Sotrovimab Pharmacokinetics and Covariate Effects in Hematopoietic Stem Cell Transplant Recipients

Hematopoietic cell transplant (HCT) recipients are at increased risk of morbidity and mortality from COVID-19. They may have lower SARS-CoV-2-directed antibody levels due to protein loss from the gastrointestinal (GI) tract as a result of preparative regimen-related toxicity and graft-vs.-host disease (GVHD). In fact, previous studies suggested that GI GVHD or diarrhea from other etiologies were associated with a reduction in the half-life of monoclonal antibodies (mAbs). Hence, understanding the pharmacokinetic (PK) profile of mAbs targeting SARS-CoV-2 in this vulnerable population is critical for dose-selection and predicting the duration of protection against COVID-19. This analysis aims to use a population pharmacokinetics (popPK) approach to evaluate the PK of sotrovimab and the effect of covariates in HCT recipients. In a Phase I trial (COVIDMAB), all participants received 500 mg sotrovimab IV prophylactically within one week prior to starting transplant conditioning. Sotrovimab serum concentrations were determined weekly for up to 12 weeks in autologous (n=5) and allogeneic (n=15) HCT recipients (129 observations). Sotrovimb PK and the effect of covariates were analyzed using popPK modeling in NONMEM (version 7.4). GVHD and diarrhea severity data were collected weekly via survey and included as time-dependent covariates during the covariate screening process. The final PK model with covariates was validated using simulation-based validation and goodness of fit plots. PK data were compared to non-transplant patients from 1891 patients with COVID-19 in COMET-ICE, COMET-PEAK, BLAZE-4, and COMET-TAIL and 38 healthy individuals enrolled in GlaxoSmithKline Pharma Study 217653. A two-compartment model best described sotrovimab PK in HCT recipients. In comparison to non-transplant patients, sotrovimab clearance (CL) was 14.0% higher in HCT recipients. Weight was a significant covariate on sotrovimab CL and (Figure Presented) volume of distribution in the central compartment (V2). With every 10 kg increase in body weight, sotrovimab CL and V2 were estimated to increase by 9.5% and 5.5%, respectively. Diarrhea severity was also a significant covariate on sotrovimab CL. HCT recipients with grade 3 diarrhea showed an increase in CL by 1.5-fold compared to those without diarrhea. Based on popPK analyses, sotrovimab CL was higher in HCT recipients compared to non-transplant patients. Higher bodyweight as well as diarrhea resulted in increased sotrovimab CL. There were only 3 patients with GI GVHD, and larger studies are needed to determine whether diarrhea due to GI GVHD or conditioning toxicity was responsible for the observed increase in sotrovimab CL. Further validation of these findings in a larger number of HCT recipients is also warranted to help optimize mAb dosing for COVID-19 prophylaxis and determine whether presence of large-volume diarrhea may require intensified dosing strategiesCopyright © 2023 American Society for Transplantation and Cellular Therapy

Nursing a Radical Imagination: Moving from Theory and History to Action and Alternate Futures

Examining the historical context of healthcare whilst focusing on building a more just, equitable world, this book proposes a radical imagination for nursing and presents possibilities for speculative futures embracing queer, feminist, posthuman, and abolitionist frames. Bringing together radical and emancipatory perspectives from an international selection of authors, this book reflects on the realities created by the COVID-19 pandemic, recognizing that our situation is not new but the result of ongoing hegemonies and injustices. The authors attend to the history of nursing and related institutions, examining the assumptions, ideologies, and discourses that shape the discipline and its place within healthcare. They explore the impact of this context on contemporary nursing and look at alternative visions for the future. The final section specifically focuses on ways that we can move forward. Envisioning new possibilities for nursing, this innovative volume is a vital resource for practitioners, scholars and students keen to promote social justice within and without nursing. It is an important contribution to nursing theory, philosophy and history. © Jess Dillard-Wright, Jane Hopkins-Walsh, and Brandon Brown 2023 selection and editorial matter, individual chapters, the contributors.

