Reasons for Reduced Willingness to Participate in Clinical Trials During the COVID-19 Pandemic: The Translational Breast Cancer Research Consortium (TBCRC) 057 Survey

Background: Historically, less than 10% of adult patients with cancer enroll in clinical trials, however, enrollment dropped further at the onset of the COVID-19 pandemic. Barriers to trial participation during the pandemic have not been reported. As part of the TBCRC 057 survey on the impact of the pandemic on willingness to participate in breast cancer trials, we assessed reasons for reluctance to participate in trials during the pandemic. Method(s): US residents who self-reported a breast cancer diagnosis were eligible to complete the online survey 8/6/21-9/30/21. Respondents indicated whether they were current trial participants and, if not, their willingness to consider participating in a trial during the pandemic using a 5-point scale (0-not at all willing to 4-definitely willing). Respondents who were not current trial participants and who were not "definitely willing" to consider participation during the pandemic were characterized as "reluctant" and asked to select reasons for their reluctance from a checklist. Pandemic-related anxiety was assessed on an 11-point scale (0-no anxiety to 10-worst anxiety possible). Respondents indicated how the option to conduct trial activities online would affect their decision to participate in a trial (much less likely, somewhat less likely, would not affect my decision, somewhat more likely, or much more likely). In exploratory analyses, we evaluated whether pandemic-related anxiety and favorable reactions towards opportunities to conduct trial activities online were associated with reluctance to consider trial participation during the pandemic due to fear of SARS-CoV-2 exposure. Means were compared with two sample t-tests and proportions with Fisher's exact tests. Result(s): Of 385 survey respondents, 185 (48%) were characterized as reluctant to consider trial participation during the pandemic. Among these 185, median age was 55 (range 25-80), 85.7% were non-Hispanic White, 48.1% had metastatic disease and 44.2% received care at academic centers. Reasons for reluctance to consider trial participation during the pandemic cited by >=15% of the 185 reluctant respondents are shown in the Table. Respondents who selected fear of exposure to SARS-CoV-2 as a reason for their reluctance to consider participating in a trial during the pandemic had higher mean pandemic-related anxiety (7.0 vs 5.2, p< 0.001). These respondents were more likely to indicate telemedicine doctor visits (p=0.01), virtual consents (p=0.001) and online study questionnaires (p=0.001) would make them somewhat or much more likely to participate in trials than respondents who did not select fear of exposure to SARS-CoV-2 as a reason for their reluctance. Conclusion(s): Reasons for reluctance of patients with breast cancer to consider participation in clinical trials during the pandemic are multifactorial. Although concerns about safety and efficacy remain prominent, fear of exposure to SARS-CoV-2 drives unwillingness to participate in >25% of reluctant patients. Trial accrual may benefit from incorporation of electronic activities when possible.

The Use of New Technologies Applied to the Project-Based Learning Method in an International Context: VII Virtual Intensive Programme on the Future of Banking and Finance

The use of new technologies applied to teaching has led to a qualitative leap in education due to the pandemic caused by COVID-19. This chapter describes the experience of converting an intensive program that had been celebrated in person since 2014, into an online event. Thus, through a project-based learning process, students of different nationalities were able to expand their knowledge related to ethics and finance, as well as other skillsets, such as autonomous and collaborative work, working in a multicultural environment, or the development of technological and language skills. All this was possible thanks to recent developments in software and applications that allow students and teachers to collaborate simultaneously while being separated by hundreds of kilometers in different European cities. © 2022, The Author(s), under exclusive license to Springer Nature Singapore Pte Ltd.

