Safety and Activity of Anti-CD14 Antibody IC14 (Atibuclimab) in ALS: Experience with an Expanded Access Protocol

Introduction: IC14 (atibuclimab) is a monoclonal anti-CD14 antibody that may target T-regulatory (T-reg) cell function. A previous phase 1 trial of 10 participants with amyotrophic lateral sclerosis (ALS) demonstrated initial safety of IC14 for a single cycle of treatment. We provided longterm treatment with IC14 to 17 individuals with ALS via an expanded access protocol (EAP) and documented target engagement, safety, and disease endpoints. Method(s): Participants received intravenous IC14 every two weeks. Consistent with FDA guidelines, participants were ineligible for clinical trials and the EAP was inclusive of a broad population. Participants unable to travel to MGH due to the COVID-19 pandemic or disease progression, were transitioned to infusions in-home or local clinics. Blood samples for hematology, chemistry, and coagulation were collected to monitor safety. The Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised (ALSFRS-R) was administered monthly to track disease progression. Respiratory function was measured through slow vital capacity tests -data for this is limited due to the COVID-19 pandemic. Whole blood and serum were collected to determine monocyte CD14 receptor occupancy (RO), soluble CD14, and antidrug antibodies (ADA). Ex vivo T regulatory functional assays were performed with five participants. Result(s): Participants received IC14 for up to 103 weeks (average: 30.1 weeks, range: 1-103 weeks). Treatmentemergent adverse events were uncommon, mild, and self-limited. There were 18 serious adverse events (SAEs) which were related to disease progression and unrelated (17) or likely unrelated (1) to IC14. Three participants died due to disease progression. Most participants achieved >80% monocyte mCD14 RO on a 14-day dosing schedule, although one individual required more frequent dosing (every 10 days) to achieve >80% RO. ADA were detected in only one participant and were transient, low titer, and non-neutralizing. Tregs were isolated from the available longitudinal samples and assayed for suppression of CD4 T cell proliferation and cytokine production versus baseline T-reg activity. Conclusion(s): IC14 administration to ALS patients was safe and well tolerated in this EAP, with no significant changes in laboratory tests and no drug-related SAEs. Measuring RO guided dosing frequency. Preliminary data suggest IC14 enhanced T-reg activity. Additional placebo-controlled trials are required to determine the efficacy of IC14 in ALS.

Risk stratification models for stroke in patients hospitalized with COVID-19 infection: An American heart association COVID-19 CVD registry study

Introduction: Coronavirus Disease 2019 (COVID-19) is associated with an increased risk of stroke and worse stroke outcomes. A clinical score that can identify high-risk patients could enable closer monitoring and targeted preventative strategies. Methods: We used data from the AHA's COVID-19 CVD Registry to create a clinical score to predict the risk of stroke among patients hospitalized with COVID-19. We included patients aged >18 years who were hospitalized with COVID-19 at 122 centers from March 2020-March 2021. To build our score, we used demographics, preexisting comorbidities, home medications, and vital sign and lab values at admission. The outcome was a cerebrovascular event, defined as any ischemic or hemorrhagic stroke, TIA, or cerebral vein thrombosis. We used two separate analytical approaches to build the score. First, we used Cox regression with cross validation techniques to identify factors associated with the outcome in both univariable (p<0.10) and multivariable analyses (p<0.05), then assigned points for each variable based on corresponding coefficients. Second, we used regularized Cox regression, XGBoost, and Random Forest machine learning techniques to create an estimator using all available covariates. We used Harrel's C-statistic to measure discriminatory performance. Results: Among 21,420 patients hospitalized with COVID-19 (mean age 61 years, 54% men), 312 (1.5%) had a cerebrovascular event. Using traditional Cox regression, we created and internally validated a risk stratification score (CANDLE) (Fig) with a C-statistic of 0.66 (95% CI, 0.60-0.72). The machine learning estimator had similar discriminatory performance, with a C-statistic of 0.69 (95% CI, 0.65-0.72). For ischemic stroke or TIA, CANDLE's C-statistic was 0.67 (95% 0.59-0.76). Conclusion: We developed an easy-to-use clinical score, with similar performance to a machine learning estimator, to help stratify stroke risk among patients hospitalized with COVID-19.

