Debamestrocel multimodal effects on biomarker pathways in amyotrophic lateral sclerosis are linked to clinical outcomes.

INTRODUCTION/AIMS: Biomarkers have shown promise in amyotrophic lateral sclerosis (ALS) research, but the quest for reliable biomarkers remains active. This study evaluates the effect of debamestrocel on cerebrospinal fluid (CSF) biomarkers, an exploratory endpoint. METHODS: A total of 196 participants randomly received debamestrocel or placebo. Seven CSF samples were to be collected from all participants. Forty-five biomarkers were analyzed in the overall study and by two subgroups characterized by the ALS Functional Rating Scale-Revised (ALSFRS-R). A prespecified model was employed to predict clinical outcomes leveraging biomarkers and disease characteristics. Causal inference was used to analyze relationships between neurofilament light chain (NfL) and ALSFRS-R. RESULTS: We observed significant changes with debamestrocel in 64% of the biomarkers studied, spanning pathways implicated in ALS pathology (63% neuroinflammation, 50% neurodegeneration, and 89% neuroprotection). Biomarker changes with debamestrocel show biological activity in trial participants, including those with advanced ALS. CSF biomarkers were predictive of clinical outcomes in debamestrocel-treated participants (baseline NfL, baseline latency-associated peptide/transforming growth factor beta1 [LAP/TGFß1], change galectin-1, all p < .01), with baseline NfL and LAP/TGFß1 remaining (p < .05) when disease characteristics (p < .005) were incorporated. Change from baseline to the last measurement showed debamestrocel-driven reductions in NfL were associated with less decline in ALSFRS-R. Debamestrocel significantly reduced NfL from baseline compared with placebo (11% vs. 1.6%, p = .037). DISCUSSION: Following debamestrocel treatment, many biomarkers showed increases (anti-inflammatory/neuroprotective) or decreases (inflammatory/neurodegenerative) suggesting a possible treatment effect. Neuroinflammatory and neuroprotective biomarkers were predictive of clinical response, suggesting a potential multimodal mechanism of action. These results offer preliminary insights that need to be confirmed.

Mis-spliced transcripts generate de novo proteins in TDP-43-related ALS/FTD.

Functional loss of TDP-43, an RNA binding protein genetically and pathologically linked to amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), leads to the inclusion of cryptic exons in hundreds of transcripts during disease. Cryptic exons can promote the degradation of affected transcripts, deleteriously altering cellular function through loss-of-function mechanisms. Here, we show that mRNA transcripts harboring cryptic exons generated de novo proteins in TDP-43-depleted human iPSC-derived neurons in vitro, and de novo peptides were found in cerebrospinal fluid (CSF) samples from patients with ALS or FTD. Using coordinated transcriptomic and proteomic studies of TDP-43-depleted human iPSC-derived neurons, we identified 65 peptides that mapped to 12 cryptic exons. Cryptic exons identified in TDP-43-depleted human iPSC-derived neurons were predictive of cryptic exons expressed in postmortem brain tissue from patients with TDP-43 proteinopathy. These cryptic exons produced transcript variants that generated de novo proteins. We found that the inclusion of cryptic peptide sequences in proteins altered their interactions with other proteins, thereby likely altering their function. Last, we showed that 18 de novo peptides across 13 genes were present in CSF samples from patients with ALS/FTD spectrum disorders. The demonstration of cryptic exon translation suggests new mechanisms for ALS/FTD pathophysiology downstream of TDP-43 dysfunction and may provide a potential strategy to assay TDP-43 function in patient CSF.

Considerations for establishing and maintaining international research collaboration: the example of chemotherapy-induced peripheral neurotoxicity (CIPN)-a white paper.