The effect of modifications to clinical trial activities implemented during the COVID-19 pandemic on willingness to participate in clinical trials: The TBCRC 057 survey

Background: In order to maintain safety, clinical trial activities have been modified during the COVID- 19 pandemic. As part of the TBCRC 057 survey, we assessed how pandemic-related modifications to trial activities affect breast cancer patients' willingness to participate in clinical trials. Method(s): US residents with breast cancer were eligible to complete the online survey 8/6/21 - 9/30/21. Respondents rated whether each of 11 modifications to clinical trial activities would affect their decision to participate in a trial during or after the pandemic. Items evaluated modifications that involved changing the location of trial activities to closer to home, switching trial activities to telemedicine and making the trial schedule more flexible and convenient. Response options were much less likely to participate, somewhat less likely to participate, would not affect my decision whether or not to participate, somewhat more likely to participate and much more likely to participate. Current trial participants were asked to consider how modifications would affect their decision to participate in another trial. Results are reported descriptively. Result(s): Among 385 respondents, median age was 52 (range 25-85), 88.6% were non-Hispanic White, 52.5% had metastatic disease, 93% were receiving active treatment, 48.6% received care at an academic center and 9.6% were current trial participants. Changing location of trial activities was viewed favorably, with 70.2%, 64.6% and 54.1% of respondents indicating they would be much or somewhat more likely to participate if they could complete trial blood tests, x-ray tests or doctor visits closer to home, respectively. Similarly, the option to complete trial activities electronically was viewed favorably, with 59.6%, 58.6% and 60.9% of respondents indicating they would be much or somewhat more likely to participate if they could complete trial doctor visits, consent and questionnaires via telemedicine, respectively. With regard to modifications to make the trial schedule more flexible and convenient, respondent feedback was also favorable. 71.4%, 67.7% and 82.4% of respondents indicated that requiring study site visits no more than once per 3 weeks, widening windows for trial activities and offering home delivery of oral study medications, respectively, would make them much or somewhat more likely to participate. Finally, 30.4% and 51.7% indicated that the flexibility to opt-out of research-only blood tests and biopsies, respectively, would make them much or somewhat more likely to participate. Conclusion(s): Patients view modifications to trial activities implemented during the pandemic favorably. Trials should be flexible and the option to conduct study activities close to home or electronically when possible should be maintained during the pandemic and beyond.

TBCRC 057: An online survey about anxiety and willingness to participate in breast cancer clinical trials during the COVID-19 pandemic

Background: Enrollment in clinical trials has declined during the COVID-19 pandemic. Simultaneously, breast cancer patients have reported heightened anxiety. We assessed whether breast cancer patients' anxiety about the pandemic affects their willingness to participate in trials. Methods: English or Spanish- speaking US residents with breast cancer were eligible to complete the online REDCap survey 8/6/ 21 - 9/30/21. Respondents rated their anxiety about the pandemic on an 11-point scale from 0 (no anxiety) to 10 (worst anxiety possible). Anxiety scores were categorized as no/mild (0-3), moderate (4- 6) or severe (7-10). Knowledge about trials was assessed with 11 true/false items and attitudes toward trials with the Attitudes Toward Cancer Trials Scales - Cancer Treatment Subscale (ATCTS-CTS). Respondents rated their willingness to participate in a breast cancer clinical trial before and during the pandemic on 5-point scales from 0 (not at all willing) to 4 (definitely willing). Trial participants were considered “definitely willing.” Change in willingness to participate in trials during the pandemic compared to prior was defined as a binary outcome, “less willing” vs “no less willing.” Means were compared via t-test and mean difference was tested via paired t-test. Multivariable logistic regression was used to model the association of anxiety and other factors with being less willing to participate in trials during compared to prior to the pandemic. Results: Among 385 respondents, median age was 52 (range 25-85), 271 (70%) were non-Hispanic White and 202 (53%) had metastatic disease. 154 (40%) received care at academic centers and 37 (10%) were current trial participants. Most rated their anxiety as moderate (43%) or severe (38%). Mean willingness to participate in a trial was lower during compared to prior to the pandemic (2.97 vs 3.10;p < 0.0001). Fifty (13%) respondents were less willing to participate in a trial during the pandemic compared to prior. After controlling for covariates, those with severe anxiety had 5.07 times odds of being less willing to participate during the pandemic compared to prior than those with no/mild anxiety (p = 0.01). For every 1-point increase in ATCTS-CTS score (indicating better attitude toward trials) there was a 3% decrease in the odds of being less willing to participate during the pandemic (p = 0.006). For every 1-point increase in the clinical trials knowledge score (indicating more knowledge) there was a 15% decrease in the odds of being less willing to participate during the pandemic (p = 0.02). Conclusions: Pandemic-related anxiety is common in breast cancer patients and is associated with being less willing to participate in trials during the pandemic compared to prior. Education about trials, including safety modifications implemented during the pandemic, may mitigate anxiety and improve willingness to participate.