Right ventricular dilation and mortality in acute covid-19

Introduction: Myocardial injury is associated with COVID-19 mortality, but the prognostic value of adverse right ventricular (RV) remodeling on transthoracic echocardiogram (TTE) is uncertain. Therefore we studied the association between RV dilation and in-hospital mortality in acute COVID19. Methods: We included all adults hospitalized with COVID-19 between March 2020 and February 2021 who had a clinical TTE performed during hospitalization at UCSF Health (Parnassus, Mission Bay, or Mount Zion) or Zuckerberg San Francisco General. Clinical and echo data were extracted from the electronic medical record. Biomarkers (BNP & troponin) were log transformed. The primary exposure was qualitative assessment of RV dilation on TTE and the primary outcome was inhospital mortality. We conducted analysis with STATA MP 16.1 using logistic regression models with adjustment for age and sex (Model 1) and age, sex, log(BNP), log(troponin), and mechanical ventilation (Model 2) and compared models with and without RV size with the likelihood ratio test. Results: There were 225 people hospitalized with COVID-19 who had a clinical TTE performed. The mean age was 62.9 years old, 77 (34%) were female, and 48 (21%) died. The majority of patients identified as Latinx (40%), and most patients received Medicaid (58%). Of 212 TTEs adequate to assess RV size, 47 (22%) had RV dilation of whom 16 (34%) died compared to 31 (19%) with normal RV size (RR 1.81, 95%CI 1.09-3.01, p=0.03). Of 185 TTEs adequate to assess RV function, 18 (10%) had RV dysfunction of whom 6 (33%) died compared to 12 (18%) with normal RV function (RR 1.86, 95%CI 0.89-3.84, p=0.12). There were no differences in tricuspid annulus plane systolic excursion or RV systolic excursion velocity. Adjusted for age and sex, RV dilation was associated with mortality (OR 2.16, 95%CI 1.02-4.58;p=0.045), with a larger effect among those with RV dilation and dysfunction (OR 3.40, 95% CI 0.93-12.4, p=0.063). This effect was attenuated after adjusting for BNP, troponin and mechanical ventilation at the time of TTE (OR 1.61, 95%CI 0.52-4.98, p=0.41). Conclusions: RV dilation on TTE is associated with mortality in acute COVID-19, although the effect is attenuated after accounting for mechanical ventilation and biomarkers.

Design and implementation of a best practice advisory in electronic medical records for hepatocellular carcinoma surveillance

Background: Hepatocellular carcinoma (HCC) surveillance is associated with early detection and improved survival in patients with cirrhosis. However, surveillance attainment is poor in clinical practice and surveillance ascertainment can be challenging. We describe the early implementation and results of a HCC surveillance best practice advisory (BPA). Methods: Within a single center EPIC based electronic medical record (EMR) we developed an HCC Surveillance BPA with accompanying dashboard. The BPA design included qualifying diagnosis codes in the problem list (i.e. cirrhosis), qualifying exams which automatically satisfied the BPA (abdominal ultrasound (US), or contrast-enhanced abdominal CT/MRI), and definition of a screening interval (every 6 months). In addition to cirrhosis diagnosis coding, patients were required to have two Hepatology clinic visits in the preceding 2 years. The BPA included the ability to enter the date of completion of outside surveillance exams, directly order abdominal US, and deactivate the BPA for patients not appropriate for surveillance (e.g. Child C non-transplant candidate). A dashboard was developed to track clinic, provider, and overall HCC surveillance attainment and percent of time under surveillance over the preceding 12 months (i.e. number of months under surveillance/12 months) (Figure). The BPA was planned to be implemented in 2-phases, 1) a soft implementation where providers were reminded to access the BPA, and 2) where providers would receive personalized reports of patients outside surveillance window. Phase 2 implementation was delayed due to the COVID-19 pandemic. Results: The BPA underwent Phase 1 implementation in Aug 2019 at which time surveillance attainment rates were 63% (1018/1608). Surveillance attainment dropped through the COVID-19 pandemic (Feb 2020: 60%;Aug 2020: 54%). Overall surveillance rates recovered by the end of 2020 to 61% (928/1518). Among 13 hepatology providers, BPA utilization increased from 16% of eligible patients (17/104) in Dec 2019 to 38% in Dec 2020 (47/123). Provider level surveillance rates varied from 45%-75% in the last quarter of 2020 and the lowest quartile and highest quartile providers were consistently in those categories during the study period. There was a significant provider-level correlation between BPA utilization and surveillance rates (Pearson r=0.729;95% CI;0.613-0.841). At the end of 2020, 35% of patients were under surveillance <50% of the preceding 12 months, while 45% of the cohort was under surveillance >75% of the preceding 12 months. Conclusion: We have developed and shown the feasibility of a HCC surveillance BPA embedded within the EMR. There is significant provider-level variation in rate of HCC surveillance completion, indicating there are targets for improvement. Feedback to providers in Phase 2 may improve surveillance rates in patients at risk for HCC.

