Hesitancy, reactogenicity and immunogenicity of the mRNA and whole-virus inactivated Covid-19 vaccines in pediatric neuromuscular diseases.

The mRNA-based BNT162b2 and inactivated whole-virus CoronaVac are two widely used COVID-19 vaccines that confer immune protection to healthy individuals. However, hesitancy toward COVID-19 vaccination appeared to be common for patients with neuromuscular diseases (NMDs) due to the paucity of data on the safety and efficacy in this high-risk patient population. Therefore, we examined the underlying factors associated with vaccine hesitancy across time for NMDs and assessed the reactogenicity and immunogenicity of these two vaccines. Patients aged 8-18 years with no cognitive delay were invited to complete surveys in January and April 2022. Patients aged 2-21 years were enrolled for COVID-19 vaccination between June 2021 and April 2022, and they recorded adverse reactions (ARs) for 7 days after vaccination. Peripheral blood was obtained before and within 49 days after vaccination to measure serological antibody responses compared to healthy children and adolescents. Forty-one patients completed vaccine hesitancy surveys for both timepoints, while 22 joined the reactogenicity and immunogenicity arm of the study. Two or more family members vaccinated against COVID-19 was positively associated with intention of vaccination (odds ratio 11.7, 95% CI 1.81-75.1, p = .010). Pain at the injection site, fatigue, and myalgia were the commonest ARs. Most ARs were mild (75.5%, n = 71/94). All 19 patients seroconverted against the wildtype SARS-CoV-2 after two doses of either vaccine, similar to 280 healthy counterparts. There was lower neutralization against the Omicron BA.1 variant. BNT162b2 and CoronaVac were safe and immunogenic for patients with NMDs, even in those on low-dose corticosteroids.

Guillain-Barre Syndrome and COVID-19 Vaccine: A Report of Nine Patients

Introduction: Guillain-Barre Syndrome (GBS) is an autoimmune acute inflammatory demyelinating polyneuropathy usually elicited by an upper respiratory tract infection. Several studies reported GBS associated with Coronavirus Disease 2019 (COVID-19) infection. In this study, we described nine GBS patients following the COVID-19 vaccine.Methods: In this study, nine patients were introduced from six referral centers for neuromuscular disorders in Iran between April 8 and June 20, 2021. Four patients received the Sputnik V, three patients received the Sinopharm, and two cases received the AstraZeneca vaccine. All patients were diagnosed with GBS evidenced by nerve conduction studies and/or cerebrospinal fluid analysis.Results: The median age of the patients was 54.22 years (ranged 26-87 years), and seven patients were male. The patients were treated with Intravenous Immunoglobulin (IVIg) or Plasma Exchange (PLEX). All patients were discharged with some improvements.Conclusion: The link between the COVID-19 vaccine and GBS is not well understood. Given the prevalence of GBS over the population, this association may be coincidental;therefore, more studies are needed to investigate a causal relationship.

Quality of Life of Latin-American People with Neuromuscular Disorders and Their Families During the COVID-19 Pandemic.

Objectives: The COVID-19 pandemic has affected the entire population, especially the population with chronic diseases. This study aimed to describe the quality of life of children and adults with neuromuscular diseases and their caregivers during the COVID-19 pandemic. Methods: A observational correlational study was conducted. Forty-seven participants, including adults with NMD and caregivers of children with NMD, took part in the study. The WHOQOL-BREF and PedsQL 4.0 GCS and FIM scales were used. Results: The PedsQL indicated a mean of 55.85 (SD = 22.05) for children, and a mean of 55.76 (SD = 16.72) for caregivers. Adults reported a mean of 67 (SD = 22.5) for their general perception of quality of life, and a M = 53 (SD = 28.25) for their perception on health. Conclusions: The results showed regular to low quality of life of all children, adults, and caregivers, mainly in the physical dimension for people with neuromuscular diseases, and in the concerns dimension for caregivers. These results warn about the physical and psychological vulnerability situation in which this population finds itself.

Telemedicine in Neuromuscular Diseases During Covid-19 Pandemic: ERN-NMD European Survey.

