COVID-19 Infection and Acute Pancreas Transplant Graft Thrombosis.

The coronavirus disease 2019 (COVID-19) pandemic created an unprecedented challenge for healthcare, and the world continues to struggle in recovering from its aftermath. COVID-19 has been clearly linked to hypercoagulable states and can lead to end-organ ischemia, morbidity, and mortality. Immunosuppressed solid organ transplant recipients represent a highly vulnerable population for the increased risk of complications and mortality. Early venous or arterial thrombosis with acute graft loss after whole pancreas transplantation is well-described, but late thrombosis is rare. We herein report a case of acute, late pancreas graft thrombosis at 13 years post pancreas-after-kidney (PAK) transplantation coinciding with an acute COVID-19 infection in a previously double-vaccinated recipient.

Resistance Analysis in the COMET-TAIL Study: Participants with Mild-to-Moderate COVID-19 Treated with Intramuscular or Intravenous Sotrovimab

Background. Sotrovimab (VIR-7831) is an engineered human monoclonal antibody targeting a conserved region of the SARS-CoV-2 spike protein;it has been shown to have a favorable safety profile and be effective for early treatment of highrisk COVID-19 patients. The COMET-TAIL phase 3 study evaluated sotrovimab administered intravenously (IV) or intramuscularly (IM) for the treatment of participants with mild to moderate COVID-19 who are at high risk of disease progression. Methods. Between June to August 2021, 973 participants were randomized and received sotrovimab by 500 mg IV infusion or by 500 or 250 mg IM injection. Deep sequencing of the spike gene was performed on nasopharyngeal samples. Baseline (BL;Day 1 or Day 3), post-BL (Day 5 or later), treatment-emergent (TE) substitutions at sotrovimab epitope positions, and presence of variants of concern/interest (VOC/ VOI), were evaluated at a >=5% allelic frequency. Phenotypic analyses were conducted using a pseudotyped virus assay. Results. Sequences were available from 764 participants (500 mg IV: 314/393;500 mg IM: 302/387;250 mg IM: 148/193). Consistent with VOC circulation during enrollment, the Delta variant was detected in 88.2% (674/764) of participants. Alpha and Mu variants were also seen at >2% prevalence. Of the 764 participants, 26 met the primary endpoint for clinical progression to hospitalization >24 hours or death due to any cause through day 29 and were infected with Delta (500 mg IV: 4;500 mg IM: 9;250 mg IM: 11), Alpha (500 mg IM: 1), or Mu (500 mg IV: 1) variants. Substitutions at sotrovimab epitope positions were similar across arms and were detected in 82/764 (10.7%) participants at any visit (500 mg IV: 42/314;500 mg IM: 27/302;250 mg IM: 13/148). Of these, 2 participants experienced clinical progression: 1 participant infected with the Mu variant (500 mg IV) carried the characteristic R346K substitution at BL;1 participant infected with the Delta variant (500 mg IM) had P337L and E340K substitutions detected at Day 3 and P337L was enriched at Day 8. The predominant TE epitope substitutions included P337L and E340A/K/V, which confer reduced susceptibility to sotrovimab in vitro. Conclusion. Overall, TE epitope substitutions were not associated with clinical progression.

DESIGNING AND IMPLEMENTING A COMPREHENSIVE KNOWLEDGE MANAGEMENT SYSTEM IN AN ACADEMIC FEDERALLY QUALIFIED HEALTH CENTER IN THE BRONX, NY