PURPOSE: This white paper provides guidance regarding the process for establishing and maintaining international collaborations to conduct oncology/neurology-focused chemotherapy-induced peripheral neurotoxicity (CIPN) research. METHODS: An international multidisciplinary group of CIPN scientists, clinicians, research administrators, and legal experts have pooled their collective knowledge regarding recommendations for establishing and maintaining international collaboration to foster advancement of CIPN science. RESULTS: Experts provide recommendations in 10 categories: (1) preclinical and (2) clinical research collaboration; (3) collaborators and consortiums; (4) communication; (5) funding; (6) international regulatory standards; (7) staff training; (8) data management, quality control, and data sharing; (9) dissemination across disciplines and countries; and (10) additional recommendations about feasibility, policy, and mentorship. CONCLUSION: Recommendations to establish and maintain international CIPN research collaboration will promote the inclusion of more diverse research participants, increasing consideration of cultural and genetic factors that are essential to inform innovative precision medicine interventions and propel scientific discovery to benefit cancer survivors worldwide. RELEVANCE TO INFORM RESEARCH POLICY: Our suggested guidelines for establishing and maintaining international collaborations to conduct oncology/neurology-focused chemotherapy-induced peripheral neurotoxicity (CIPN) research set forth a challenge to multinational science, clinical, and policy leaders to (1) develop simple, streamlined research designs; (2) address logistical barriers; (3) simplify and standardize regulatory requirements across countries; (4) increase funding to support international collaboration; and (5) foster faculty mentorship.

Femoral neuropathy: A clinical and electrodiagnostic review.

INTRODUCTION/AIMS: Femoral neuropathies can cause severe, prolonged debility, yet there have been few clinical and electrodiagnostic (EDx) studies addressing this condition. The aim of this study was to better understand the etiologies, EDx features, and clinical course of femoral neuropathy. METHODS: We identified patients evaluated at Mayo Clinic Rochester between January 1, 1999 and July 31, 2019, with possible new femoral neuropathy ascertained via International Classification of Diseases-versions 9 and 10 diagnosis codes presenting within 6 months of symptom onset. RESULTS: A retrospective review of 1084 records was performed and we ultimately identified 159 patients with isolated femoral neuropathy for inclusion. The most common femoral neuropathy etiologies were compressive (40%), perioperative stretch (35%), and inflammatory (6%). Presenting symptoms included weakness (96%), sensory loss (73%), and pain (53%). Presenting motor physical exam findings demonstrated moderate weakness (34%) or no activation (25%) of knee extension and mild (32%) or moderate (35%) weakness of hip flexion. Seventy-two percent of patients underwent EDx testing, including 22 with femoral motor nerve conduction studies. Treatment often involved physical therapy (89%) and was otherwise etiology-specific. In patients with follow-up data available (n = 154), 83% had subjective clinical improvement at follow-up with a mean time to initial improvement of 3.3 months and mean time to recovery at final follow-up of 14.8 months. Only 48% of patients had nearly complete or complete recovery. DISCUSSION: In our cohort, the most common etiologies of femoral neuropathy were compression or perioperative stretch with high initial morbidity. Although motor recovery is common, improvement is often prolonged and incomplete.

Nerve transcriptomes in autoimmune and genetic demyelinating neuropathies: Pathogenic pathway assessment of nerve demyelination.

The pathogenesis of autoimmune demyelinating neuropathies is poorly understood compared to inherited demyelinating forms. We performed whole transcriptome (RNA-Seq) using nerve biopsy tissues of patients with different autoimmune and inherited demyelinating neuropathies (CIDP n = 10, POEMS n = 18, DADS n = 3, CMT1 n = 3) versus healthy controls (n = 6). A limited number of differentially expressed genes compared to healthy controls were identified (POEMS = 125, DADS = 15, CMT = 14, CIDP = 5). Divergent pathogenic pathways including inflammatory, demyelinating and neurite regeneration such as with the triggering receptor expressed on myeloid cells (TREM1) part of the immunoglobulin superfamily and RhoGD1 are found. Shared and discordant pathogenic injury are discovered between autoimmune and inherited forms.

Clinical trials in Charcot-Marie-Tooth disorders: a retrospective and preclinical assessment.