Emergency Distance Learning at the University: Features of Applied Technologies

Purpose: The purpose of this work is to study the technologies used and distance learning opportunities of university students in pandemic conditions. Design/methodology/approach: The conceptual framework of the research was the model of technology adoption, the theory of social learning and the theory of diffusion of innovation. It was shown that the satisfaction of its participants is an important factor in the adoption of information and communication technologies in the educational process. In order to assess the experience of implementing emergency distance learning at the university, a situational analysis method was used. Findings: The work discloses the content of distance learning. Its connection with e-learning and development of information and communication technologies environment is shown. Comparative characteristics of distance learning and emergency distance learning were carried out. The case of the Russian university on introductions of the emergency distance learning is given during COVID-19 pandemic. Features of emergency implementation of Internet platforms in educational process are shown. Originality/value: The presented research of the features of the introduction of emergency distance learning in pandemic conditions allows assessing the prospects of using distance learning technologies at universities and the loyalty to them of the main participants in the educational process. © 2022, The Author(s), under exclusive license to Springer Nature Switzerland AG.

Transforming the Intensive Programme on the Future of Banking and Finance into an online event

The outbreak of the pandemic caused by the SARS-COVID 19 virus has forced us to rethink our lives. Immersed in this new context, and with the aim of continuing to offer our students a comprehensive training that includes not only knowledge but also skills that will enable them to join a labour market that will also have to adapt to this new situation in the short term. With this objective in mind, the decision was taken to transform the Intensive Programme on the Future of Banking and Finance into an online event, in which the participating students would continue to work collaboratively in a multicultural environment. Copyright © 2021 for this paper by its authors. Use permitted under Creative Commons License Attribution 4.0 International (CC BY 4.0).

Comparison of mechanical homogenization versus enzymatic digestion sample preparation methodologies for SARS-CoV-2 detection in saliva for surveillance of variants of concern on the University of Tennessee campus in early 2021. (preprint)

The SARS-CoV-2 pandemic has profoundly impacted communities across the globe, requiring accurate and accessible diagnostic technologies in support of public health mitigation efforts. As testing has evolved throughout the course of the pandemic, varying sample preparation methodologies have been employed. Herein we perform a comparison of three commercial sample preparation methods: two mechanical homogenization workflows and one enzymatic digestion approach for the detection of SARS-CoV-2 from biomarker genes in 20 human saliva pools. SARS-CoV-2 variants of concern were also identified on the University of Tennessee, Knoxville campus during the spring semester of 2021 utilizing the commercial PerkinElmer PKamp VariantDetect SARS-CoV-2 RT-PCR Assay kit. Two hundred and ten (210) human saliva pools were selected and analyzed for the presence of SARS-CoV-2 variants of concern providing insight into the utility of these various commercial workflows for integration into current public health SARS-CoV-2 surveillance measures.

Securely sharing DSMB reports to speed decision making from multiple, concurrent, independent studies of similar treatments in COVID-19.

Introduction: As clinical trials were rapidly initiated in response to the COVID-19 pandemic, Data and Safety Monitoring Boards (DSMBs) faced unique challenges overseeing trials of therapies never tested in a disease not yet characterized. Traditionally, individual DSMBs do not interact or have the benefit of seeing data from other accruing trials for an aggregated analysis to meaningfully interpret safety signals of similar therapeutics. In response, we developed a compliant DSMB Coordination (DSMBc) framework to allow the DSMB from one study investigating the use of SARS-CoV-2 convalescent plasma to treat COVID-19 to review data from similar ongoing studies for the purpose of safety monitoring. Methods: The DSMBc process included engagement of DSMB chairs and board members, execution of contractual agreements, secure data acquisition, generation of harmonized reports utilizing statistical graphics, and secure report sharing with DSMB members. Detailed process maps, a secure portal for managing DSMB reports, and templates for data sharing and confidentiality agreements were developed. Results: Four trials participated. Data from one trial were successfully harmonized with that of an ongoing trial. Harmonized reports allowing for visualization and drill down into the data were presented to the ongoing trial's DSMB. While DSMB deliberations are confidential, the Chair confirmed successful review of the harmonized report. Conclusion: It is feasible to coordinate DSMB reviews of multiple independent studies of a similar therapeutic in similar patient cohorts. The materials presented mitigate challenges to DSMBc and will help expand these initiatives so DSMBs may make more informed decisions with all available information.