IBRUTINIB AND RITUXIMAB AS FIRST LINE THERAPY FOR MANTLE CELL LYMPHOMA: A MULTICENTRE, REAL-WORLD UK STUDY

Background: Ibrutinib (IBR) is an oral covalent Bruton tyrosine kinase inhibitor (BTKi), licensed for treatment of relapsed or refractory mantle cell lymphoma (MCL). Under NHS interim Covid-19 agreements in England, IBR with or without rituximab (R) was approved for the frontline treatment for MCL patients (pts) as a safer alternative to conventional immunochemotherapy. Although recent phase 2 studies have reported high response rates in low-risk patients for this combination in the frontline setting, randomised phase 3 and real-world data are currently lacking. Aims: To describe the real-world response rates (overall response rate (ORR), complete response (CR) rate) and toxicity profile of IBR +/-R in adult patients with previously untreated MCL. Methods: Following institutional approval, adults commencing IBR +/-R for untreated MCL under interim Covid-19 arrangements were prospectively identified by contributing centres. Hospital records were interrogated for demographic, pathology, response, toxicity and survival data. ORR/CR were assessed per local investigator according to the Lugano criteria using CT and/or PET-CT. Results: Data were available for 66 pts (72.7% male, median age 71 years, range 41-89). Baseline demographic and clinical features are summarised in Table 1. 23/66 pts (34.8%) had high-risk disease (defined as presence of TP53 mutation/deletion, blastoid or pleomorphic variant MCL, or Ki67%/MiB-1 ≥30%). IBR starting dose was 560mg in 56/62 pts (90%) and was given with R in 22/64 pts (34%). At a median follow up of 8.7 months (m) (range 0-18.6), pts had received a median of 7 cycles of IBR. 19/60 pts (32%) required a dose reduction or delay in IBR treatment. New atrial fibrillation and grade ≥3 any-cause toxicity occurred in 3/59 pts (5.8%) and 8/57 (14.0%) respectively. For the whole population and high-risk pts only, ORR was 74.4% and 64.7% respectively (p=0.2379), with a median time to response of 3.8m, coinciding with the first response assessment scan. Seven pts (16.7%), of whom 2 had highrisk disease, attained CR at a median of 6.0m. ORR for pts receiving vs not receiving R were 84.2% and 66.7% respectively (p=0.1904). IBR was discontinued in 20/61 pts (32.8%) at a median time to discontinuation of 4.1m, due to progressive disease (PD, 19.7%), toxicity (4.9%), death (3.3%;1 pt each of Covid-19 and E. coli infection), pt choice (3.3%) and other unspecified reasons (1.6%). 15/66 pts (22.7%) overall and 7/23 (30.4%) with high-risk disease progressed on IBR at a median time to PD of 4.0m. No pts underwent autologous stem cell transplantation consolidation during the study period. 12/57 pts (21.1%) received second line treatment (R-chemotherapy n=7, Nordic MCL protocol n=2, VR-CAP n=2, pirtobrutinib n=1). Response to second line treatment was CR in 4/11 pts, PD in 7/11. Of the 2 Nordic-treated patients, 1 had CR after cycle 2 and 1 PD. Fourteen pts (21.2%) died during the follow up period, due to MCL (n=11), Covid-19 (n=2) and congestive cardiac failure (n=1). Overall survival was lower for patients with high-risk disease (HR 0.55, p=0.038). Image: Summary/Conclusion: In this real-world UK cohort of pts receiving first-line IBR +/-R for MCL, including older and high-risk pts, we report high ORR rates in a similar range to the phase II Geltamo IMCL-2015 study of combination IBR-R in an exclusively low-risk population. Documented CR rates were lower, possibly reflecting a low usage of rituximab in the Covid-19 pandemic as well as CT assessment of response. Treatment was generally well tolerated, with low rates of toxicityrelated treatment discontinuation. The study is ongoing.

An Argument for Asynchronous Course Delivery in the Early Stages of the COVID-19 Pandemic

I argue that campus closures and shifts to online instruction in the early stages of the COVID-19 pandemic created an obligation to offer courses asynchronously. This is because some students could not have reasonably foreseen circumstances making continued synchronous participation impossible. Offering synchronous participation options to students who could continue to participate thusly would have been unfair to students who could not participate synchronously. I also discuss why ex post facto consideration of this decision is warranted, noting that similar actions may be necessary in the future and that other tough pedagogical cases share important similarities with this case.