Objective: This study aimed to evaluate the progression of clinical and preclinical trials in Charcot-Marie-Tooth (CMT) disorders. Background: CMT has historically been managed symptomatically and with genetic counseling. The evolution of molecular and pathologic understanding holds a therapeutic promise in gene-targeted therapies. Methods: ClinicalTrials.gov from December 1999 to June 2022 was data extracted for CMT with preclinical animal gene therapy trials also reviewed by PubMed search. Results: The number of active trials was 1 in 1999 and 286 in 2022. Academic settings accounted for 91% and pharmaceutical companies 9%. Of the pharmaceutical and academic trials, 38% and 28%, respectively, were controlled, randomized, and double-blinded. Thirty-two countries participated: the United States accounted for 26% (75/286). In total, 86% of the trials were classified as therapeutic: 50% procedural (21% wrist/elbow surgery; 22% shock wave and hydrodissection therapy), 23% investigational drugs, 15% devices, and 11% physical therapy. Sixty-seven therapeutic trials (49%) were designated phases 1-2 and 51% phases 3-4. The remaining 14% represent non-therapeutic trials: diagnostic testing (3%), functional outcomes (4%), natural history (4%), and standard of care (3%). One-hundred and three (36%) resulted in publications. Phase I human pharmaceutical trials are focusing on the safety of small molecule therapies (n = 8) and AAV and non-viral gene therapy (n = 3). Preclinical animal gene therapy studies include 11 different CMT forms including viral, CRISPR-Cas9, and nanoparticle delivery. Conclusion: Current CMT trials are exploring procedural and molecular therapeutic options with substantial participation of the pharmaceutical industry worldwide. Emerging drug therapies directed at molecular pathogenesis are being advanced in human clinical trials; however, the majority remain within animal investigations.

Biomolecular alterations detected in multiple sclerosis skin fibroblasts using Fourier transform infrared spectroscopy.

Multiple sclerosis (MS) is the leading cause of non-traumatic disability in young adults. New avenues are needed to help predict individuals at risk for developing MS and aid in diagnosis, prognosis, and outcome of therapeutic treatments. Previously, we showed that skin fibroblasts derived from patients with MS have altered signatures of cell stress and bioenergetics, which likely reflects changes in their protein, lipid, and biochemical profiles. Here, we used Fourier transform infrared (FTIR) spectroscopy to determine if the biochemical landscape of MS skin fibroblasts were altered when compared to age- and sex-matched controls (CTRL). More so, we sought to determine if FTIR spectroscopic signatures detected in MS skin fibroblasts are disease specific by comparing them to amyotrophic lateral sclerosis (ALS) skin fibroblasts. Spectral profiling of skin fibroblasts from MS individuals suggests significant alterations in lipid and protein organization and homeostasis, which may be affecting metabolic processes, cellular organization, and oxidation status. Sparse partial least squares-discriminant analysis of spectral profiles show that CTRL skin fibroblasts segregate well from diseased cells and that changes in MS and ALS may be unique. Differential changes in the spectral profile of CTRL, MS, and ALS cells support the development of FTIR spectroscopy to detect biomolecular modifications in patient-derived skin fibroblasts, which may eventually help establish novel peripheral biomarkers.

Skin Extracellular Matrix Breakdown Following Paclitaxel Therapy in Patients with Chemotherapy-Induced Peripheral Neuropathy.

The chemotherapeutic agent paclitaxel causes peripheral neuropathy, a dose-limiting side effect, in up to 68% of cancer patients. In this study, we investigated the impact of paclitaxel therapy on the skin of breast cancer patients with chemotherapy-induced peripheral neuropathy (CIPN), building upon previous findings in zebrafish and rodents. Comprehensive assessments, including neurological examinations and quality of life questionnaires, were conducted, followed by intraepidermal nerve fiber (IENF) density evaluations using skin punch biopsies. Additionally, RNA sequencing, immunostaining for Matrix-Metalloproteinase 13 (MMP-13), and transmission electron microscopy provided insights into molecular and ultrastructural changes in this skin. The results showed no significant difference in IENF density between the control and CIPN patients despite the presence of patient-reported CIPN symptoms. Nevertheless, the RNA sequencing and immunostaining on the skin revealed significantly upregulated MMP-13, which is known to play a key role in CIPN caused by paclitaxel therapy. Additionally, various genes involved in the regulation of the extracellular matrix, microtubules, cell cycle, and nervous system were significantly and differentially expressed. An ultrastructural examination of the skin showed changes in collagen and basement membrane structures. These findings highlight the presence of CIPN in the absence of IENF density changes and support the role of skin remodeling as a major contributor to CIPN.

Clinical, Neurophysiologic, and Pathologic Features in Patients With Early-Onset Postradiation Neuropathy.