Assessment of Awake Prone Positioning in Hospitalized Adults With COVID-19: A Nonrandomized Controlled Trial.

Importance: Awake prone positioning may improve hypoxemia among patients with COVID-19, but whether it is associated with improved clinical outcomes remains unknown. Objective: To determine whether the recommendation of awake prone positioning is associated with improved outcomes among patients with COVID-19-related hypoxemia who have not received mechanical ventilation. Design, Setting, and Participants: This pragmatic nonrandomized controlled trial was conducted at 2 academic medical centers (Vanderbilt University Medical Center and NorthShore University HealthSystem) during the COVID-19 pandemic. A total of 501 adult patients with COVID-19-associated hypoxemia who had not received mechanical ventilation were enrolled from May 13 to December 11, 2020. Interventions: Patients were assigned 1:1 to receive either the practitioner-recommended awake prone positioning intervention (intervention group) or usual care (usual care group). Main Outcomes and Measures: Primary outcome analyses were performed using a bayesian proportional odds model with covariate adjustment for clinical severity ranking based on the World Health Organization ordinal outcome scale, which was modified to highlight the worst level of hypoxemia on study day 5. Results: A total of 501 patients (mean [SD] age, 61.0 [15.3] years; 284 [56.7%] were male; and most [417 (83.2%)] were self-reported non-Hispanic or non-Latinx) were included. Baseline severity was comparable between the intervention vs usual care groups, with 170 patients (65.9%) vs 162 patients (66.7%) receiving oxygen via standard low-flow nasal cannula, 71 patients (27.5%) vs 62 patients (25.5%) receiving oxygen via high-flow nasal cannula, and 16 patients (6.2%) vs 19 patients (7.8%) receiving noninvasive positive-pressure ventilation. Nursing observations estimated that patients in the intervention group spent a median of 4.2 hours (IQR, 1.8-6.7 hours) in the prone position per day compared with 0 hours (IQR, 0-0.7 hours) per day in the usual care group. On study day 5, the bayesian posterior probability of the intervention group having worse outcomes than the usual care group on the modified World Health Organization ordinal outcome scale was 0.998 (posterior median adjusted odds ratio [aOR], 1.63; 95% credibility interval [CrI], 1.16-2.31). However, on study days 14 and 28, the posterior probabilities of harm were 0.874 (aOR, 1.29; 95% CrI, 0.84-1.99) and 0.673 (aOR, 1.12; 95% CrI, 0.67-1.86), respectively. Exploratory outcomes (progression to mechanical ventilation, length of stay, and 28-day mortality) did not differ between groups. Conclusions and Relevance: In this nonrandomized controlled trial, prone positioning offered no observed clinical benefit among patients with COVID-19-associated hypoxemia who had not received mechanical ventilation. Moreover, there was substantial evidence of worsened clinical outcomes at study day 5 among patients recommended to receive the awake prone positioning intervention, suggesting potential harm. Trial Registration: ClinicalTrials.gov Identifier: NCT04359797.

Non-Invasive Monitoring for Rejection in Kidney Transplant Recipients After SARS-CoV-2 mRNA Vaccination.