Telemedicine Perspectives in Radiation Oncology

Given the changes to Radiation Oncology clinic workflow inspired by the COVID-19 pandemic, this study sought to determine the attitudes and perceptions of radiation oncologists towards the integration of telemedicine in the clinical setting. An online survey was sent nationwide to radiation oncologists, accompanied by a $10 gift card incentive for completing the survey. Of 117 complete responses received, the majority of respondents reported practicing in an academic setting (92%) and in an urban area (95%). 42% of respondents were still in training, while the rest had graduated from residency 0-5 years (16%), 6-10 years (8%), 11-20 years (15%), and 21+ years (19%) ago. Of all respondents, 79% worked at institutions that had implemented a work-from-home policy. Satisfaction was reported to be 87% regarding work-from-home flexibility, 84% regarding decreased commute to work, 40% regarding interaction with patients, 46% regarding impact on workflow, and 76% regarding overall impression. Before COVID-19, 99% of all visits were completed in-person whereas after COVID-19, telephone and telemedicine video visits comprised approximately 35% of new patient consults, 12% of on-treatment visits (OTVs), and 51% of follow-up visits. The primary factors in determining whether a patient was seen via telemedicine were patient preference (46%), physician preference (32%), and department policy (22%). Overall, in-person visits were felt to be better than telemedicine encounters in obtaining information during consultation (55%), establishing a personal connection with the patient/family (89%), answering questions about radiation treatment (45%), assessing for toxicity while on-treatment (87%), and assessing for toxicity/recurrence during follow-up (70%). 70% of respondents were in favor of more telemedicine utilization even after the COVID-19 pandemic, while 22% were in favor of telemedicine use only during the pandemic, and 8% were against the use of telemedicine unless absolutely necessary. Telemedicine visits for OTV encounters were deemed somewhat appropriate or extremely appropriate by 86% of respondents for patients confirmed to be COVID-positive, 79% for patients with mild symptoms who had not been tested, 65% for asymptomatic patients living with an at-risk person, 57% for asymptomatic patients who had recently traveled to a high-risk zone within the last 14 days, 92% for physician with mild symptoms who had not been tested, and 89% for asymptomatic physician living with an at-risk person. Telemedicine has become quickly integrated into the Radiation Oncology clinical workflow allowing for convenience, flexibility, and minimization of infection transmission. These encounters are likely to play a role in conjunction with – not in place of – in-person visits, which allow physicians the ability to obtain crucial information during consultation, establish a personal connection with patients, and assess for toxicity/recurrence. [ABSTRACT FROM AUTHOR] Copyright of International Journal of Radiation Oncology, Biology, Physics is the property of Pergamon Press - An Imprint of Elsevier Science 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 abstract 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 abstract. (Copyright applies to all Abstracts.)