BACKGROUND: Telemedicine (TM) contributes to bridge the gap between healthcare facilities and patients' homes with neuromuscular disease (NMD) because of mobility issues. However, its deployment is limited due to difficulties evaluating subtle neurological signs such as mild weakness or sensory deficits. The COVID-19 pandemic has disrupted healthcare delivery worldwide, necessitating rapid measures implementation by health care providers (HCPs) to protect patients from acquiring SARS-CoV-2 while maintaining the best care and treatment. OBJECTIVES: Given the challenges faced by remote healthcare assistance of NMD patients, we aim to evaluate the use of TM in NMD during the COVID-19 pandemic. METHODS: Based on the Model for Assessment-of-Telemedicine-Applications (MAST), we conducted a survey amongst clinicians of the ERN EURO NMD (European-Reference-Network-for-Rare-Neuromuscular-Diseases). RESULTS: Based on 42 responses over 76 expected ones, our results show that the COVID-19 pandemic significantly increased the number of HCPs using TM (from 60% to 100%). The TM types most used during the COVID-19 period are teleconsultation and consultation by phone, particularly in the context of symptoms worsening in NMD patients with COVID-19 infection. Most European HCPs were satisfied when using TM but as a complementary option to physical consultations. Many responses addressed the issue of technical aspects needing improvement, particularly for elderly patients who need caregivers' assistance for accessing the TM platform. CONCLUSIONS: TM has been essential during COVID-19, but its use still presents some limitations for NMD patients with cognitive deficits or for first-time diagnosis. Thus, TM should be used as complement to, rather than substitute, for face-to-face consultations.

Factors associated with the severity of COVID-19 outcomes in people with neuromuscular diseases: Data from the International Neuromuscular COVID-19 Registry.

BACKGROUND AND PURPOSE: Clinical outcome information on patients with neuromuscular diseases (NMDs) who have been infected with SARS-CoV-2 is limited. The aim of this study was to determine factors associated with the severity of COVID-19 outcomes in people with NMDs. METHODS: Cases of NMD, of any age, and confirmed/presumptive COVID-19, submitted to the International Neuromuscular COVID-19 Registry up to 31 December 2021, were included. A mutually exclusive ordinal COVID-19 severity scale was defined as follows: (1) no hospitalization; (2) hospitalization without oxygenation; (3) hospitalization with ventilation/oxygenation; and (4) death. Multivariable ordinal logistic regression analyses were used to estimate odds ratios (ORs) for severe outcome, adjusting for age, sex, race/ethnicity, NMD, comorbidities, baseline functional status (modified Rankin scale [mRS]), use of immunosuppressive/immunomodulatory medication, and pandemic calendar period. RESULTS: Of 315 patients from 13 countries (mean age 50.3 [±17.7] years, 154 [48.9%] female), 175 (55.5%) were not hospitalized, 27 (8.6%) were hospitalized without supplemental oxygen, 91 (28.9%) were hospitalized with ventilation/supplemental oxygen, and 22 (7%) died. Higher odds of severe COVID-19 outcomes were observed for: age ≥50 years (50-64 years: OR 2.4, 95% confidence interval [CI] 1.33-4.31; >64 years: OR 4.16, 95% CI 2.12-8.15; both vs. <50 years); non-White race/ethnicity (OR 1.81, 95% CI 1.07-3.06; vs. White); mRS moderately severe/severe disability (OR 3.02, 95% CI 1.6-5.69; vs. no/slight/moderate disability); history of respiratory dysfunction (OR 3.16, 95% CI 1.79-5.58); obesity (OR 2.24, 95% CI 1.18-4.25); ≥3 comorbidities (OR 3.2, 95% CI 1.76-5.83; vs. ≤2; if comorbidity count used instead of specific comorbidities); glucocorticoid treatment (OR 2.33, 95% CI 1.14-4.78); and Guillain-Barré syndrome (OR 3.1, 95% CI 1.35-7.13; vs. mitochondrial disease). CONCLUSIONS: Among people with NMDs, there is a differential risk of COVID-19 outcomes according to demographic and clinical characteristics. These findings could be used to develop tailored management strategies and evidence-based recommendations for NMD patients.

Atrial Flutter in Particular Patient Populations.

"Despite being one of the best understood cardiac arrhythmias, the clinical meaning of atrial flutter varies according to the specific context, and its optimal treatment may be limited by both the suboptimal response to rate/rhythm control drugs and by the complexity of the underlying substrate. In this article, we present a state-of-the-art overview of mechanisms, prognostic impact, and medical/interventional management options for atrial flutter in several specific patient populations, including heart failure, cardiomyopathies, muscular dystrophies, posttransplant patients, patients with respiratory disorders, athletes, and subjects with preexcitation, aiming to stimulate further research in this challenging field and facilitate appropriate patient care."

