Dried blood spot (DBS) sample analysis for drug and metabolomic profiling in oncology clinical trials: Cost-effective decentralized sampling modality for precision Oncology

The COVID19 pandemic accelerated opportunities for innovation within the decentralization process of clinical trials with opportunities for implementation of patient-centric workflows for efficiency and cost-reduction. Decentralized sample collection, particularly whole blood using dried blood spots (DBS) provides the ideal mechanism for patient driven sample collection with ease of access to sample generation, drug level assessments and metabolomic prMegofiling, providing longitudinal real-time measure of drug specific pharmacodynamic readout for safety and efficacy. In this study, we report the development of a protocol for the capture and comprehensive profiling of metabolomics using dried blood spots from a cohort of 49 healthy volunteer donors. Using liquid chromatography combined with mass spectrometric (UPLC-MS/MS) methods an untargeted metabolomic approach resulted in the identification of >800 biochemicals of which a significant subset was found to be presented in corresponding matched plasma (from whole blood) samples. The biochemicals identified from the DBS samples included metabolites that were part of the lipid, amino acid, nucleotide, peptide, cofactors, carbohydrate and energy super pathways. A significant number of metabolites identified in the DBS samples were xenobiotics including those representing the biotransformation products of drugs. The overall metabolite profiles were analyzed for precision and accuracy of measure, variability in performance and dynamic range to establish benchmarks for evaluation. An additional cohort with a longitudinal sampling as part of the protocol provided the reproducibility of the analytic method for inter-day variability of metabolite performance over time. Although metabolomic profiles varied between individuals from a population perspective, there was minimal variation observed within individuals when samples were profiled longitudinally over several weeks. Thus, the protocols for DBS collection and the corresponding capture of a large set of metabolites with reproducible performance provides an opportunity for its implementation in oncological clinical trials as part of a de-centralized clinical trial solution.

Caring Through COVID Findings from a Quality Improvement Project

This multisite quality improvement (QI) project reports on a psychotherapy group for family care partners of persons living with neurodegenerative conditions. Following the plan-do-study-act model, a team of geropsychologists iteratively developed, implemented, and refined the 8-week "Caring Through COVID" psychotherapy group across five cycles from January 2021 to April 2022. Participants were 21 spouses or adult children of persons living with neurodegenerative conditions. Across two clinics, participants evidenced moderate improvements in caregiver burden (d = .59), self-efficacy for caregiving (d = -.64), and self-efficacy for emotion regulation (d = -.60). The group was perceived positively by participants. This QI project demonstrates the real-world implementation of a psychotherapy group developed during the COVID-19 pandemic and refined to remain ongoing.

Validity of the Modified SIT-Q 7d for Estimating Sedentary Break Frequency and Duration in Home-Based Office Workers During the COVID-19 Global Pandemic: A Secondary Analysis

Office workers who transitioned to working from home are spending an even higher percentage of their workday sitting compared with being "in-office” and this is an emerging health concern. With many office workers continuing to work from home since the onset of the COVID-19 pandemic, it is imperative to have a validated self-report questionnaire to assess sedentary behavior, break frequency, and duration, to reduce the cost and burden of using device-based assessments. This secondary analysis study aimed to validate the modified Last 7-Day Sedentary Behavior Questionnaire (SIT-Q 7d) against an activPAL4™ device in full-time home-based "office” workers (n = 148;mean age = 44.90). Participants completed the modified SIT-Q 7d and wore an activPAL4 for a full work week. The findings showed that the modified SIT-Q 7d had low (ρ =.35–.37) and weak (ρ =.27–.28) criterion validity for accurate estimates of break frequency and break duration, respectively. The 95% limits of agreement were large for break frequency (26.85–29.01) and medium for break duration (5.81–8.47), indicating that the modified SIT-Q 7d may not be appropriate for measuring occupational sedentary behavior patterns at the individual level. Further validation is still required before confidently recommending this self-report questionnaire to be used among this population to assess breaks in sedentary time. © 2023 Human Kinetics, Inc.

Safety and tolerability of Evusheld in patients with CVID: The Mayo Clinic experience.