Resident-performed immediate sequential bilateral cataract surgery during the COVID19 pandemic

Purpose : Minimizing healthcare-related exposures for patients and providers are paramount during the coronavirus (COVID-19) pandemic. We performed a retrospective cohort study to compare visual outcomes and patient satisfaction in senior residentperformed immediate sequential bilateral cataract surgery (ISBCS) versus delayed sequential bilateral cataract surgery (DSBCS). Methods : All ISBCS and DSBCS patients who underwent senior resident-performed cataract surgery in the Comprehensive Ophthalmology division of a single academic institution from May to September 2020 were included. Outcome measures were final corrected distance visual acuity (CDVA), final manifest refraction (MRx), incidence of intraoperative and postoperative complications, total number of clinical and surgical visits, and patient satisfaction, assessed postoperatively by telephone questionnaire. Results : Fourteen (22 eyes) and 28 (56 eyes) patients underwent senior residentperformed ISBCS and DSBCS, respectively. Final CDVA was 20/25 or better in 21 (95%) ISBCS eyes and 51 (91%) DSBCS eyes (p=0.670). The deviation of final MRx from target refraction was within 0.50 D in 17 (77%) ISBCS eyes and 47 (84%) DSBCS eyes (p=0.522). There was no significant difference in intraoperative (p=1.000) or postoperative (p=1.000) complications. ISBCS patients averaged 3.5 fewer visits than DSBCS patients (5.9 vs 9.5, p<0.001). All ISBCS and 20 DSBCS patients (87%) reported they were overall “very satisfied” or “satisfied” with their experience (p=0.701), and there was no significant difference in the overall visual function 7 score, where 0 indicates the worst possible functional impairment and 100 indicates no disability (p=0.561). Finally, five of the six senior residents who performed the ISBCS cases included in this study reported that they preferred performing ISBCS over DSBCS. Conclusions : This early experience demonstrates that senior resident-performed ISBCS is as safe and effective as DSBCS, with the added benefit of averaging fewer in-person visits for patients. Residency programs should consider offering senior resident-performed ISBCS to select patients during the COVID-19 pandemic.

Resident-driven telehealth visits after cataract surgery: Minimizing exposures during COVID-19

Purpose : During the coronavirus (COVID-19) pandemic, reducing unnecessary clinic visits is critical to limit risk of exposure for patients and providers. We hypothesized that final visual outcomes and postoperative complication rates in patients with postoperative week 1 (POW1) telehealth visits would be similar to patients with in-person POW1 visits in this retrospective cohort study. Methods : All uncomplicated cataract surgeries performed by senior residents with routine postoperative day 1 (POD1) exams and POW1 telehealth visits conducted from July 1, 2020 to December 31, 2020 at a single academic institution were reviewed. Controls were drawn from uncomplicated surgeries performed by senior residents with in-office POW1 visits during the same period the year prior (7/1/19 - 12/31/19). Visual outcomes, including final corrected distance visual acuity (CDVA) and deviation of manifest refraction from the target refraction, were compared between the two groups, along with rates of significant postoperative complications. Results : Thirty-eight patients (51 eyes) with POW1 telehealth visits and 44 patients (57 eyes) with POW1 in-office visits were included in the study. There were no statistically significant differences in baseline demographics or preoperative CDVA and biometry measurements between the two groups. The average final postoperative month 1 (POM1) logMAR CDVA was 0.030 and 0.021 (p=0.284) in the telehealth and in-office groups, respectively, with 44 (86%) telehealth eyes and 51 (90%) in-office eyes within 0.50 D of the target refraction (p=0.610). Six eyes (12%) in the telehealth group and 3 eyes (5%) in the inoffice group developed complications noted at the POM1 visit (p=0.222), comprised of pseudophakic cystoid macular edema (CME) or mild persistent/recurrent postoperative iritis. In all instances, the CME and iritis resolved with topical steroids and/or NSAIDs, with final CDVA 20/30 or better. Conclusions : There was no statistically significant difference in final CDVA, refractive outcomes, or postoperative complication rates in eyes undergoing POW1 telehealth as compared to in-office visits. In uncomplicated cataract surgeries, POW1 telehealth visits can be a safe and effective alternative to in-office visits to minimize exposure risks during the COVID-19 pandemic.