STATEMENT OF PROBLEM/QUESTION: Effective knowledge management systems (KMS) - interactive technologies to reliably catalogue and communicate a group's most updated collective knowledge - have been underutilized and uncoordinated in healthcare, particularly in health systems that could benefit most due to limited resources and high staff turnover (e.g. medical residency clinics in underserved areas). This project assessed if a cloud- based comprehensive knowledge management system could be developed for, implemented in, and uniformly adopted by a Federally Qualified Health Center in the Bronx that serves as the ambulatory site for Montefiore's Primary Care Social Internal Medicine residents and faculty. DESCRIPTION OF PROGRAM/INTERVENTION: This project surveyed physicians, nurses, and other support staff to identify opportunities to catalogue all clinic work-flow knowledge. One medical resident worked closely with physician, nurse, and administrative leadership to identify clinic workflow content that previously was not independently accessible in any standardized approach (i.e. other than asking colleagues verbally or through individual emails). After evaluation of numerous KMS products, we chose to use the no-cost open-source Google Sites platform to catalogue all possible information into a KMS in the form of a wiki. Nurse leadership was enlisted to implement change management strategies to incorporate use of this new wiki into physician and nurse workflows. MEASURES OF SUCCESS: Google Forms was integrated into the wiki to solicit real-time contributions for expeditious updating and to solicit user experience feedback. Google Analytics was used to track adoption and usage metrics. FINDINGS TO DATE: A fully functioning open-source private clinic KMS in the form of an adaptive wiki has been fully implemented at Montefiore's Comprehensive Health Care Center for six months. The wiki relies on realtime staff contributions to update content as it changes, including daily announcements, daily room assignments, workflow updates, COVID protocol updates, and resource sharing. Google Analytics tracking showed 14,000 page views in six months. 93% of staff surveyed have incorporated the wiki into their standard workflows. 70% have adopted the virtual workflow communication strategy rolled out to improve efficiency. 87% reported that it made their job easier. 61% reported that it directly improved job satisfaction. KEY LESSONS FOR DISSEMINATION: This project demonstrates the value and possibility of introducing high- quality, highly utilized, scalable health technology with zero-product-cost to improve the quality of care provided in a Federally Qualified Health Center that was prior unaware of these technology applications. The authors hope this pilot serves as inspiration for other clinics in underserved areas to invest in health technology and healthcare management innovations as transformative tools to advance healthcare equity.

INTRAMUSCULAR SOTROVIMAB IS NONINFERIOR to INTRAVENOUS SOTROVIMAB for COVID-19

Background: Sotrovimab is a pan-sarbecovirus neutralizing monoclonal antibody shown to be safe and effective for the treatment of early COVID-19 in high-risk patients and retains activity against variants of concern, including delta and omicron. To facilitate wider access to sotrovimab, it was formulated to allow for either intramuscular (IM) or intravenous (IV) administration. Methods: COMET-TAIL (NCT04913675) is a Phase III, randomized, multicenter, open-label, noninferiority (NI) study of IM vs IV sotrovimab for the treatment of mild/moderate COVID-19 in participants ≥12 years of age at high risk of disease progression. Participants were randomized to receive sotrovimab by single 500 mg IV infusion or IM injection (500 mg or 250 mg). The primary objective was to evaluate the efficacy of 500 mg IM vs 500 mg IV sotrovimab in preventing hospitalization for >24 hours for acute management of illness due to any cause or death. The 250 mg IM arm discontinued early due to a greater number of hospitalizations seen in that arm. A 3.5% NI margin on the risk difference scale was prespecified. Results: COMET-TAIL enrollment occurred from Jun-Aug 2021, coinciding with a surge in the SARS-CoV-2 delta variant in southern USA. The majority (∼85%) of participants were Hispanic or Latino and ∼25% were ≥65 years of age. In the 500 mg IM sotrovimab arm, 10/376 (2.7%) participants compared with 5/378 (1.3%) in the sotrovimab 500 mg IV arm met progression criteria for the primary endpoint (adjusted risk difference: 1.07% [95% CI:-1.25%, 3.39%]), meeting the NI margin of 3.5%. The overall rate of adverse events and injection/infusion-related reactions was low and similar between the 500 mg treatment arms. Most injection-site reactions were mild (grade 1), occurred shortly after dosing, and were limited in duration. Disease-related events (DREs) were balanced between the 500 mg IV and 500 mg IM arms. The most frequent DREs were COVID-19 pneumonia and pneumonia. There was a low percentage of participants (∼1%) with serious adverse events across all treatment arms, and none were considered related to treatment. Two participants (1 with BMI 69 mg/kg2 and an 82-year-old man) in the 500 mg IM arm died due to progression of COVID-19;no deaths occurred in the 500 mg IV arm. Conclusion: In the COMET-TAIL trial, sotrovimab given by 500 mg IM injection was found to be noninferior to IV infusion and was well tolerated. The option of IM administration will expand the potential for outpatient treatment with sotrovimab.