THE USE OF INPATIENT VIRTUAL SHARED MEDICAL APPOINTMENTS FOR PATIENTS WITH ACUTE CEREBROVASCULAR PATHOLOGIES AND THEIR CAREGIVERS: A PILOT STUDY TO IMPROVE HEALTH LITERACY, PATIENT SELF-EFFICACY AND REDUCE PROVIDER BURNOUT

Objective Admission to the hospital for an acute cerebrovascular condition such as stroke or brain hemorrhage can be a traumatic and disorienting experience for patients and their family members. The COVID-19 pandemic has further intensified this experience in addition to exacerbating clinician and resident burnout. To ameliorate some of these concerns, a team of resident and medical student trainees implemented a virtual shared medical appointment (vSMA) program for inpatients with acute cerebrovascular disorders and their caregivers. This study hypothesized that an early intervention vSMA improves patient and caregiver health literacy and preparedness, simultaneously educates trainees on effective communication skills, and reduces clinician burnout. Methods Patients and caregivers of admitted patients were screened through the neurosurgery, neurocritical care, and neurology electronic medical record census. A weekly 60- minute secure virtual session consisted of introductions, a 10- minute standardized presentation on cerebrovascular disease management, followed by participant-guided discussion. Participants completed pre- and post-surveys. We report data on this feasibility study and present challenges, both expected and unforeseen. Results A total of 170 patients were screened;13 patients and 26 caregivers participated in at least 1 session. A total of 6 different healthcare providers facilitated sessions. The vSMA program received overwhelmingly positive feedback from caregivers. Surveys demonstrated 96.4% of caregivers and 75% of patients were satisfied with the session. 96.4% of caregivers and 87.5% of patients would recommend this type of appointment to a friend or family member. 88.8% of providers felt validated by conducting the session. The participant group had a 20% greater percentage of patients discharged home without home needs compared to the non-participant group. The primary obstacle encountered included technological frustrations with the consent process and the sessions themselves. Conclusions Implementation of a vSMA program at a tertiary care center during a pandemic was feasible. Themes caregivers expressed on the post-survey included better understanding of caring for a stroke patient, and coping with the unpredictability of a patient's prognosis. The pandemic has precipitated shifts towards telehealth, but our study highlights the importance of avoiding marginalization of the elderly and less technologically inclined populations (Table Presented).

PRIMARY CARE ANYWHERE: A RESIDENT-LED PODCAST

SETTING AND PARTICIPANTS: Internal Medicine residents at the University of Utah DESCRIPTION: The COVID-19 pandemic has presented unique challenges in delivering high-quality educational experiences in outpatient medicine. With social distancing measures in place, educational sessions are now often delivered virtually or asynchronously, generating a need for creative, engaging ways to deliver our ambulatory medicine curriculum. Our Internal Medicine residency program created a resident-led podcast called “Primary Care Anywhere.” This was integrated within ambulatory medicine rotations as an optional assignment to complete with protected academic time. Podcast episode topics consisted of high-yield topics in primary care. Residents were invited to contribute in a variety of ways: create and record a segment, host the episode, generate show notes and design an infographic. A review article and instructions for each task were provided. Residents worked on contributions independently and these were then compiled into one cohesive episode. The Primary Care Anywhere podcast is free and available to the general public. Episodes average 500-700 downloads. EVALUATION: We observed that residents readily volunteered for this optional activity and were very enthusiastic about participating during ambulatory rotations. A total of 40 residents have participated since its initiation in August of 2020, with contributions from faculty and medical students as well. When asked about the primary motivation for participating, 29% hoped to improve primary care knowledge, 21% wanted experience with podcast production, 29% wanted protected academic time and 14% wanted to build their CV. Residents who created and recorded segments felt that it was a very worthwhile experience, specifically that this type of content creation made them more accountable to learning the topic and, by the end, they felt like experts on their sub-topic. When participants were asked to identify which aspect of the experience they found most beneficial, 64% noted improved knowledge of the topic discussed and 21% cited their gained experience with podcast production. Resident contributors appreciated the opportunity to contribute to free, open-access medical education (FOAMed), and listeners felt it was a valuable supplement to their outpatient education. DISCUSSION / REFLECTION / LESSONS LEARNED: Especially in the setting of a pandemic, podcasts seem to be a popular way to learn among medical trainees. While many of our Internal Medicine residents report learning through listening to existing Internal Medicine podcasts, the vast majority had never had an opportunity to contribute to a podcast. Creating a resident-led podcast provided a creative new learning opportunity for residents to actively engage in content creation and peer education while improving clinical knowledge, gaining a new skill in podcast production and building their CV. This is a project that could be easily adopted by other residency programs.