Introduction: Studies have shown reduced antiviral responses in kidney transplant recipients (KTRs) following SARS-CoV-2 mRNA vaccination, but data on post-vaccination alloimmune responses and antiviral responses against the Delta (B.1.617.2) variant are limited. Materials and methods: To address this issue, we conducted a prospective, multi-center study of 58 adult KTRs receiving mRNA-BNT162b2 or mRNA-1273 vaccines. We used multiple complementary non-invasive biomarkers for rejection monitoring including serum creatinine, proteinuria, donor-derived cell-free DNA, peripheral blood gene expression profile (PBGEP), urinary CXCL9 mRNA and de novo donor-specific antibodies (DSA). Secondary outcomes included development of anti-viral immune responses against the wild-type and Delta variant of SARS-CoV-2. Results: At a median of 85 days, no KTRs developed de novo DSAs and only one patient developed acute rejection following recent conversion to belatacept, which was associated with increased creatinine and urinary CXCL9 levels. During follow-up, there were no significant changes in proteinuria, donor-derived cell-free DNA levels or PBGEP. 36% of KTRs in our cohort developed anti-wild-type spike antibodies, 75% and 55% of whom had neutralizing responses against wild-type and Delta variants respectively. A cellular response against wild-type S1, measured by interferon-γ-ELISpot assay, developed in 38% of KTRs. Cellular responses did not differ in KTRs with or without antibody responses. Conclusions: SARS-CoV-2 mRNA vaccination in KTRs did not elicit a significant alloimmune response. About half of KTRs who develop anti-wild-type spike antibodies after two mRNA vaccine doses have neutralizing responses against the Delta variant. There was no association between anti-viral humoral and cellular responses.

Rationale and process for N95 respirator sanitation and reuse in the coronavirus disease 2019 (COVID-19) pandemic.

OBJECTIVE: The novel severe acute respiratory coronavirus virus 2 (SARS-CoV-2) was first reported in Wuhan, China, in December 2019 and is notable for being highly contagious and potentially lethal; and SARS-CoV-2 is mainly spread by droplet transmission. The US healthcare system's response to the COVID-19 pandemic has been challenged by a shortage of personal protective equipment (PPE), especially N95 respirators. Restricted use, reuse, and sanitation of PPE have been widely adopted to provide protection for frontline healthcare workers caring for often critically ill and highly contagious patients. Here, we describe our validated process for N95 respirator sanitation. DESIGN: Process development, validation, and implementation. SETTING: Level 1, urban, academic, medical center. METHODS: A multidisciplinary team developed a novel evidence-based process for N95 respirator reprocessing and sanitation using ultraviolet (UV) light. Dose measurement, structural integrity, moisture content, particle filtration, fit testing, and environmental testing were performed for both quality control and validation of the process. RESULTS: The process achieved UV light dosing for sanitation while maintaining the functional and structural integrity of the N95 respirators, with a daily potential throughput capacity of ∼12,000 masks. This process has supported our health system to provide respiratory PPE to all frontline team members. CONCLUSIONS: This novel method of N95 respirator sanitation can safely enable reuse of the N95 respirators essential for healthcare workers caring for patients with COVID-19. Our high-throughput process can extend local supplies of this critical PPE until the national supply is replenished.

First Clinical Experience With Ophthalmic e-Device for Unaided Patient Self-Examination During COVID-19 Lockdown.

PURPOSE: The aim of this study was to describe a new type of medical device that allows for internet-enabled patient self-screening, without the aid of an ophthalmic professional, through biomicroscopy self-imaging and self-measurement of the best-corrected visual acuity (BCVA). METHODS: In this prospective nonrandomized comparative study, 56 patients were instructed to screen their own eyes using a custom-built e-Device containing miniaturized slitlamp optics and a visual acuity Snellen chart virtually projected at 20 ft. BCVA measurements were recorded, and biomicroscopic videos were scored for image quality of the anterior segment status on a scale from 1 to 5 (1 = poor and 5 = excellent) by a blinded observer. RESULTS: After a short instruction, all patients were able to self-image their eyes and perform a self-BCVA measurement using the e-Device. Patient self-image quality with the e-Device scored on average 3.3 (±0.8) for videos (n = 76) and 3.6 (±0.6) for photographs (n = 49). Self-BCVA measurement was within 1 Snellen line from routine BCVA levels in 66 of 72 eyes (92%). When compared with conventional biomicroscopy, patient self-biomicroscopy allowed for recognition of the relevant pathology (or absence thereof) in 26 of 35 eyes (74%); 9 cases showed insufficient image quality attributed to device operating error (n = 6) and mild corneal edema and/or scarring (n = 3). Patient satisfaction with the device was 4.4 (±0.9). CONCLUSIONS: An e-Device for combined BCVA self-measurement and biomicroscopy self-imaging may have potential as an aid in remote ophthalmic examination in the absence of an ophthalmic professional and may be considered for patients who are unable to visit an ophthalmic clinic for routine follow-up.