OBJECTIVES: The objective of this study was to study early-onset radiation-induced neuropathy reviewing neurologic course, steroid response, and available nerve biopsies. METHODS: Patients coded with radiation-induced neuropathy within 6 months of radiation were reviewed from January 1,1999, to August 31, 2022. Patients had to have electrodiagnostically confirmed neuropathy localized within or distal to radiation fields. Neurologic course and nerve biopsies were reviewed. RESULTS: Twenty-eight patients (16 male and 12 female patients, mean age 63.8 years) were identified. The average radiation dose was 4,659 cGy (range 1,000-7,208). Tumor infiltration was not observed on MRI and PET. Postradiation onsets averaged 2 months (range 0-5). Localizations included brachial (n = 4) plexopathies, lumbosacral (n = 12) plexopathies, radiculopathies (n = 10), and mononeuropathies (n = 2). Neuropathic pain (n = 25) and weakness (n = 25) were typical. The clinical courses were subacute monophasic (n = 14), chronic progressive (n = 8), or static (n = 1), and 5 were without follow-up. Nerve biopsies (n = 8) showed an inflammatory ischemic process with perivascular inflammatory infiltrates (n = 7) or microvasculitis (n = 2). Nine patients, 7 with monophasic courses, received steroid burst therapy with symptom improvement in 8. No patients recovered entirely back to baseline. DISCUSSION: In contrast to chronic radiation-induced neuropathy, early-onset patients most commonly have painful monophasic courses with residual deficits, possibly steroid responsive. An ischemic inflammatory pathogenesis is suggested.

Radiologically Inserted Gastrostomy Tube Placement Guided by the Assessment and Primary Palliative Care Provided by an Amyotrophic Lateral Sclerosis Multidisciplinary Clinic: A Single-Arm Retrospective Clinical Study.

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease with a median survival of about 3 years. An ALS multidisciplinary team can provide primary palliative care and improve outcomes and quality of life for patients. Feeding tube insertion may be considered for patients with significant weight loss, or respiratory insufficiency. While radiologically inserted gastrostomy (RIG) tube placement may be an option, further studies are required to determine its best timing and appropriateness. This study's objectives were to evaluate the feasibility and outcomes of RIG tube placement in ALS patients over a 90-day follow-up period through the assessment and primary palliative care provided by the multidisciplinary team. This retrospective study reviewed the placement of 16 or 18 French RIG-tube without intubation or endoscopy for 36 ALS patients at a single center between April 2019 and December 2021. Measures included ALS Functional Rating Scale-Revised (ALSFRS-R) scores to determine the ALS stage. Demographic, clinical, procedural, and follow-up data were reviewed. Results showed that the RIG tube placement had a low rate of minor adverse events (11%) and no major procedure-related adverse events. The mean ALSFRS-R score at the time of procedure in subjects who died within 90 days was lower than of those alive beyond 90 days (P = .04). This study found that RIG-tube placement is a safe and effective way to manage dysphagia in ALS patients and highlights the importance of educating members of the multidisciplinary clinic in palliative care principles to determine the appropriateness of RIG tube placement.

Identification of potential pathways and biomarkers linked to progression in ALS.

OBJECTIVE: To identify potential diagnostic and prognostic biomarkers for clinical management and clinical trials in amyotrophic lateral sclerosis. METHODS: We analysed proteomics data of ALS patient-induced pluripotent stem cell-derived motor neurons available through the AnswerALS consortium. After stratifying patients using clinical ALSFRS-R and ALS-CBS scales, we identified differentially expressed proteins indicative of ALS disease severity and progression rate as candidate ALS-related and prognostic biomarkers. Pathway analysis for identified proteins was performed using STITCH. Protein sets were correlated with the effects of drugs using the Connectivity Map tool to identify compounds likely to affect similar pathways. RNAi screening was performed in a Drosophila TDP-43 ALS model to validate pathological relevance. A statistical classification machine learning model was constructed using ridge regression that uses proteomics data to differentiate ALS patients from controls. RESULTS: We identified 76, 21, 71 and 1 candidate ALS-related biomarkers and 22, 41, 27 and 64 candidate prognostic biomarkers from patients stratified by ALSFRS-R baseline, ALSFRS-R progression slope, ALS-CBS baseline and ALS-CBS progression slope, respectively. Nineteen proteins enhanced or suppressed pathogenic eye phenotypes in the ALS fly model. Nutraceuticals, dopamine pathway modulators, statins, anti-inflammatories and antimicrobials were predicted starting points for drug repurposing using the connectivity map tool. Ten diagnostic biomarker proteins were predicted by machine learning to identify ALS patients with high accuracy and sensitivity. INTERPRETATION: This study showcases the powerful approach of iPSC-motor neuron proteomics combined with machine learning and biological confirmation in the prediction of novel mechanisms and diagnostic and predictive biomarkers in ALS.