A Case Report and Literature Review of New-Onset Myasthenia Gravis After COVID-19 Infection.

Myasthenia gravis (MG) is an autoimmune disorder affecting the neuromuscular junction caused by a B-cell-mediated, T-cell-dependent immunologic attack at the end plate of the postsynaptic membrane. Attack on muscle acetylcholine receptors (AChR) of the postsynaptic membrane due to the AChR, muscle-specific tyrosine kinase, or lipoprotein receptor-related peptide 4 antibodies lead to symptoms of painless, fluctuating weakness of muscle groups and often begins with ocular signs and symptoms. Coronavirus disease 2019 (COVID-19) is an acute respiratory disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), a novel coronavirus closely related to SARS-CoV. Serious neurologic complications are infrequent and diverse with reported cases of stroke, encephalitis/meningitis, Guillain-Barré syndrome, acute disseminated encephalomyelitis, ataxia, and unspecified limb weakness. MG is a rarely reported sequela of COVID-19 infection. To date, there are 15 reported cases of post-COVID-19 MG. In this article, we present a case of post-COVID-19 MG and a concise review of other reported cases. An 83-year-old Caucasian male with a medical history of atrial fibrillation status post-ablation and non-ischemic cardiomyopathy was initially admitted for COVID-19 pneumonia. He was treated with remdesivir, convalescent plasma, and supplemental oxygen therapy but did not require invasive mechanical intubation. One month after discharge, he started experiencing fatigue with muscle weakness and progressive dyspnea. He progressed to develop dysphonia, especially at the end of the day. After extensive workup, he was diagnosed with MG with a positive antibody against the AChR. The chronological events of developing slowly worsening muscular weakness after recovering from COVID-19 infection and positive AChR antibody led to the diagnosis of post-COVID-19 new-onset MG. Post-COVID-19 fatigue, long-term use of steroids, and intensive care unit-related physical deconditioning can be confounders in the clinical presentation of post-COVID-19 new-onset MG. Careful history-taking and meticulous assessment of chronological events are needed to diagnose this rare entity.

Pandemic decrease of in-person physiotherapy as a factor in parent perceived decline in function in children with neuromuscular disorders.

PURPOSE: Restrictions related to the COVID-19 pandemic can negatively affect patients who require physiotherapy. This study aimed to analyze the consequences of limited physiotherapy on the functional state of children with neuromuscular diseases (NMD). In addition, the caregivers' well-being and caregiver opinions on physiotherapy were analyzed. METHODS: A questionnaire was shared with parents of children with NMD immediately after the COVID-19 lockdown. The survey included questions regarding the physical and mental condition of children and parents before the pandemic and during lockdown as well as their views on physiotherapy and telephysiotherapy. Statistical analysis was performed using the Wilcoxon Matched-Pairs Signed Ranks test, Spearman's Rank Correlation test, McNemar test, and Chi-square test. RESULTS: Parents of 235 children participated in the study. Results indicated that children devoted more time to physiotherapy before the pandemic than during the lockdown period, which was true for those living in cities and the countryside. The functional state of 50.2% of the children deteriorated during the lockdown, in the opinion of their parents. Significant correlations were found between limited physiotherapy time and the deterioration of children's functional condition, ability to maintain a standing position, and increased anxiety. The majority of parents reported increased levels of fear and anxiety (72.8%), fatigue (67.7%), and pain (53.2%). In-person physiotherapy was rated significantly higher than telephysiotherapy by parents. CONCLUSIONS: Limited access to physiotherapy and shorter therapy times may lead to functional deterioration in children with NMD, but this assumption needs to be objectively confirmed. According to the parents' opinions, telephysiotherapy is less beneficial than direct physiotherapy but may support therapy conducted directly by a physiotherapist. Results based on subjective parental opinions may be helpful in planning future projects.

Ultrasonography Assessment Based on Muscle Thickness and Echo Intensity in Post-Polio Patients.