Background: The past 2 years of the COVID-19 pandemic brought with it many unknowns for patients with immunodeficiency. Because of the concern for severe infection in those with immunocompromise, patients have been eager for effective prevention, vaccination, and treatment strategies. Preexposure prophylaxis provides another means of prevention in those with immunocompromise. A combination of tixagevimab and cilgavimab (Evusheld [AstraZeneca Cambridge, United Kingdom]) was granted emergency use authorization for preexposure prophylaxis at the end of 2021, but questions remained regarding how this would be tolerated and the side effects associated with its use. Objectives: Our aim was to evaluate the safety and tolerability of Evusheld in patients with CVID from our tri-site institution. Methods: We performed an institutional review board-approved, retrospective chart review of patients with common variable immunodeficiency (CVID) who received Evusheld before March 26, 2022. Results: Of the 45 patients with CVID who received Evusheld, 41 (91%) received the recommended full dose of 600 mg. The majority of patients (39 of 45 [87%]) tolerated Evusheld without adverse events. The adverse events reported included immediate injection site pain, fatigue and cough, an episode of shingles, and chest pain. Conclusions: This is an initial report on the safety and tolerability of Evusheld injections in patients with CVID. The majority of patients tolerated the injections without adverse events. For patients with reported chest pain, the results of a subsequent cardiac workup were negative. The efficacy of Evusheld could not be evaluated owing to the short median follow-up of this study (19 days).

Identification and mechanistic basis of non-ACE2 blocking neutralizing antibodies from COVID-19 patients with deep RNA sequencing and molecular dynamics simulations.

Variants of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) continue to cause disease and impair the effectiveness of treatments. The therapeutic potential of convergent neutralizing antibodies (NAbs) from fully recovered patients has been explored in several early stages of novel drugs. Here, we identified initially elicited NAbs (Ig Heavy, Ig lambda, Ig kappa) in response to COVID-19 infection in patients admitted to the intensive care unit at a single center with deep RNA sequencing (>100 million reads) of peripheral blood as a diagnostic tool for predicting the severity of the disease and as a means to pinpoint specific compensatory NAb treatments. Clinical data were prospectively collected at multiple time points during ICU admission, and amino acid sequences for the NAb CDR3 segments were identified. Patients who survived severe COVID-19 had significantly more of a Class 3 antibody (C135) to SARS-CoV-2 compared to non-survivors (15059.4 vs. 1412.7, p = 0.016). In addition to highlighting the utility of RNA sequencing in revealing unique NAb profiles in COVID-19 patients with different outcomes, we provided a physical basis for our findings via atomistic modeling combined with molecular dynamics simulations. We established the interactions of the Class 3 NAb C135 with the SARS-CoV-2 spike protein, proposing a mechanistic basis for inhibition via multiple conformations that can effectively prevent ACE2 from binding to the spike protein, despite C135 not directly blocking the ACE2 binding motif. Overall, we demonstrate that deep RNA sequencing combined with structural modeling offers the new potential to identify and understand novel therapeutic(s) NAbs in individuals lacking certain immune responses due to their poor endogenous production. Our results suggest a possible window of opportunity for administration of such NAbs when their full sequence becomes available. A method involving rapid deep RNA sequencing of patients infected with SARS-CoV-2 or its variants at the earliest infection time could help to develop personalized treatments using the identified specific NAbs.

Surviving Sepsis Campaign: Guidelines on the Management of Critically Ill Adults with Coronavirus Disease 2019 (COVID-19).

BACKGROUND: The novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the cause of a rapidly spreading illness, Coronavirus Disease 2019 (COVID-19), affecting thousands of people around the world. Urgent guidance for clinicians caring for the sickest of these patients is needed. METHODS: We formed a panel of 36 experts from 12 countries. All panel members completed the World Health Organization conflict of interest disclosure form. The panel proposed 53 questions that are relevant to the management of COVID-19 in the ICU. We searched the literature for direct and indirect evidence on the management of COVID-19 in critically ill patients in the ICU. We identified relevant and recent systematic reviews on most questions relating to supportive care. We assessed the certainty in the evidence using the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) approach, then generated recommendations based on the balance between benefit and harm, resource and cost implications, equity, and feasibility. Recommendations were either strong or weak, or in the form of best practice recommendations. RESULTS: The Surviving Sepsis Campaign COVID-19 panel issued 54 statements, of which four are best practice statements, nine are strong recommendations, and 35 are weak recommendations. No recommendation was provided for six questions. The topics were: 1) infection control, 2) laboratory diagnosis and specimens, 3) hemodynamic support, 4) ventilatory support, and 5) COVID-19 therapy. CONCLUSION: The Surviving Sepsis Campaign COVID-19 panel issued several recommendations to help support healthcare workers caring for critically ill ICU patients with COVID-19. When available, we will provide new evidence in further releases of these guidelines.