Outpatient evaluation of transient ischemic attack and minor, non-disabling stroke during the COVID-19 pandemic

Introduction: Reductions in hospital visits for stroke have been seen during the COVID-19 pandemic, partly reflecting perceived risks of in-hospital care. We recently implemented an evidence-based protocol for outpatient rapid evaluation of transient and minor, non-disabling stroke symptoms for patients seeking care 24 hours after symptom onset. We present our early experience through the pandemic. Methods: We conducted a retrospective review of patients evaluated in the RESCUE-TIA (Rapid Evaluation of minor Stroke and CerebrovascUlar Events including TIA) clinic from December 2019- August 2020. The clinic sees patients with TIA symptoms or with fixed, non-disabling deficits seeking care > 24 hours after symptom onset. We introduced telemedicine in March 2020. Magnetic resonance brain and vascular imaging is available within 24 hours of visit. We summarized patient characteristics and quality data with standard descriptive statistics. Results: A total of 21 patients were seen in the RESCUE-TIA clinic, including 15 patients during the height of the pandemic in NY;67% were seen by telemedicine. The median age was 75 years (interquartile range [IQR], 61-82), and 71% were women. The median NIH Stroke Score for patients with minor stroke was 0 (IQR, 0-1), and the median ABCD score for TIA patients was 3 (IQR, 2-3). Median time from symptom onset to evaluation was 3 days (IQR, 2.5-17.5). Median time from evaluation to laboratory diagnostics was 8 hours (IQR, 2-21), and to completion of imaging was 1 day (IQR, 0-5). Outpatient telemetry commenced in a median of 5 days (IQR, 1-9), and echocardiography was completed in a median of 8 days (IQR, 0-10). One patient was referred to the emergency room for a carotid occlusion. Final diagnoses were TIA (n=12), ischemic stroke (n=5), transient global amnesia (n=2), migraine (n=1), and non-aneurysmal, distal subarachnoid hemorrhage (n=1). Secondary prevention was initiated or optimized in 94% of TIA and stroke patients. Recurrent TIA occurred in 1 patient after 67 days, and ischemic stroke occurred in 1 patient 55 days after TIA. Conclusion: Timely outpatient evaluation of patients with recent TIA and minor, non-disabling stroke is feasible and may be useful during the pandemic, especially during emergency room crowding.

Brain Imaging of Patients with COVID-19: Findings at an Academic Institution during the Height of the Outbreak in New York City.

BACKGROUND AND PURPOSE: A large spectrum of neurologic disease has been reported in patients with coronavirus disease 2019 (COVID-19) infection. Our aim was to investigate the yield of neuroimaging in patients with COVID-19 undergoing CT or MR imaging of the brain and to describe associated imaging findings. MATERIALS AND METHODS: We performed a retrospective cohort study involving 2054 patients with laboratory-confirmed COVID-19 presenting to 2 hospitals in New York City between March 4 and May 9, 2020, of whom 278 (14%) underwent either CT or MR imaging of the brain. All images initially received a formal interpretation from a neuroradiologist within the institution and were subsequently reviewed by 2 neuroradiologists in consensus, with disputes resolved by a third neuroradiologist. RESULTS: The median age of these patients was 64 years (interquartile range, 50-75 years), and 43% were women. Among imaged patients, 58 (21%) demonstrated acute or subacute neuroimaging findings, the most common including cerebral infarctions (11%), parenchymal hematomas (3.6%), and posterior reversible encephalopathy syndrome (1.1%). Among the 51 patients with MR imaging examinations, 26 (51%) demonstrated acute or subacute findings; notable findings included 6 cases of cranial nerve abnormalities (including 4 patients with olfactory bulb abnormalities) and 3 patients with a microhemorrhage pattern compatible with critical illness-associated microbleeds. CONCLUSIONS: Our experience confirms the wide range of neurologic imaging findings in patients with COVID-19 and suggests the need for further studies to optimize management for these patients.