Metabolic and inflammatory health in SARS-CoV-2 and the potential role for habitual exercise in reducing disease severity.

INTRODUCTION: The rapid emergence and spread of SARS-CoV-2 in late 2019 has infected millions of people worldwide with significant morbidity and mortality with various responses from health authorities to limit the spread of the virus. Although population-wide inoculation is preferred, currently, there is large variation and disparity in the acquisition, development, and deployment of vaccination programs in many countries. Even with availability of a vaccine, achieving herd immunity does not guarantee against reinfection from SARS-CoV-2. Emerging evidence indicates that vaccines do not eliminate infection but protect against severe disease and potential hospitalisation. Therefore, additional strategies which strengthen the immune system should be strongly considered to assist in reducing the overall health care burden and stem the rate of infection. There is now substantial evidence that SARS-CoV-2 disease severity and death are linked to existing comorbidities such as cardiovascular disease, obesity, and metabolic disorders. PURPOSE: In this review, we discuss the potential medium-to-long-term strategy of habitual exercise and its relationship to targeted comorbidities and underlying inflammation as a protective mechanism against SARS-CoV-2 disease severity. CONCLUSION: We conclude that engagement in habitual physical activity and exercise could be a strategy to mitigate the development of comorbidities and improve the response of the immune system, potentially reducing the risk of symptoms and life-threatening complications if infected.

Housing preferences during the pandemic: effect on home price, rent, and inflation measurement

With shelter comprising a one-third weight in the Consumer Price Index, an accurate measure of rent change is essential for determining factors affecting inflation measurement, economic policy, and consumer and business decisions. The pandemic led to a shift in consumer demand for more residential space, both in the home’s interior and exterior. With remote work severing the need to be located near the place of employment, some households opted for more space in lower-density areas, moving out of high-rise structures in the urban core to suburban and exurban single-family and low-rise homes, altering the price and rent-growth patterns among single-family detached, attached, and multifamily properties. While measures of rent change are available for multifamily residential properties, none exist for the single-family rental market, which makes up one-half of the residential rental market. The CoreLogic Single-Family Rent Index (SFRI) fills the gap in rent measurement. The SFRI is a repeat-transaction rent index for single-family homes and is available monthly for the U.S., by major metros, by rent price tier and by property type. The SFRI reveals that after 12 months of the pandemic annual rent growth for detached properties was more than 5 percentage points higher than for attached properties. Substituting the SFRI for Owners’ Equivalent Rent, we find that Core CPI inflation would be nearly 2 percentage points higher by mid-2021. To the extent the rapid acceleration in single-family detached rent growth has yet to be reflected in the CPI, inflation measurement will be understated with delayed signals for economic policy makers.

Counting Pandemic Statistics Remotely Using Webcams.

OBJECTIVE: Lack of mask use during large public events might spread COVID-19. It is now possible to measure this and similar public health information using publicly available webcams. We demonstrate a rapid assessment approach for measuring mask usage at a public event. METHOD: We monitored crowds at public areas in Sturgis, SD using a live, high-definition, town-sponsored video stream to analyze the prevalence of mask wearing. We developed a rapid coding procedure for mask wearing and analyzed brief (5 to 25 min) video segments to assess mask-wearing compliance in outdoor public areas. We calculated compliance estimates and compared reliability among the human coders. RESULTS: We were able to observe and quantify public behavior on the public streets. This approach rapidly estimated public health information (e.g., 512 people observed over 25 minutes with 2.3% mask usage) available on the same day. Coders produced reliable estimates across a sample of videos for counting masked users and mask-wearing proportion. Our video data is stored in Databrary.org. CONCLUSIONS: This approach has implications for disaster responses and public health. The approach is easy to use, can provide same day results, and can provide public health stakeholders with key information on public behavior.

High titers and low fucosylation of early human anti-SARS-CoV-2 IgG promote inflammation by alveolar macrophages.