Assessing Craniofacial Team Functioning During Virtual Multidisciplinary Team Meetings

Background/Purpose: The craniofacial team meeting represents a critical timepoint at which a diverse group of disciplines assemble in quorum to discuss the complex medical and psychosocial issues facing their patients and create treatment plans to address them. Professionals from not only different disciplines but from entirely different fields must efficiently amalgamate their expertise to create one intricate plan for their unique patient population. It is this diversity of disciplines represented and the complexity of subject matter that makes craniofacial team meetings ideal for studying team functioning during multidisciplinary meetings. The global pandemic necessitated a shift of these complex meetings to the virtual setting. While providing direct patient care (i.e. tele-health) has been studied extensively, the literature on virtual team meetings is lacking. The authors of this study evaluated the team functioning of one craniofacial team by studying their virtual team meetings. Methods/Description: Ten virtual team meetings, including 94 patient case discussions, from a 3-month period in late 2020 were recorded and scored individually by three members of the research team using modified versions of the standardized multidisciplinary team Meeting Observational Tool (MOT) and the Metric of Decision-Making (MODe). The mean score amongst the three observers for each category of team functioning was used for analysis. Participants' subjective assessments of team meetings were elicited through monthly Qualtrics surveys. Results: Our results indicate that team functioning during virtual team meetings was high for providing case history, exhibiting optimal team behavior, and providing a treatment plan for individual case discussions. Patient-centered and psychosocial categories received lower scores. Survey respondents generally regarded their team as highly functioning during team meetings, with lower marks given only for decision-making efficiency and full participation from all disciplines. The meeting technology and equipment received a high score on average. Additionally, participants indicated that the virtual format did not enhance or hinder team functioning during team meetings. Conclusions: Amidst the ongoing COVID-19 pandemic it is important to study the effectiveness of multidisciplinary team meetings held in a virtual format. Our findings suggest that virtual setting allows for high team functioning as measured by both objective and subjective assessments and should therefore be considered a viable alternative to in-person meetings. The team performed best in discussing clinical topics, generating treatment plans, and team behavior, including equality among disciplines. Psychosocial matters and patient perspectives were not discussed as extensively as clinical topics and the team overestimated their coverage of both psychosocial matters and patient perspectives, consistent with previous studies on team functioning.

Prone-Position Ventilation in Patients with Neurologic Conditions: A Systematic Review of the Literature and Suggested Protocol

INTRODUCTION: Recommendations regarding ventilation strategies in the setting of COVID-19, which may culminate in a clinical picture similar to ARDS, have not yet been well established. Prone positioning has shown benefit as an adjunct supportive measure for patients who develop ARDS. However, studies assessing the benefit of prone positioning have excluded patients with reduced intracranial compliance resulting in a unique predicament, whereby patients with concomitant neurological diagnoses and ARDS have no defined treatment algorithm or recommendations for management. METHODS: A systematic review of the literature, performed in accordance with the Preferred Reporting Items for Systematic Review and Meta-Analyses (PRISMA) 2009 guidelines, yielded 10 articles for analysis. Utilizing consensus from these articles, in combination with review of multi-institutional proning protocols for patients with non-neurologic conditions, a proning protocol for patients with intracranial pathology and concomitant ARDS was developed. RESULTS: Among the 10 studies included in final analysis, there was consensus that prone positioning should be considered when there is evidence of acute lung injury or ARDS in patients with neurologic injury. Patients may be proned with a speciality bed or manually on a standard bed with the assistance of seven to nine personnel, in the manner described herein. Special consideration for patients requiring frequent neurologic exams and patients at risk of cardiac arrest or seizure are discussed. CONCLUSION: While elevations in ICP and reductions in CPP do occur during proning, they may not occur to a degree that would warrant exclusion of prone ventilation as a treatment modality for patients with ARDS and concomitant neurological diagnoses. In cases where ICP, CPP, and PbtO2 can be monitored, prone-position ventilation should be considered a safe and viable therapy.