There is nospecific designed diagnostic test for post-poliomyelitis syndrome. The most important symptoms of this syndrome are new loss of muscle strength and more fatigue. Previous studies have investigated muscle ultrasound parameters to distinguish neuromuscular disease patients from healthy controls. The aim of this study was to investigate if muscle thickness and echo intensity measured by ultrasound can discriminate post-poliomyelitis syndrome patients from healthy controls. A total of 29 post-polio patients and 27 healthy controls participated in this cross-sectional study. Anthropometric measures, muscle thickness, echo intensity using B-mode ultrasound in rectus femoris and biceps brachii muscles, and muscle strength test data were collected. Muscle thickness in rectus femoris was significantly lower in post-poliomyelitis patients than in healthy controls, but not in biceps brachii. Echo intensity in rectus femoris and biceps brachii was higher in post-poliomyelitis syndrome patients than in healthy controls. Correlations were found between muscle thickness and strength in the upper and lower limbs. The results of the present study showed that muscle thickness in rectus femoris and echo intensity in rectus femoris and biceps brachii can discriminate post-poliomyelitis syndrome patients from healthy controls. A better assessment is possible because it can observe differences and relevant parameters in this clinical population.

Theme 12 - Clinical Management and Support

Power wheelchair prescription, utilization, satisfaction, and cost for patients with amyotrophic lateral sclerosis: preliminary data for evidence-based guidelines. Stage at which riluzole treatment prolongs survival in patients with amyotrophic lateral sclerosis: a retrospective analysis of data from a dose-ranging study. Support needs and interventions for family caregivers of patients with amyotrophic lateral sclerosis (ALS): a narrative review with report of telemedicine experiences at the time of COVID-19 pandemic. [Extracted from the article]

ACTA1 associated myopathy with neurogenic EMG changes

BackgroundWe describe a proband and her son who have proximal limb and facial weakness and marked hand involvement. A congenital myopathy panel demonstrated two RYR1 variants and the p.Ile289Phe novel variant in ACTA1.Cases: The proband had initially been diagnosed with SMA following premature birth, late milestones, scoliosis and proximal and distal weakness which was relatively static until age 40. EMG as a child was neurogenic. Her son had poor feeding after birth, delayed motor milestones, intellectual delay, and by his teens, severe facial weakness and distal upper limb wasting particularly the finger flexors and extensors, with hip flexion of grade 3. Repeat neurophysiological evaluation of the proband at age 60, demonstrated a neurogenic pattern but also brief polyphasic motor units, raising suspicion of an addi- tional myopathic process.DiscussionZukosky and colleagues1 also described a family with a different missense mutation in the ACTA1 gene who had been diagnosed with SMA on the basis of neurogenic EMG findings. Our additional family confirms that myopathy can be accompanied by neurogenic EMG changes in ACTA1 associated myopathy.Reference1. Zukosky K, Meilleur K, Traynor BJ, Dastgir J, Medne L, Devoto M, et al. Association of a Novel ACTA1 Mutation With a Dominant Progressive Scapuloperoneal Myopathy in an Extended Family. JAMA Neurol. 2015 Jun 1;72(6):689–98.carolynnedoherty@doctors.org.uk;NIHR Bursary

A Rare Case of Guillain-Barré Syndrome Associated With SARS-CoV-2 Infection Requiring Mechanical Ventilation.

Coronavirus disease 2019 (COVID-19) has become a worldwide pandemic since the first case of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection was identified in December 2019. Numerous neurological consequences have been reported with COVID-19 infection and its approved vaccines. However, Guillain-Barré syndrome (GBS) is a rare neurological complication associated with COVID-19 infection. This case report describes a 62-year-old female with a three-week history of COVID-19 infection who presented with symmetric polyneuropathy in bilateral lower extremities that progressed to involve bilateral upper extremities and skeletal muscles of respiration, resulting in respiratory distress and necessitating intubation and mechanical ventilation. Cerebrospinal fluid (CSF) analysis revealed albumino-cytologic dissociation, and our patient met the National Institute of Neurological Disorders and Strokes (NINDS) criteria for diagnosing Guillain-Barré Syndrome, making GBS to be the most likely diagnosis. This case report aims to strengthen the association of GBS with COVID-19 infection and describes the hospital course of GBS.