Patients diagnosed with coronavirus disease 2019 (COVID-19) become critically ill primarily around the time of activation of the adaptive immune response. Here, we provide evidence that antibodies play a role in the worsening of disease at the time of seroconversion. We show that early-phase severe acute respiratory distress syndrome coronavirus 2 (SARS-CoV-2) spike protein-specific immunoglobulin G (IgG) in serum of critically ill COVID-19 patients induces excessive inflammatory responses by human alveolar macrophages. We identified that this excessive inflammatory response is dependent on two antibody features that are specific for patients with severe COVID-19. First, inflammation is driven by high titers of anti-spike IgG, a hallmark of severe disease. Second, we found that anti-spike IgG from patients with severe COVID-19 is intrinsically more proinflammatory because of different glycosylation, particularly low fucosylation, of the antibody Fc tail. Low fucosylation of anti-spike IgG was normalized in a few weeks after initial infection with SARS-CoV-2, indicating that the increased antibody-dependent inflammation mainly occurs at the time of seroconversion. We identified Fcγ receptor (FcγR) IIa and FcγRIII as the two primary IgG receptors that are responsible for the induction of key COVID-19-associated cytokines such as interleukin-6 and tumor necrosis factor. In addition, we show that anti-spike IgG-activated human macrophages can subsequently break pulmonary endothelial barrier integrity and induce microvascular thrombosis in vitro. Last, we demonstrate that the inflammatory response induced by anti-spike IgG can be specifically counteracted by fostamatinib, an FDA- and EMA-approved therapeutic small-molecule inhibitor of Syk kinase.

Comparing an operation tomonitoring, with or without endocrine therapy (COMET): Aprospective randomized trial for low-risk DCIS (AFT-25)

Background: Approximately 50,000 women in the U.S. are diagnosed with ductal carcinoma in situ (DCIS)annually. Without treatment, it is estimated that 20-30% of DCIS will lead to invasive breast cancer. Currently, morethan 97% of women undergo surgery, with many also undergoing radiation. An alternative to surgery for low-riskDCIS is active monitoring (AM), an approach in which regularly scheduled mammography and physical exams areused to monitor breast changes and determine if, or when, surgery is needed. Trial design: COMET, a multicenterphase III prospective randomized trial, opened in the U.S. in June 2017 (clinicaltrials.gov reference: NCT02926911).The hypothesis is that management of low-risk DCIS using an AM approach does not yield inferior invasive breastcancer and/or quality of life outcomes compared to surgery. Eligibility criteria: Patients with a new diagnosis of unilateral, bilateral, unifocal, multifocal, or multicentric DCIS, or atypia verging on DCIS are eligible. Patients mustbe ≥40 years of age, have no contraindication for surgery, and pathologic confirmation of grade I/II DCIS. DCIS mustbe ER and/or PR≥ 10% and HER2-negative without invasion, diagnosed within 120 days of registration. Breasttissue, blood and imaging are collected at trial entry and if invasive cancer subsequently occurs, and are stored incentral repositories. Specific aims: The primary aim is to assess whether the 2-yr ipsilateral invasive breast cancerrate for AM is non-inferior to surgery. Secondary aims include comparison of 2-, 5-, and 10-yr mastectomy rate, contralateral invasive breast cancer rate, overall survival and invasive breast cancer-specific survival, as well as 5-and 10-yr ipsilateral invasive breast cancer rate between groups. Patient reported outcomes (PRO) using validatedtools are critical secondary endpoints, and will enable comparison of health-related quality of life and psychosocialoutcomes between surgery and AM groups at prespecified time points over a period of 5 years. Statisticalmethods: An accrual goal of 1200 was estimated using a 2-group test of noninferiority of proportions, with the 2-yrinvasive breast cancer rate in the surgery group assumed to be 0.10, including accounting for upstaging. Theprojected drop-out rate is 25%, for a total of 900 patients treated per allocation arm. The non-inferiority boundarywas set at 0.05. Based on a 1-sided un-pooled z-test, with alpha=0.05, a sample size of n=446 per group will have80% power to detect the specified noninferiority margin. Intention-to-treat analysis of the 2-yr invasive breast cancerrate will be conducted using all patients as randomized, and will be completed using Kaplan-Meier estimates,stratified by group, combined with Greenwood's confidence interval. Several sensitivity analyses (per protocol, as-treated, and instrumental variable) are also planned to account for loss of follow-up, rejection of randomizationallocation and withdrawals. Present and target accrual: Trial accrual as of 7/1/20 is 540 randomized patients from84 activated Alliance for Clinical Trials in Oncology sites. Despite logistical challenges posed by the COVID-19crisis, patients continue to be recruited to the COMET trial. Over 80% of patients have sample sets/images stored inthe tissue and image repositories. This trial will provide definitive clinical, quality of life and biomarker evidenceregarding the trade-offs of surgery vs AM in patients with low-risk DCIS.