The Effects of the COVID-19 Pandemic on Penetrating Neurotrauma at a Level 1 Trauma Center

INTRODUCTION: The COVID-19 pandemic forced the implementation of social distancing guidelines to minimize spread of the coronavirus. However, it is not yet understood what effects these precautions had on the rates of penetrating neurotrauma. METHODS: We retrospectively analyzed neurotrauma data from our institutional trauma registry from distinct periods defined as pre-COVID-19 (March 2019-September 2019) and COVID-19 (March 2020-September 2020). Demographics, injury characteristics, mechanisms of trauma, and past medical history (including psychiatric diagnosis) were collected. Data were analyzed for between-group differences and presented as odds ratios. RESULTS: We observed a significant rise in the number of neurotrauma cases in 2020 (558 vs. 630, OR 1.129 [1.0071, 1.2657]). There was a decrease in the proportion of male victims (71.3% vs. 68.6%, p = 0.03). There were significant differences noted in the mechanism of injury between groups. Patients in 2020 were less likely to present with falls (42.3% vs. 34.3%, OR 0.7119 [0.5627, 0.9005]) and more likely to present with GSW (4.48% vs. 7.78%, OR 1.7981 [1.0951, 2.9523]). Of the patients with penetrating cranial injuries, the most common motive was assault (56.7% vs. 60.0%), followed by self-inflicted (13.3% vs. 20.0%) and accidental (20.0% vs. 18.3%) with a significant difference between years (p = 0.0043). The presence of comorbid psychiatric illness or substance abuse did not confer an increased odds of presenting with penetrating injuries. No significant differences were noted in mean arrival or discharge GCS or injury severity as measured by ISS. However we did observe significant increases in patients presenting with bilaterally reactive pupils (48.3% vs 59.3%, p = 0.0025), patients discharged home (27.6% vs 37.3%, p = 0.0002), and survival at 6 months (41.4% vs. 54.2%, p = 0.0188). CONCLUSION: We observed a higher rate of penetrating neurotrauma while social distancing measures were in place. It is unclear if the psychosocial effects of quarantine and social distancing had a causative relationship with the increased rates of assault and self-inflicted penetrating injuries.

Protecting expert advice for the public: promoting safety and improved communications

The drivers of the harassment and intimidation of researchers are complex, widespread, and global in their reach and were being studied across many disciplines even before COVID-19. This policy briefing reviews some of the scholarship on this wide-ranging problem but focuses on what can be done to help ensure that Canadians fully benefit from the work of Canada's researchers while also preserving the security and safety of those researchers. It identifies policies and actions that can be implemented in the near term to gather information on the problem, better frame public research communications, and ensure that mechanisms are readily available to support researchers who are threatened. The policy briefing is concerned with researchers, but these behaviours are also harming journalists, politicians, public health communicators, and many others more fully in the public eye than researchers. Some recommendations here may help to address this wider problem.

Disinfection of Respirators with Ultraviolet Radiation

Data for interpreting virus inactivation on N95 face filtering respirators (FFRs) by ultraviolet (UV) radiation are important in developing UV strategies for N95 FFR disinfection and reuse for any situation, whether it be everyday practices, contingency planning for expected shortages, or crisis planning for known shortages. Data regarding the integrity, form, fit, and function of N95 FFR materials following UV radiation exposure are equally important. This article provides these data for N95 FFRs following UV-C irradiation (200 nm to 280 nm) in a commercial UV-C enclosure. Viral inactivation was determined by examining the inactivation of OC43, a betacoronavirus, inoculated on N95 FFRs. Different metrological approaches were used to examine irradiated N95 FFRs to determine if there were any discernible physical differences between non-irradiated N95 FFRs and those irradiated using the UV-C enclosure. Material integrity was examined using high-resolution scanning electron microscopy. Form, fit, and function were examined using flow resistance, tensile strength, and particle filtration measurements. A separate examination of filter efficiency, fit, and strap tensile stress measurements was performed by the National Personal Protective Technology Laboratory. Data from these metrological examinations provide evidence that N95 FFR disinfection and reuse using the UV-C enclosure can be effective.