Ensuring the business sustainability of minor league baseball after the COVID global pandemic

The COVID global pandemic greatly impacted the sports industry as leagues had drastic budget cuts and were forced to compensate for the lost revenues. The purpose of this study is to examine the strategies used by Minor League Baseball (MiLB) teams and leagues to ensure their survival in the short-term and to sustain their operations in a post-COVID environment. Consultation with officials of a local minor league team, in addition to extensive information search, identified the strategies used by teams and leagues. A cluster analysis was then performed to classify the strategies into categories of similar topics. The results suggested teams and leagues took an "Income Statement Approach" to ensuring their survival. That is, they focused on: (a) maximizing revenue and finding new revenue sources;while (b) finding ways to reduce operating expenses. Minor league baseball teams navigated the loss of the 2020 season and the adjusted operations of the 2021 season to return to more-normal operations in the 2022 season. Lessons learned during the COVID period were applied to streamline their operations in the short-run and to ensure the sustainability of their business in the long-run. Coaches seek to develop an 'adjust-and-adapt mentality' in their athletes. The COVID global pandemic forced all of society to adopt this approach. Minor league baseball leagues and teams adopted this approach and they successful sustained their operations. Today, the industry continues to be a vital source of family entertainment and community pride while concurrently serving as the primary development path for the Major League Baseball (MLB) players of the future.

Predominant SARS-CoV-2 variant impacts accuracy when screening for infection using exhaled breath vapor.

BACKGROUND: New technologies with novel and ambitious approaches are being developed to diagnose or screen for SARS-CoV-2, including breath tests. The US FDA approved the first breath test for COVID-19 under emergency use authorization in April 2022. Most breath-based assays measure volatile metabolites exhaled by persons to identify a host response to infection. We hypothesized that the breathprint of COVID-19 fluctuated after Omicron became the primary variant of transmission over the Delta variant. METHODS: We collected breath samples from 142 persons with and without a confirmed COVID-19 infection during the Delta and Omicron waves. Breath samples were analyzed by gas chromatography-mass spectrometry. RESULTS: Here we show that based on 63 exhaled compounds, a general COVID-19 model had an accuracy of 0.73 ± 0.06, which improved to 0.82 ± 0.12 when modeling only the Delta wave, and 0.84 ± 0.06 for the Omicron wave. The specificity improved for the Delta and Omicron models (0.79 ± 0.21 and 0.74 ± 0.12, respectively) relative to the general model (0.61 ± 0.13). CONCLUSIONS: We report that the volatile signature of COVID-19 in breath differs between the Delta-predominant and Omicron-predominant variant waves, and accuracies improve when samples from these waves are modeled separately rather than as one universal approach. Our findings have important implications for groups developing breath-based assays for COVID-19 and other respiratory pathogens, as the host response to infection may significantly differ depending on variants or subtypes.

In recent decades, scientists have found we exhale thousands of compounds that reveal much about our health, including whether we are sick with COVID-19. Our team asked whether the breath profile of someone infected with the Delta variant of COVID-19 would match the breath profile caused by the Omicron variant­a version of the virus that is more transmissible. We analyzed breath samples from 142 people, some sick with either the Delta or Omicron variant of COVID-19, and others who were negative for COVID-19. Our results indicate that the Delta variant altered the contents of our breath in a different way than the Omicron variant, and breath-based tests improved when optimized to detect only one of the variants. These findings might impact the design of future breath-based tests for COVID-19.

International cohort study indicates no association between alpha-1 blockers and susceptibility to COVID-19 in benign prostatic hyperplasia patients.

Purpose: Alpha-1 blockers, often used to treat benign prostatic hyperplasia (BPH), have been hypothesized to prevent COVID-19 complications by minimising cytokine storm release. The proposed treatment based on this hypothesis currently lacks support from reliable real-world evidence, however. We leverage an international network of large-scale healthcare databases to generate comprehensive evidence in a transparent and reproducible manner. Methods: In this international cohort study, we deployed electronic health records from Spain (SIDIAP) and the United States (Department of Veterans Affairs, Columbia University Irving Medical Center, IQVIA OpenClaims, Optum DOD, Optum EHR). We assessed association between alpha-1 blocker use and risks of three COVID-19 outcomes-diagnosis, hospitalization, and hospitalization requiring intensive services-using a prevalent-user active-comparator design. We estimated hazard ratios using state-of-the-art techniques to minimize potential confounding, including large-scale propensity score matching/stratification and negative control calibration. We pooled database-specific estimates through random effects meta-analysis. Results: Our study overall included 2.6 and 0.46 million users of alpha-1 blockers and of alternative BPH medications. We observed no significant difference in their risks for any of the COVID-19 outcomes, with our meta-analytic HR estimates being 1.02 (95% CI: 0.92-1.13) for diagnosis, 1.00 (95% CI: 0.89-1.13) for hospitalization, and 1.15 (95% CI: 0.71-1.88) for hospitalization requiring intensive services. Conclusion: We found no evidence of the hypothesized reduction in risks of the COVID-19 outcomes from the prevalent-use of alpha-1 blockers-further research is needed to identify effective therapies for this novel disease.