Healthcare applications of single camera markerless motion capture: a scoping review

Background Single camera markerless motion capture has the potential to facilitate at home movement assessment due to the ease of setup, portability, and affordable cost of the technology. However, it is not clear what the current healthcare applications of single camera markerless motion capture are and what information is being collected that may be used to inform clinical decision making. This review aims to map the available literature to highlight potential use cases and identify the limitations of the technology for clinicians and researchers interested in the collection of movement data. Survey Methodology Studies were collected up to 14 January 2022 using Pubmed, CINAHL and SPORTDiscus using a systematic search. Data recorded included the description of the markerless system, clinical outcome measures, and biomechanical data mapped to the International Classification of Functioning, Disability and Health Framework (ICF). Studies were grouped by patient population. Results A total of 50 studies were included for data collection. Use cases for single camera markerless motion capture technology were identified for Neurological Injury in Children and Adults;Hereditary/Genetic Neuromuscular Disorders;Frailty;and Orthopaedic or Musculoskeletal groups. Single camera markerless systems were found to perform well in studies involving single plane measurements, such as in the analysis of infant general movements or spatiotemporal parameters of gait, when evaluated against 3D marker-based systems and a variety of clinical outcome measures. However, they were less capable than marker-based systems in studies requiring the tracking of detailed 3D kinematics or fine movements such as finger tracking. Conclusions Single camera markerless motion capture offers great potential for extending the scope of movement analysis outside of laboratory settings in a practical way, but currently suffers from a lack of accuracy where detailed 3D kinematics are required for clinical decision making. Future work should therefore focus on improving tracking accuracy of movements that are out of plane relative to the camera orientation or affected by occlusion, such as supination and pronation of the forearm.

Reply

What is important, I think, is to examine typical complications that are reported relatively frequently and to discuss the effects of COVID-19 infection on the brain, nerves, and muscles from their pathogenesis. If you read the article straightforwardly, you will easily understand that they refer to symptoms or complications found in the brain, nerves, and muscles associated with COVID-19. Even Guillain-Barré syndrome (GBS), the International GBS Outcome Study reported that there has been no significant increase in patient enrollment.3 In addition, the significance of discussing the subtypes of GBS in detail in this paper is not clear. [Extracted from the article] Copyright of Clinical & Experimental Neuroimmunology is the property of Wiley-Blackwell and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full . (Copyright applies to all s.)

Neurological manifestations in patients with COVID‐19: A systematic review and meta‐analysis

IntroductionThe intensification of coronavirus disease 2019 (COVID‐19) complications, severe symptoms, and high mortality rate has led researchers to focus on this significant issue. While respiratory and cardiac complications have been described as high‐risk manifestations in patients with COVID‐19, neurological complications can also enhance mortality. This study aimed to evaluate the prevalence of neurological complications arises from SARS‐CoV‐2 and assess the mortality rate from neurological complications.Material and MethodsLiterature review was conducted by searching in PubMed/Medline, Web of Sciences, and Embase. After performing search strategies with relevant terms, a number of articles were excluded, including review articles, systematic review or meta‐analysis, duplicate publication of same researchers, congress s, animal studies, case reports, case series, and articles reporting a history of neurological features prior to COVID‐19 infection. After retrieving the data, statistical analysis was performed using the STATA Version 14 software.ResultsFrom 4455 retrieved publications, 20 articles were selected for further analysis. Among 18,258 included patients, 2791 showed neurological symptoms, which were classified into different groups. Headache, confusion, and fatigue were reported as the most non‐specific neurological features in confirmed COVID‐19 patients. Psychiatric symptoms, CNS disorders, cerebrovascular disorders, CNS inflammatory disorders, PNS disorders, neuromuscular disorders, etc., were defined as specific neurological manifestations. The pooled prevalence of neurological manifestations and mortality rate of COVID‐19 patients with neurological features were estimated to be 23.0% (95% CI: 17.8–29.2) and 29.1% (95% CI: 20.3–39.8), respectively.ConclusionNeurological manifestations may commonly happen in patients with COVID‐19. This study reported a high prevalence of neurological complications and mortality rates in COVID‐19 patients. Therefore, patients with COVID‐19 who indicated neurological symptoms should be taken seriously and should receive early treatment to prevent undesirable events.

Issue Information

This special issue includes 35 articles focusing on COVID-19 as an unforgettable challenge for the neurology community. Topics discussed are: dementia and cognitive disorders;stroke;movement disorders;infectious diseases;multiple sclerosis;muscled and MNJ disorders;headaches;neurocritical care;neuroimmunology;and neuropathies.

Frailties and critical issues in neuromuscular diseases highlighted by SARS-CoV-2 pandemic: how many patients are still "invisible"?

Almost 90% of neuromuscular diseases (NMDs) are classified as rare diseases, defined as conditions affecting less than 5 individuals in 10.000 (0.05%). Their rarity and diversity pose specific challenges for healthcare and research. Epidemiological data on NMDs are often lacking and incomplete. The COVID-19 pandemic has further highlighted the management difficulties of NMDs patients and the necessity to continue the program of implementation of standard of care. This article summarizes the Italian experience during pandemic.