EFFECT of SEROSTATUS on the EFFICACY of SOTROVIMAB in PREVENTING COVID-19 PROGRESSION

Background: Sotrovimab is a pan-sarbecovirus monoclonal antibody clinically evaluated for prevention of progression of COVID-19 in high-risk patients early in the course of infection. We investigated the rate of prevention of hospitalization or death by baseline anti-SARS-CoV-2 serostatus. Methods: COMET-ICE (NCT04545060) was a multicenter, double-blind, Phase III trial in nonhospitalized adults with symptomatic COVID-19 and ≥1 risk factor for disease progression. Participants were randomized 1:1 to an IV infusion of sotrovimab 500 mg or placebo. The primary efficacy endpoint was all-cause hospitalization >24 hours or death due to any cause within 29 days. Anti-nucleocapsid SARS-CoV-2 antibody was measured by the Abbott SARS-CoV-2 IgG assay run on the Architect i2000SR immunoassay analyzer. Results: In the final dataset (N=1057), the adjusted relative risk (RR) reduction in all-cause hospitalization or death due to any cause in the sotrovimab group compared to the placebo group was 79% (p<0.001) at Day 29. 70% and 19% of participants were seronegative and seropositive for anti-nucleocapsid protein at baseline, respectively. 11% of participants had unknown antibody status and were excluded. In the seronegative subgroup, 4/365 (1%) participants in the sotrovimab group met the primary endpoint compared to 26/375 (7%) in the placebo group (84% reduction in risk [RR: 0.16;95% CI: 0.06, 0.45]). Of the 4 seronegative participants who received sotrovimab and met the primary endpoint, 1 participant was hospitalized for small intestinal obstruction that was likely unrelated to COVID-19. Two of the 26 seronegative participants in the placebo arm who met the primary endpoint died compared to no deaths in the sotrovimab group. In the seropositive subgroup, conclusions are limited by small numbers. Numerically fewer participants in the sotrovimab group (2/105, 2%) were hospitalized compared to the placebo group (4/97, 4%). Importantly, both hospitalized seropositive participants in the sotrovimab group had an alternative reason for their hospitalization that was likely unrelated to COVID-19 (diabetic foot ulcer, non-small cell lung cancer). Progression rates in the sotrovimab arm were low and similar regardless of serostatus (1% seronegative, 2% seropositive). Safety profile by serostatus was consistent with that reported in the overall population. Conclusion: Sotrovimab appeared to consistently reduce the likelihood of a COVID-19-related hospitalization or death regardless of baseline serostatus.

Racial and Ethnic Disparities in COVID-19 Incidence among Persons with HIV in a Multisite-Cohort

Background. Little is known about how race and ethnicity, imperfect (albeit accessible) proxies for structural racism, impact COVID-19 incidence among people with HIV (PWH). We report the cumulative incidence and incidence rate ratios (IRR) for COVID-19 in a long-term multi-site cohort of PWH across the US Figure 1. Cumulative incidence of COVID-19 in the CNICS cohort Methods. We examined COVID-19 cumulative incidence and IRR among PWH in care between 3/1/2020 and 12/31/2020 at seven sites in the CFAR Network of Integrated Clinical Systems (CNICS) cohort. We define COVID-19 incident case as having a laboratory-confirmed (RT-PCR/Ag) SARS-CoV-2 positive result or diagnosis verified by chart review. Reinfections were excluded. Results are presented as monthly and quarterly cumulative incidence and IRR with 95% CI stratified by CD4 count, self-reported race/ethnicity, and site. Follow-up was censored on the earliest of diagnosis of COVID-19 disease, loss to follow up, or 12/31/2020 Results. Among 15,780 PWH in care in the CNICS cohort during the study period, 62% were non-white, with a median (IQR) age of 52 (IQR 40-59), 95% were on antiretroviral therapy, 17% had a CD4 count less than 350, and 6% less than 200. Overall, 651 PWH tested positive for COVID-19 for a cumulative incidence of 4.13%. COVID-19 cumulative incidence increased from 0.77% at the end of the first quarter to 4.12% by the end of December 2020. At the peak of the pandemic in December 2020, the cumulative incidence in Black PWH was 1.68 fold higher than in white PWH (p=.033) and 2.35 fold higher in Hispanics than in whites (P< .0001), figure 1. Similarly, the IRR for COVID-19 was 1.71 (95% CI 1.42-2.07) for Black and 2.40 (95% CI 1.91-3.01) for Hispanic PWH relative to white. Although there was variation across sites, reflecting geographic differences in pandemic waves and access to COVID-19 testing, overall individual trends remained the same. COVID-19 cumulative incidence was similar across CD4 cell count strata Conclusion. Our results suggest effects of structural racial disparities on COVID-19 incidence in this diverse population of PWH across the US, with higher and disproportionate rates of COVID-19 in Black and Hispanic PWH. Incidence estimates are conservative because testing was not uniform, and no systematic testing was conducted.