Burnout, personal and secondary trauma among mental health care professionals during the COVID-19 pandemic

BACKGROUND: The psychiatric community is beginning to document the psychological effects of the COVID-19 pan-demic upon individuals with and without a preexisting psychiatric disorder. As the demand for mental health services is increasing, there are concerns about the wellbeing of mental health professionals (MHPs) as past research has highlighted problems with therapist burnout, anxiety compassion fatigue and secondary trauma when exposed to high rates of stress, increased workload, and isolation.METHODS: MHPs were recruited from two listserves and completed a questionnaire that included demographic ques-tions, stress-related questions as measured by the Impact of Event Scale - Revised (IES-R), actual amounts of supervision as measured by the Coping Strategies Inventory (CSI), counselor burnout as measured by the Counselor Burnout Inven -tory (CBI), and secondary trauma as measured by the Professional Quality of Life Scale (ProQOL). RESULTS: We utilized a 3-stage hierarchical regression to evaluate what variables predicted trauma in MHPs and found that counselor burnout and secondary trauma explained a significant amount of the variance in predicting trauma as measured by the IES-R. CONCLUSIONS: MHPs are experiencing personal trauma, secondary trauma, and burnout while trying to provide men-tal health services during the pandemic. More research is needed to fully understand what mental health professionals can engage in to mitigate the effects of burnout and trauma.

International cohort study indicates no association between alpha-1 blockers and susceptibility to COVID-19 in benign prostatic hyperplasia patients

Purpose: Alpha-1 blockers, often used to treat benign prostatic hyperplasia (BPH), have been hypothesized to prevent COVID-19 complications by minimising cytokine storm release. The proposed treatment based on this hypothesis currently lacks support from reliable real-world evidence, however. We leverage an international network of large-scale healthcare databases to generate comprehensive evidence in a transparent and reproducible manner. Methods: In this international cohort study, we deployed electronic health records from Spain (SIDIAP) and the United States (Department of Veterans Affairs, Columbia University Irving Medical Center, IQVIA OpenClaims, Optum DOD, Optum EHR). We assessed association between alpha-1 blocker use and risks of three COVID-19 outcomes—diagnosis, hospitalization, and hospitalization requiring intensive services—using a prevalent-user active-comparator design. We estimated hazard ratios using state-of-the-art techniques to minimize potential confounding, including large-scale propensity score matching/stratification and negative control calibration. We pooled database-specific estimates through random effects meta-analysis. Results: Our study overall included 2.6 and 0.46 million users of alpha-1 blockers and of alternative BPH medications. We observed no significant difference in their risks for any of the COVID-19 outcomes, with our meta-analytic HR estimates being 1.02 (95% CI: 0.92–1.13) for diagnosis, 1.00 (95% CI: 0.89–1.13) for hospitalization, and 1.15 (95% CI: 0.71–1.88) for hospitalization requiring intensive services. Conclusion: We found no evidence of the hypothesized reduction in risks of the COVID-19 outcomes from the prevalent-use of alpha-1 blockers—further research is needed to identify effective therapies for this novel disease.

The Effect of COVID-19 on Orthopaedic Trauma Theatre Efficiency and Surgical Training in the North and East of Scotland Major Trauma Centres - a Year On

Aim: To determine the orthopaedic trauma theatre efficiency in two large major trauma centres (MTCs) in Scotland before and after the outbreak of Coronavirus disease (COVID-19) pandemic. Method: All trauma patients presented to the North and East of Scotland's MTCs prior to the outbreak of COVID-19 (7th May to 7th June 2019), during the first peak of COVID-19 (7th May to 7th June 2020), after Aerosol Generating Procedures updates (7th November to 7th December 2020) and the 'new normal' (7th May to 7th June 2021) were retrospectively reviewed. Training opportunities and theatre time were compared. The Kruskall-Wallis test was used. Results: There were no significant differences in the length of hospital stay (p=0.117, 0.065) and time from injuries and surgery within groups in both MTCs (p=0.508, 0.384). The pandemic has negatively affected the anaesthetic and surgical preparation time, time between end of procedure and send for next case, and turnover time, with more profound effect on the North of Scotland's MTC. The trainee's involvement as main surgeon had decreased with the outbreak of the pandemic, with the junior trainees being affected most severely in North of Scotland. The time taken for patient to arrive to theatre after sending and total downtime were twice as long in the North of Scotland. Conclusion: The COVID-19 pandemic has negatively impacted the orthopaedic trauma theatre efficiency and training opportunities. Actions should be taken to improve the turnover time to maximise theatre efficiency while prioritizing training opportunities.