ProtPipe: A Multifunctional Data Analysis Pipeline for Proteomics and Peptidomics.

Mass spectrometry (MS) is a technique widely employed for the identification and characterization of proteins, personalized medicine, systems biology and biomedical applications. By combining MS with different proteomics approaches such as immunopurification MS, immunopeptidomics, and total protein proteomics, researchers can gain insights into protein-protein interactions, immune responses, cellular processes, and disease mechanisms. The application of MS-based proteomics in these areas continues to advance our understanding of protein function, cellular signaling, and complex biological systems. Data analysis for mass spectrometry is a critical process that includes identifying and quantifying proteins and peptides and exploring biological functions for these proteins in downstream analysis. To address the complexities associated with MS data analysis, we developed ProtPipe to streamline and automate the processing and analysis of high-throughput proteomics and peptidomics datasets. The pipeline facilitates data quality control, sample filtering, and normalization, ensuring robust and reliable downstream analysis. ProtPipe provides downstream analysis including identifying differential abundance proteins and peptides, pathway enrichment analysis, protein-protein interaction analysis, and MHC1-peptide binding affinity. ProtPipe generates annotated tables and diagnostic visualizations from statistical postprocessing and computation of fold-changes across pairwise conditions, predefined in an experimental design. ProtPipe is well-documented open-source software and is available at https://github.com/NIH-CARD/ProtPipe , accompanied by a web interface.

Update on Toxic Neuropathies.

Purpose of Review: Toxic neuropathies are an important preventable and treatable form of peripheral neuropathy. While many forms of toxic neuropathies have been recognized for decades, an updated review is provided to increase vigilant in this area of neurology. A literature review was conducted to gather recent information about toxic neuropathies, which included the causes, clinical findings, and treatment options in these conditions. Recent Findings: Toxic neuropathies continue to cause significant morbidity throughout the world and the causative agents, particularly with regards to medications, do not appear to be diminishing. A wide variety of causes of toxic neuropathies exist, which include alcohol, industrial chemicals, biotoxins, and medications. Unfortunately, no breakthrough treatments have been developed and prevention and symptom management remain the standard of care. Summary: A detailed medication, occupational and hobby exposure history is critical to identifying toxic neuropathies. Increased research is warranted to identify mechanisms of neurotoxic susceptibility and potential common pathomechanistic pathways for treatment across diverse toxic neuropathies.

Plexus MRI helps distinguish the immune-mediated neuropathies MADSAM and MMN.

BACKGROUND: Among immune-mediated neuropathies, clinical-electrophysiological overlap exists between multifocal acquired demyelinating sensory and motor neuropathy (MADSAM) and multifocal motor neuropathy (MMN). Divergent immune pathogenesis, immunotherapy response, and prognosis exist between these two disorders. MRI reports have not shown distinction of these disorders, but biopsy confirmation is lacking in earlier reports. MADSAM nerves are hypertrophic with onion bulbs, inflammation, and edema, whereas MMN findings are limited to multifocal axonal atrophy. OBJECTIVES: To understand if plexus MRI can distinguish MADSAM from MMN among pathologically (nerve biopsy) confirmed cases. METHODS: Retrospective chart review and blinded plexus MRI review of biopsy-confirmed MADSAM and MMN cases at Mayo Clinic. RESULTS: Nine brachial plexuses (MADSAM-5, MMN-4) and 6 lumbosacral plexuses (MADSAM-4, MMN-2) had fascicular biopsies of varied nerves. Median follow-up in MADSAM was 93 months (range: 7-180) and 27 (range: 12-109) in MMN (p = 0.34). MRI hypertrophy occurred solely in MADSAM (89%, 8/9) with T2-hyperintensity in both. There was no correlation between time to imaging for hypertrophy, symptom onset age, or motor neuropathy impairments (mNIS). At last follow-up, on diverse immunotherapies mNIS improved in MADSAM (median - 4, range: -22 to 0), whereas MMN worsened (median 3, range: 0 to 6, p = 0.03) on largely IVIG. CONCLUSION: Nerve hypertrophy on plexus MRI helps distinguish MMN from MADSAM, where better immunotherapy treatment outcomes were observed. These findings are consistent with the immune pathogenesis seen on biopsies. Radiologic distinction is possible independent of time to imaging and extent of motor deficits, suggesting MRI is helpful in patients with uncertain clinical-electrophysiologic diagnosis, especially motor-onset MADSAM.