Early COVID-19 Treatment with SARS-CoV-2 Neutralizing Antibody Sotrovimab

Background. COVID-19 disproportionately results in hospitalization and death in older patients and those with underlying comorbidities. Sotrovimab is a pan-sarbecovirus monoclonal antibody that binds a highly conserved epitope of the SARSCoV-2 receptor binding domain and has an Fc modification that increases half-life. Sotrovimab retains activity against UK, S. Africa, Brazil, India, New York and California variants in vitro. Objectives. To evaluate the efficacy and safety of treatment with sotrovimab in high-risk, non-hospitalized patients with mild/moderate COVID-19, as part of the COMET-ICE clinical trial. Methods. Multicenter, double-blind, phase 3 trial in non-hospitalized patients with symptomatic COVID-19 and ≥1 risk factor for disease progression were randomized 1:1 to an IV infusion of sotrovimab 500 mg or placebo. The primary efficacy endpoint was the proportion of patients with COVID-19 progression, defined as hospitalization > 24 hours or death, due to any cause, ≤29 days of randomization. Results. The study met the pre-defined primary efficacy endpoint in a preplanned interim analysis: the risk of COVID-19 progression was significantly reduced by 85% (97.24% CI, 44% to 96%;P = 0.002) in 583 patients. In the final intention-to-treat analysis (N = 1057), the adjusted relative risk reduction was 79% (95% CI, 50% to 91%;p< 0.001) through Day 29 in recipients of sotrovimab (n=528) vs. placebo (n=529). Treatment with sotrovimab (ITT) resulted in a numerical reduction in the need for ER visits for illness management, hospitalization for acute illness management (any duration) or death (any cause) compared to placebo. No participants on sotrovimab required ICU admission, compared to 9 participants on placebo, of whom 4 participants required mechanical ventilation. No participants who received sotrovimab died, compared to 4 participants on placebo. The incidence of adverse events was similar between treatment arms and SAEs were numerically more common in the placebo arm. Conclusion. Treatment with sotrovimab 500 mg IV resulted in a clinically and statistically significant reduction in progression of COVID-19 to hospitalization or death in patients with mild/moderate disease and was well-tolerated.

Influenza adverse events in patients with rheumatoid arthritis in the tofacitinib clinical programme

