes in patients with disorders of consciousness (DoC) after brain injury, but its applicability in COVID-19 is unknown. We describe our experience implementing an early neurorehabilitation protocol for patients with COVID-19-associated DoC in the intensive care unit (ICU) and evaluate factors associated with recovery. METHODS:During the initial COVID-19 surge in New York City between March 10 and May 20, 2020, faced with a disproportionately high number of ICU patients with prolonged unresponsiveness, we developed and implemented an early neurorehabilitation protocol, applying standard practices from brain injury rehabilitation care to the ICU setting. Twenty-one patients with delayed recovery of consciousness after severe COVID-19 participated in a pilot early neurorehabilitation program that included serial Coma Recovery Scale-Revised (CRS-R) assessments, multimodal treatment, and access to clinicians specializing in brain injury medicine. We retrospectively compared clinical features of patients who did and did not recover to the minimally conscious state (MCS) or better, defined as a CRS-R total score (TS) ≥ 8, before discharge. We additionally examined factors associated with best CRS-R TS, last CRS-R TS, hospital length of stay, and time on mechanical ventilation. RESULTS:Patients underwent CRS-R assessments a median of six (interquartile range [IQR] 3-10) times before discharge, beginning a median of 48 days (IQR 40-55) from admission. Twelve (57%) patients recovered to MCS after a median of 8 days (IQR 2-14) off continuous sedation; they had lower body mass index (p = 0.009), lower peak serum C-reactive protein levels (p = 0.023), higher minimum arterial partial pressure of oxygen (p = 0.028), and earlier fentanyl discontinuation (p = 0.018). CRS-R scores fluctuated over time, and the best CRS-R TS was significantly higher than the last CRS-R TS (median 8 [IQR 5-23] vs. 5 [IQR 3-18], p = 0.002). Earlier fentanyl (p = 0.001) and neuromuscular blockade (p = 0.015) discontinuation correlated with a higher last CRS-R TS. CONCLUSIONS:More than half of our cohort of patients with prolonged unresponsiveness following severe COVID-19 recovered to MCS or better before hospital discharge, achieving a clinical benchmark known to have relatively favorable long-term prognostic implications in DoC of other etiologies. Hypoxia, systemic inflammation, sedation, and neuromuscular blockade may impact diagnostic assessment and prognosis, and fluctuations in level of consciousness make serial assessments essential. Early neurorehabilitation of these patients in the ICU can be accomplished but is associated with unique challenges. Further research should evaluate factors associated with longer-term neurologic recovery and benefits of early rehabilitation in patients with severe COVID-19.
PMCID:8491764
PMID: 34611810
ISSN: 1556-0961
CID: 5067712
Practical guidance for telemedicine use in neuro-oncology
While the COVID-19 pandemic has catalyzed the expansion of telemedicine into nearly every specialty of medicine, few articles have summarized current practices and recommendations for integrating virtual care in the practice of neuro-oncology. This article identifies current telemedicine practice, provides practical guidance for conducting telemedicine visits, and generates recommendations for integrating virtual care into neuro-oncology practice. Practical aspects of telemedicine are summarized including when to use and not use telemedicine, how to conduct a virtual visit, who to include in the virtual encounter, unique aspects of telehealth in neuro-oncology, and emerging innovations.
PMCID:8965064
PMID: 35371525
ISSN: 2054-2577
CID: 5219512
Observational study of medical marijuana as a treatment for treatment-resistant epilepsies
OBJECTIVES/OBJECTIVE:Medical cannabis formulations with cannabidiol (CBD) and delta-9-tetrahydrocannabinol (THC) are widely used to treat epilepsy. We studied the safety and efficacy of two formulations. METHODS:We prospectively observed 29 subjects (12 to 46 years old) with treatment-resistant epilepsies (11 Lennox-Gastaut syndrome; 15 with focal or multifocal epilepsy; three generalized epilepsy) were treated with medical cannabis (1THC:20CBD and/or 1THC:50CBD; maximum of 6 mg THC/day) for ≥24 weeks. The primary outcome was change in convulsive seizure frequency from the pre-treatment baseline to the stable optimal dose phase. RESULTS:There were no significant differences during treatment on stable maximal doses for convulsive seizure frequency, seizure duration, postictal duration, or use of rescue medications compared to baseline. No benefits were seen for behavioral disorders or sleep duration; there was a trend for more frequent bowel movements compared to baseline. Ten adverse events occurred in 6/29 patients, all were transient and most unrelated to study medication. No serious adverse events were related to study medication. INTERPRETATION/CONCLUSIONS:Our prospective observational study of two high-CBD/low-THC formulations found no evidence of efficacy in reducing seizures, seizure duration, postictal duration, or rescue medication use. Behavioral disorders or sleep duration was unchanged. Study medication was generally well tolerated. The doses of CBD used were lower than prior studies. Randomized trials with larger cohorts are needed, but we found no evidence of efficacy for two CBD:THC products in treating epilepsy, sleep, or behavior in our population.
PMID: 35267245
ISSN: 2328-9503
CID: 5182322
Recurrent intracerebral hemorrhages due to central nervous system vasculitis: A neuropsychological case report [Case Report]
OBJECTIVE:Primary angiitis of the central nervous system (PACNS) is a rare and devastating form of vasculitis that destroys the vessels of the brain and spinal cord, resulting in progressive and debilitating neurologic symptoms. The objective of the present study was to detail the diagnostic process of a case of a patient with PACNS who suffered from six intracerebral hemorrhages (ICHs). METHOD/METHODS:The patient was an African American woman with a history of recurrent ICHs of unclear etiology who received serial neuropsychological evaluations over the course of a 5-year period. Two comprehensive neuropsychological evaluations are included, as well as an overview of her clinical course, including differential diagnostic considerations and treatment planning. RESULTS:Neuropsychological assessment revealed marked deficits in visuospatial abilities and processing speed associated with her underlying neuropathology. Integrated review of her medical records indicated a probable diagnosis of PACNS as the likely etiology of her recurrent ICHs. CONCLUSIONS:This study demonstrates the importance of differential diagnosis of low base-rate conditions, functional neuroanatomy and neurobehavioral phenomenology, serial assessment, and cognitive reserve in clinical neuropsychological practice.
PMID: 32715901
ISSN: 1744-4144
CID: 5592712