Clinical and electrophysiological findings in C9ORF72 ALS.

INTRODUCTION/AIMS: Amyotrophic lateral sclerosis (ALS) is a progressive, fatal, neurodegenerative disorder of motor neurons in which the cause is mostly unknown. Early identification of genetic ALS cases, of which C9ORF72 (C9ALS) is the most frequent, can have important implications for evaluation, prognosis, and therapeutics. Here, we aimed to characterize the clinical and electrophysiological hallmarks of C9ALS and investigate differences from C9ORF72 negative ALS (non-C9ALS). METHODS: We retrospectively reviewed clinical and electrodiagnostic (EDX) data for all genetically confirmed C9ALS cases seen between 1/1/2012 and 10/1/2020 who met Gold Coast criteria and compared them 1:1 with non-C9ALS patients within the same time frame. RESULTS: A total of 99 C9ALS and 99 non-C9ALS cases were identified. Compared to non-C9ALS, C9ALS demonstrated higher prevalence in women, lesser racial variability, stronger family history of ALS, and higher frequency of upper motor neuron signs. EDX testing of C9ALS showed higher median sensory nerve and lower fibular compound muscle action potential amplitudes. DISCUSSION: Although the differences between C9ALS and non-C9ALS reached statistical significance in certain nerve conduction parameters, they were not sufficient to discriminate between groups on a case-by-case basis. Genetic testing is required to identify C9ALS patients.

Comparative Performance of Different Respiratory Test Parameters for Detection of Early Respiratory Insufficiency in Patients With ALS.

BACKGROUND AND OBJECTIVES: To compare the performance of different respiratory function testing parameters in a multidisciplinary amyotrophic lateral sclerosis (ALS) clinic. METHODS: Demographics, clinical data, and respiratory testing parameters were abstracted from the medical records of patients who attended a multidisciplinary ALS clinic from 2008 to 2016. We compared the performance of the 3 primary respiratory test parameters used by Medicare for the initiation of noninvasive ventilation (NIV) (forced vital capacity [FVC] < 50% predicted, maximum inspiratory pressure [MIP] < 60 cm H2O, and abnormal overnight pulse oximetry [OvOx]) on how they related to several clinically relevant attributes. RESULTS: Four hundred seventy-six patients were identified who underwent at least 1 respiratory test. Abnormalities of OvOx, MIP, and FVC occurred at a median of 1.6, 1.5, and 3.8 years from disease onset, respectively (p < 0.00001). Patients with bulbar-onset ALS exhibited earlier abnormalities in MIP and FVC than in spinal-onset ALS (p < 0.005). The median survival after an abnormal OvOx, MIP, or FVC test was 1.4, 1.4, and 0.9 years, respectively (p < 0.0001). Using the ALS Functional Rating Score respiratory subscales, at the time of reported respiratory symptoms there were abnormalities in OvOx (60%), MIP (69%), and FVC (19%). Conversely, when respiratory parameter abnormalities preceded reported respiratory symptoms, this occurred with frequencies in OvOx (79%), MIP (42%), or FVC (24%). Four hundred forty-three patients (93.1%) developed at least 1 abnormal respiratory measure meeting Medicare criteria for NIV consideration, but fewer than 50% in our cohort demonstrated NIV use. Improved survival in subjects using NIV was statistically significant in patients with bulbar-onset ALS. DISCUSSION: Abnormalities in OvOx and MIP perform better than FVC at early detection of neuromuscular respiratory weakness in ALS. Initiation of NIV in patients with respiratory insufficiency may improve the overall survival in ALS. In the setting of the COVID-19 pandemic, FVC and MIP have not been routinely performed because of infectious aerosol generation. OvOx, which we now routinely mail to patients' homes, has been used exclusively during the COVID-19 pandemic and allows for continued remote monitoring of the respiratory status of patients with ALS. CLASSIFICATION OF EVIDENCE: This cohort study provides Class III evidence that in people with ALS, OvOx and MIP are valuable respiratory parameters for the detection of early respiratory insufficiency.

Lessons Learned from Clinical and Translational Science Faculty and Student Survey as COVID-19 Pandemic Continues to Shift Education Online.