Background: Patients (pts) with rheumatoid arthritis (RA) have an increased susceptibility to seasonal influenza and its complications.1 In light of the COVID-19 pandemic, there is a need to better understand acute respiratory viral RNA infections, such as influenza, in pts with RA. Objectives: To present a comprehensive summary of data on influenza adverse events (AEs) occurring in the tofacitinib RA clinical programme. Methods: Influenza AEs were evaluated in pts with RA from 21 Phase (P)1-3b/4 trials and two open-label, long-term extension (LTE) studies from 2005-2019. These were analysed as two cohorts: P2-3b/4 cohort (pts who received tofacitinib 5 or 10 mg twice daily [BID] as monotherapy or with conventional synthetic [cs]DMARDs, adalimumab, methotrexate or placebo, in P2-3b/4 controlled studies) and Overall cohort (pts who received ≥1 tofacitinib dose, as monotherapy or with csDMARDs, in P1-3b/4 and LTE studies;data were summarised by average tofacitinib dose [average tofacitinib 5 or 10 mg BID based on average total daily dose of <15 or ≥15 mg, respectively]). Incidence rates (IRs;unique pts with events/100 pt-years of exposure;censored at day of first event or up to last dose +28 days) were evaluated for influenza AEs, influenza complication AEs, influenza-like illness (all composites of several MedDRA preferred/verbatim terms) and overall influenza AEs (composite of all preferred/verbatim terms included under influenza AEs, influenza complication AEs and influenza-like illness). In the Overall cohort, the incidence of serious non-influenza AEs within 28 days of the start of an overall influenza AE and time taken to resolution of overall influenza AEs by action taken were summarised descriptively. Results: In total, 7964 pts were included;517 (6.5%) pts reported overall influenza AEs, three of which occurred outside the risk period. In the P2-3b/4 cohort (N=6690), IRs for influenza AEs, influenza-like illness and overall influenza AEs generally appeared similar across treatment arms (Figure 1a). In the Overall cohort, IRs for influenza AEs and influenza-like illness were similar between tofacitinib doses (Figure 1b), and IRs for overall influenza AEs were similar between tofacitinib doses and pt age groups (Figure 1c). No influenza complication AEs (eg pneumonia/encephalitis influenzal) were reported in either cohort. Among pts with overall influenza AEs, nine (1.7%) had serious overall influenza AEs (average tofacitinib 5 mg BID, n=6;average tofacitinib 10 mg BID, n=3). Of these pts, eight (1.5%) were hospitalised (average tofacitinib 5 mg BID, n=6;average tofacitinib 10 mg BID, n=2) and two (0.4%) died (average tofacitinib 5 mg BID, n=1;average tofacitinib 10 mg BID, n=1). Both deaths occurred in pts with H1N1 Influenza A. Twelve (2.3%) pts had a serious non-influenza AE within 28 days of the start of the overall influenza AE (average tofacitinib 5 mg BID, n=6;average tofacitinib 10 mg BID, n=6). The most common serious non-influenza AEs (one event each in average tofacitinib 5 and 10 mg BID groups) were acute respiratory distress syndrome and pneumonia. In most pts with overall influenza AEs, no change to tofacitinib treatment was made (70.2%, n=363) or treatment was stopped temporarily (28.2%, n=146) for a mean duration of 11.0 days. The mean number of days to resolution of overall influenza AEs was numerically similar, ranging from 10.4-11.8 days across tofacitinib doses, irrespective of these actions. Conclusion: This post hoc analysis of influenza AEs across the tofacitinib RA clinical programme, over 14-15 influenza seasons, showed generally similar rates between treatment groups, and between tofacitinib doses and pt age groups. Limitations include varying exposure across treatment arms in the P2-3b/4 cohort. Most influenza AEs were non-serious (98.3%), and were not associated with changes to tofacitinib treatment.

COVID-19 cases & hospitalizations in a US multisite cohort of people with HIV

Background: COVID-19 outcomes among people with HIV (PWH) remain inconclusive. We characterized all cases of COVID-19 identified in a long-term multi-site cohort of PWH, as well as factors associated with increasing severity of COVID-19 during the early months of the COVID-19 pandemic. Methods: We examined all PWH with SARS-CoV-2 infection and COVID-19 disease identified from laboratory testing data (RT-PCR, antigen test results) and ICD-10 codes March-July 2020 from seven sites in the CFAR Network of Integrated Clinical Systems (CNICS) cohort. Cases were verified by medical record review. We evaluated predictors of increased disease severity, indicated by hospitalization. Relative risks were estimated using Poisson regression, adjusted for clinical and demographic characteristics using disease risk scores. Results: Among 13,862 PWH in care (20% female, median age 52 (IQR 40-59), 58% Black or Hispanic race/ethnicity), 198 COVID-19 cases were detected during the study period. A higher proportion of PWH with COVID-19 were female (27%), Black or Hispanic (76%), and had BMI ≥30 (45%). No significant differences in CD4+ count (current or lowest) were seen between PWH with and without COVID-19. We found evidence suggesting more unstable housing among COVID-19 cases compared to non-cases (14% vs. 9%). Among PWH with COVID-19, 38 (19%) were hospitalized, 10 (5%) required intensive care, 8 (4%) received invasive mechanical ventilation, and 4 (2%) died. Hospitalization among PWH with COVID-19 was associated with: CD4+ count ≤350 (aRR 1.77;95% CI 1.05, 2.98);age ≥60 (aRR 2.0;95%CI 1.13, 3.54);pre-existing kidney disease with eGFR <60 (aRR 1.76;95% CI 0.99, 3.13);and BMI ≥30 (aRR 1.96;95% CI 1.02, 3.78) (Table). Conclusion: The population frequency of COVID-19 detected in PWH was 1.4%, likely an underestimate of the true frequency of SARS-CoV-2 infection and COVID-19 disease due to evolving testing availability and access over time. A higher proportion of PWH with COVID-19 were Black or Hispanic, in excess of the overrepresentation of people of color with HIV compared to the general population. PWH with decreased eGFR, low CD4+ count, and obesity had greater risk of more severe COVID-19 disease. Our results highlight disparities in risk of COVID-19 acquisition among PWH in the US and indicate additional vigilance in screening and monitoring of COVID-19 among PWH with these characteristics. The expected accrual of additional COVID-19 cases will allow more precise evaluation of the impact of comorbidities. (Figure Presented).