Anti-C5a antibody IFX-1 (vilobelimab) treatment versus best supportive care for patients with severe COVID-19 (PANAMO): an exploratory, open-label, phase 2 randomised controlled trial.

BACKGROUND: Severe COVID-19 is characterised by inflammation and coagulation in the presence of complement system activation. We aimed to explore the potential benefit and safety of selectively blocking the anaphylatoxin and complement protein C5a with the monoclonal antibody IFX-1 (vilobelimab), in patients with severe COVID-19. METHODS: We did an exploratory, open-label, randomised phase 2 trial (part of the adaptive phase 2/3 PANAMO trial) of intravenous IFX-1 in adults with severe COVID-19 at three academic hospitals in the Netherlands. Eligibility criteria were age 18 years or older; severe pneumonia with pulmonary infiltrates consistent with pneumonia, a clinical history of severe shortness of breath within the past 14 days, or a need for non-invasive or invasive ventilation; severe disease defined as a ratio of partial pressure of arterial oxygen to fractional concentration of oxygen in inspired air (PaO2/FiO2) between 100 mm Hg and 250 mm Hg in the supine position; and severe acute respiratory syndrome coronavirus 2 infection confirmed by RT-PCR. Patients were randomly assigned 1:1 to receive IFX-1 (up to seven doses of 800 mg intravenously) plus best supportive care (IFX-1 group) or best supportive care only (control group). The primary outcome was the percentage change in PaO2/FiO2 in the supine position between baseline and day 5. Mortality at 28 days and treatment-emergent and serious adverse events were key secondary outcomes. The primary analysis was done in the intention-to-treat population and safety analyses were done in all patients according to treatment received. This trial is registered at ClinicalTrials.gov (NCT04333420). FINDINGS: Between March 31 and April 24, 2020, 30 patients were enrolled and randomly assigned to the IFX-1 group (n=15) or the control group (n=15). During the study it became clear that several patients could not be assessed regularly in the supine position because of severe hypoxaemia. It was therefore decided to focus on all PaO2/FiO2 assessments (irrespective of position). At day 5 after randomisation, the mean PaO2/FiO2 (irrespective of position) was 158 mm Hg (SD 63; range 84-265) in the IFX-1 group and 189 mm Hg (89; 71-329) in the control group. Analyses of the least squares mean relative change in PaO2/FiO2 at day 5 showed no differences between treatment groups (17% change in the IFX-1 group vs 41% in the control group; difference -24% [95% CI -58 to 9], p=0·15. Kaplan-Meier estimates of mortality by 28 days were 13% (95% CI 0-31) for the IFX-1 group and 27% (4-49) for the control group (adjusted hazard ratio for death 0·65 [95% CI 0·10-4·14]). The frequency of serious adverse events were similar between groups (nine [60%] in the IFX-1 group vs seven [47%] in the control group) and no deaths were considered related to treatment assignment. However, a smaller proportion of patients had pulmonary embolisms classed as serious in the IFX-1 group (two [13%]) than in the control group (six [40%]). Infections classed as serious were reported in three (20%) patients in the IFX-1 group versus five (33%) patients in the control group. INTERPRETATION: In this small exploratory phase 2 part of the PANAMO trial, C5a inhibition with IFX-1 appears to be safe in patients with severe COVID-19. The secondary outcome results in favour of IFX-1 are preliminary because the study was not powered on these endpoints, but they support the investigation of C5a inhibition with IFX-1 in a phase 3 trial using 28-day mortality as the primary endpoint. FUNDING: InflaRx.