TYK2 as a Biomarker and Therapeutic Target for NF1-Associated Malignant Peripheral Nerve Sheath Tumors

Malignant peripheral nerve sheath tumors (MPNST) are aggressive sarcomas that account for approximately 5% of all soft tissue sarcomas. These tumors occur at an increased frequency in patients with the Neurofibromatosis Type 1 (NF1) cancer predisposition syndrome, but also occur sporadically or as a secondary complication of radiation therapy. In the setting of NF1, MPNST arise from malignant transformation of a benign precursor lesion, a plexiform neurofibroma. Initial treatment for MPNST typically involves surgery and radiation with or without chemotherapy. However, despite aggressive therapy, the recurrence rate is high and the vast majority of people with these cancers will die within 5 years of diagnosis. Treatment for metastatic disease is limited to cytotoxic chemotherapy and clinical trials. As such, there is a pressing need to identify novel therapeutic targets. Prior work from our laboratory identified TYK2 as a gene mutated in a subset of MPNSTs. More recently, we have shown that genetic knockdown of TYK2 in both human and murine MPNST cell lines results in decreased tumor growth and increased cell death in vitro. Additionally, genetic knockdown of Tyk2 in murine MPNST cells resulted in decreased tumor burden in subcutaneous tumors and metastatic tumor models. Immunohistochemistry (IHC) for TYK2 was performed on 27 MPNST and 16 plexiformneurofibromas to evaluate TYK2 association with tumor type, overall survival, metastasis and therapeutic response. Additionally, similar to genetic knockdown, pharmacologic inhibition of TYK2 dose-dependently decreased the percent cell confluence and induced apoptosis over time in four MPNST cell-lines, as assessed by IncuCyte proliferation and apoptosis assays. In murine MPNST JW23.3 cells, incubation with TYK2 inhibitors reduced pSTAT3 levels, but not pERK or pS6K.

Characterization of a Novel Humanized Mouse Model of Neurofibromatosis

The purpose of this study was to characterize a mutant mouse that bears an NF1 mutation that is identical to one found in humans. No human samples exist to determine the nature of how this particular mutation affects the NF1 gene and protein. This mutation is particularly important to understand as it does not lead to the neurofibroma formation found in most patients, but it can lead to learning challenges, developmental delay and in some cases epilepsy. This study was able to determine that this particular mutant NF1 protein neither affects the most common pathways associated with the function of the NF1 protein nor leads to some inflammatory aspects of the disease. These are critical findings as they reveal that the protein has additional functions that are linked to a very specific region of the protein and that this mutation may be acting in very distinct ways from the effects of complete loss of the NF1 protein. This study also found a link between this mutation and programmed cell death in a region of the brain critical for learning and memory. This information will allow new studies to more clearly define the molecular basis for the neurological aspects of Neurofibromatosis with this new understanding bringing the potential for new therapeutic targets.

Direct Regulation of Estrogen Receptor Transcription Activity by NF1

This project centers on the NF1/neurofibromin tumor suppressor, which was best known as a GTPase Activating Protein (GAP)that repress Ras activity. The parent DoD award has successfully defined a new and GAP-independent activity that NF1 is also a transcriptional co-repressor for estrogen receptor (ER) in ER+ breast cancer. While the parent DoD award focused on endocrine therapy resistance caused by NF1 loss, in this Expansion Award, the focus instead is on metastasis, for which currently has no cure. An important feature of ER+ breast cancer metastasis is that greater than 70% of the metastasis is in the bone. We hypothesized that the transcriptional co-repressor role of NF1 is also responsible for driving bone metastasis in ER+ breast cancer. Therefore, the objective of this Expansion Award is to assess NF1s role in metastasis in order to establish a strategy to stop it. We have made progress in accomplish Task1/Aim 1 to fully define NF1-controlled genes that can impact bone metastasis. This was a key part of the data that was just published in the high impact journal Cancer Cell. This award has also supported the launching a Phase-II clinical trial to treat ER+ NF1-depleted breast cancer, and the awards of a SPORE and another DoD Level-2 project. However, in Aim 2 (Tasks 2 and 30) we are dependent on the use of animals to study how NF1-depleted cancer cells interact with the bone, but this line of study has been severely and negatively impacted by COVID-19. We discuss how we plan to overcome this problem in the future.