INTRODUCTION: As the pandemic continues with new variants emerging, faculty and students require support with education's rapid shift to the virtual space. The Mayo Clinic Center for Clinical and Translational Science curriculum team works closely with faculty to support a smooth transition to offering graduate courses in a virtual learning environment. The aim of the present project was to explore faculty and student perceptions of these remote learning strategies to gain an understanding of the innovations required to improve future educational offerings. METHODS: All faculty and learners involved in nine Clinical and Translational Science courses in spring 2020 were invited to participate in a web-based questionnaire. Quantitative analysis was performed on closed-ended items, including 5-point Likert-scale questions used to assess the range of views. Qualitative free-text responses were independently analyzed for repetitive themes and summarized. Additionally, comparisons of faculty and course evaluations and student grade point averages (GPAs) from the in-person courses and their subsequent virtual course offerings were considered. RESULTS: Survey results indicated several positive impacts with moving courses into the virtual environment, including increased accessibility as well as more student-centered education. Learners joining from sites outside of the originating campus were especially grateful for the virtual classroom because they felt newly integrated within classes. Faculty and course evaluations, as well as student GPAs, remained consistent. CONCLUSION: New COVID-19 variants continue to shift education online, and innovative ideas are required to further improve future virtual course offerings. Increased engagement is warranted, both from faculty to incorporate activities designed specifically for a virtual classroom, and from students to increase participation by activating their microphones and webcams. Greater opportunities for global involvement and connectedness arise. Finally, this project advocates for adequate eLearning staffing to support quality online education as the need for pedagogical and technical provision continues.

Toward a fully implantable ecosystem for adaptive neuromodulation in humans: Preliminary experience with the CorTec BrainInterchange device in a canine model.

This article describes initial work toward an ecosystem for adaptive neuromodulation in humans by documenting the experience of implanting CorTec's BrainInterchange (BIC) device in a beagle canine and using the BCI2000 environment to interact with the BIC device. It begins with laying out the substantial opportunity presented by a useful, easy-to-use, and widely available hardware/software ecosystem in the current landscape of the field of adaptive neuromodulation, and then describes experience with implantation, software integration, and post-surgical validation of recording of brain signals and implant parameters. Initial experience suggests that the hardware capabilities of the BIC device are fully supported by BCI2000, and that the BIC/BCI2000 device can record and process brain signals during free behavior. With further development and validation, the BIC/BCI2000 ecosystem could become an important tool for research into new adaptive neuromodulation protocols in humans.

A randomized placebo-controlled phase 3 study of mesenchymal stem cells induced to secrete high levels of neurotrophic factors in amyotrophic lateral sclerosis.

INTRODUCTION/AIMS: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative illness with great unmet patient need. We aimed to evaluate whether mesenchymal stem cells induced to secrete high levels of neurotrophic factors (MSC-NTF), a novel autologous cell-therapy capable of targeting multiple pathways, could safely slow ALS disease progression. METHODS: This randomized, double-blind, placebo-controlled study enrolled ALS participants meeting revised El Escorial criteria, revised ALS Functional Rating Scale (ALSFRS-R) ≥25 (screening) and ≥3 ALSFRS-R points decline prior to randomization. Participants received three treatments of MSC-NTF or placebo intrathecally. The primary endpoint evaluated efficacy of MSC-NTF through a responder analysis and safety. A change in disease progression post-treatment of ≥1.25 points/mo defines a clinical response. A pre-specified analysis leveraged baseline ALSFRS-R of 35 as a subgroup threshold. RESULTS: Overall, MSC-NTF treatment was well tolerated; there were no safety concerns. Thirty-three percent of MSC-NTF and 28% of placebo participants met clinical response criteria at 28 wk (odds ratio [OR] = 1.33, P = .45); thus, the primary endpoint was not met. A pre-specified analysis of participants with baseline ALSFRS-R ≥ 35 (n = 58) showed a clinical response rate at 28 wk of 35% MSC-NTF and 16% placebo (OR = 2.6, P = .29). Significant improvements in cerebrospinal biomarkers of neuroinflammation, neurodegeneration, and neurotrophic factor support were observed with MSC-NTF, with placebo unchanged. DISCUSSION: The study did not reach statistical significance on the primary endpoint. However, a pre-specified subgroup suggests that MSC-NTF participants with less severe disease may have retained more function compared to placebo. Given the unmet patient need, the results of this trial warrant further investigation.