The role of a federally qualified health center during a pandemic

The COVID-19 pandemic has caused a signicant loss of life and dramatically upended the livelihood of communities across the world. However, as with other health crises, the pandemic has hit low-income communities particularly hard. Epidemiological data have shown that individuals in poorer communities are not only at a higher risk for severe COVID-19 illness and fatality, but are also at a heightened risk of suffering long-term economic and social consequences as indirect effects of the pandemic, highlighting the need for community-wide interventions. As community-based institutions, whose primary role is to provide primary care and divert patients from emergency care, Federally Qualied Health Centers (FQHCs) have a particularly important role to play. The purpose of this presentation is to describe the efforts of a FQHC located in the South Bronx, to prevent the disruption of health care services during the COVID-19 pandemic, and to facilitate critical continuity of care for medically and socially vulnerable patients in an eeffort to mitigate adverse health outcomes. Our FQHC mobilized a COVID-19 response to address two primary goals: 1) to prevent disruption inprimary care during a pandemic and shelter-in-place mandate through targeted outreach and telehealthservices to medically and socially vulnerable populations, and 2) to identify and address the increased socialneeds of families adversely impacted by the pandemic through referrals to in-house and communityresources. Our data team compiled lists of patients for outreach based on the aforementioned goals anddistributed them to clinical teams. Priorities for outreach included patients who rely on continuous clinicalcare and families at increased economic and social risk, such as newly-arrived immigrant families and familiesexperiencing homelessness. Telehealth and in-person visits were systematically prioritized to include infants 0to 2 years for well-child visits and vaccinations, children with persistent asthma, and adolescents withcontraceptive needs (e.g. depo provera). Additional outreach was done to patients at heightened risk ofadverse outcomes from a disruption of clinical care, specically pregnant women, patients 70 years of age andolder, and patients with comorbid medical conditions. Social needs were addressed through the expansion ofan existing emergency food pantry to offer household cleaning supplies, personal hygiene products, facemasks, and health education material, and through referrals to community resources. Contactless delivery ofthese supplies was provided for homebound patients. As this work is ongoing, future analysis will describe theextent of need during the COVID-19 pandemic and the impact of our efforts through analysis of clinicaloutcomes including timely immunizations, asthma outcomes, and adherence to reproductive healthtreatments. Lessons learned in our systematic response to this pandemic may be valuable for other healthcenters in planning for how to provide care for children and families during this, and future crises.

Failed hybrids: The death and life of Bluetooth proximity marketing

Bluetooth Low Energy (BLE) beacons were once heralded as the “holy grail of marketing,” a “cookie” for the physical world. An entire industry—proximity marketing—evolved to capture value from beacon-enabled micro-location networks, with venture capitalists, startups, mobile operating systems suppliers, and major platforms all making substantial investments of data, labor, and resources in the technology. Despite these investments, beacons fell out of favor abruptly, with observers dismissing the technology as an overly cumbersome solution in search of a problem, a “low-value fad.” We offer a microhistorical account of beacons’ small yet untenable role in the ecologies of location-based commercial surveillance—from the standards wars between Apple and Google to the efforts of startups and tech giants to capitalize on the market’s enthusiasm for beacons, and finally, to the industry’s quiet collapse. Our analysis builds upon work on the relationship between platform and infrastructure. We argue that proximity marketers failed to construct a viable platform-infrastructure hybrid capable of monetizing beacon proximity data and identify three axes along which beacons frustrated marketers’ ambitions for the technology: scalability, exclusivity, and visibility. We conclude by revisiting the platform-infrastructure relationship to discuss beacons’ legacy in two surveillance systems: student tracking on college campuses and contact-tracing initiatives during the COVID-19 pandemic. © The Author(s) 2020.