THE ROLE OF FDG-PET IN STAGING AND TREATMENT FOR STAGE III NSCLC IN ONTARIO BETWEEN 2009-2017

Purpose: Fluoro-2-deoxyglucose positron-emission tomography (PET) is now considered standard of care in the staging evaluation for new cases of Stage III NSCLC however, there is not level 3 evidence demonstrating efficacy of PET. Using retrospective population-based data, we sought to examine the role and timing that PET scans play in influencing treatment choice, as well as survival in patients treated with chemoradiation (CRT) for Stage III NSCLC. Materials and Methods: A retrospective cohort of patients diagnosed with Stage III NSCLC from 2009-2017 in Ontario were identified from the Institute of Clinical Evaluative Sciences (ICES). Overall survival (OS), using a landmark analysis of six months, was explored in the entire cohort (PET versus no PET) as well as in patients who received CRT for Stage III disease. Survival time was calculated using Kaplan Meier methods, logistic regression was used to evaluate type of treatment received, and Cox regression was used to evaluate factors prognostic of OS amongst patients who received CRT. Results: A total of 13 796 cases were included in our analysis: 6536 patients underwent PET scanning prior to treatment and 7260 did not. Over time, there was a significantly increased utilization of PET from 12.4% in 2009 to 74.1% in 2017 (p<0.001). In regard to treatment modality, significantly more patients received curative intent therapy in the PET group including: CRT (1472 versus 939 patients;p<0.001), and surgery (1483 versus 734 patients;p<0.001). There was significantly improved OS in the whole cohort with upfront PET versus not with median OS of 17.1 (95% CI=16.3-17.8) versus 11.2 (10.6-11.9) months (p<0.001). In patients specifically receiving CRT, OS was similarly improved in the PET versus no PET subgroups with median OS of 21.7 (19.7-24.2) versus 18.5 (16.8-20.7) months (p=0.004). Examining the timing of PET scan and commencement of therapy, no significant difference was found among patients who had their scan <28 days prior to treatment (median OS =16 months), 2956 days prior to treatment (17.8 months), and >56 days prior to treatment (18.6 months), (p=0.38);these results were similar in the CRT only subgroup. On multivariate analysis, the only factors predicting survival in the CRT group were male gender (HR 1.20;1.08-1.33), increasing age (HR 1.07;1.04-1.10), surgery as part of trimodality therapy (HR 0.60;0.52-0.70), and receipt of PET prior to treatment (HR 0.83;0.72-0.95). Conclusions: Significant differences in treatment received and OS due to receipt of PET may be due to stage migration or unmeasured confounders. However, in a CRT subgroup, receipt of PET was associated with improved OS. Advocating for increased access to PET scans in this patient population is of utmost importance especially now with an additional survival benefit of adjuvant immunotherapy following CRT. The timing of the PET scan relative to initiating treatment did not have an obvious impact on survival, which may be reassuring for centres that may lack the capability to perform timely scans or are experiencing delays due to the COVID-19 pandemic.

Investing in a better future: higher education and post-COVID Canada

Post-secondary education (PSE) is a vital part of civil society and any modern economy. When broadly accessible, it can enable socioeconomic mobility, improve health outcomes, advance social cohesion, and support a highly skilled workforce. It yields public benefits not only in improved well-being and economic prosperity, but also in reduced costs in health care and social services. Canada also relies heavily on the PSE sector for research. During the COVID-19 pandemic, PSE has supported research related to the pandemic response and other critical areas, including providing expert advice to support public health and government decision-making, while maintaining educational programs and continuing to contribute to local and regional economies. But the pandemic effort has stretched already strained PSE resources and people even further: for decades, declining public investment has driven increases in tuition and decreases in faculty complement, undermining Canada's research capacity and increasing student debt as well as destabilizing the sector through a growing reliance on volatile international education markets. Given the challenges before us, including climate change, reconciliation, and the pandemic, it is imperative that we better draw on the full range of experience, knowledge, and creativity in Canada and beyond through an inclusive, stable, and globally engaged PSE. Supporting PSE's recovery will be key to Canada's ongoing pandemic response and recovery. The recommendations in this report are guided by a single goal-to make the post-secondary sector a more effective partner and support in building a more equitable, sustainable, and evidence-driven future for Canada, through and beyond the COVID-19 pandemic.