Deep RNA sequencing of intensive care unit patients with COVID-19.

COVID-19 has impacted millions of patients across the world. Molecular testing occurring now identifies the presence of the virus at the sampling site: nasopharynx, nares, or oral cavity. RNA sequencing has the potential to establish both the presence of the virus and define the host's response in COVID-19. Single center, prospective study of patients with COVID-19 admitted to the intensive care unit where deep RNA sequencing (> 100 million reads) of peripheral blood with computational biology analysis was done. All patients had positive SARS-CoV-2 PCR. Clinical data was prospectively collected. We enrolled fifteen patients at a single hospital. Patients were critically ill with a mortality of 47% and 67% were on a ventilator. All the patients had the SARS-CoV-2 RNA identified in the blood in addition to RNA from other viruses, bacteria, and archaea. The expression of many immune modulating genes, including PD-L1 and PD-L2, were significantly different in patients who died from COVID-19. Some proteins were influenced by alternative transcription and splicing events, as seen in HLA-C, HLA-E, NRP1 and NRP2. Entropy calculated from alternative RNA splicing and transcription start/end predicted mortality in these patients. Current upper respiratory tract testing for COVID-19 only determines if the virus is present. Deep RNA sequencing with appropriate computational biology may provide important prognostic information and point to therapeutic foci to be precisely targeted in future studies.

How COVID-19 Taught Us to Address Self-identified Learning Gaps: A Simulation Based Approach

Background: The COVID-19 pandemic presented a variety of challenges to learners at all levels of training. The fall and winter seasons are when Pediatric trainees are exposed to a high volume of respiratory illnesses such as bronchiolitis, croup and asthma. However the advent of social distancing and use of face masks showed a significant decrease in the burden of infectious diseases. A multi-center study using the Pediatric Health Information System (PHIS) showed that ED visit rates decreased by 45.7% during the pandemic as compared to the three years prior(1). At our institution we saw a 90% reduction in bronchiolitis cases after the stay-at-home order went into effect March 30, 2020 compared to 2019 data for the same time period. With less hands-on experience, trainees are struggling to identify, triage and manage respiratory distress. Methods: Given the missed learning opportunities associated with COVID-19 and a low volume respiratory season, interns requested an expansion of the simulation curriculum to include specific content review for respiratory distress. The session started with a brief fifteen minute overview in the Just-in-Time-Teaching (JiTT) style(2). Learning objectives included recognizing the signs and symptoms of respiratory distress, reviewing the differential diagnoses, initiating treatment for the various differentials and escalating care in a timely fashion. Interns then moved on to the simulated cases. We used a high-fidelity baby mannequin for a bronchiolitis case and pediatric mannequin for an asthma case. Cases were debriefed in the Advocacy-Inquiry Method and interns were asked to share one piece of practice changing knowledge. Results: Interns (n=17) were anonymously surveyed before and after the session with responses measured on the 5- point Likert scale(3). 80% of interns reported that the COVID-19 pandemic impacted their medical education and, following the completion of cases, 94% strongly agreed that simulations were a helpful way to supplement their medical training. Two interns completed a post-survey but did not complete a pre-survey. Before the simulation, 13% of interns reported not feeling adequately prepared to identify respiratory distress and only 6% felt adequately prepared to manage it. After the simulation, 82% of interns felt adequately prepared to identify respiratory distress and 82% felt prepared to manage it. Conclusion: Public health mandates during the COVID-19 pandemic proved effective for controlling disease spread, but created a knowledge gap for Pediatric trainees regarding commonly encountered respiratory diseases. We addressed this gap in real time by modifying our simulation curriculum to include a content review of respiratory distress. Interns showed improved self-reported confidence in their diagnostic and treatment abilities. Continued use of JiTT in the simulation setting could be a helpful way to bridge resident-identified knowledge gaps on a more routine basis. Further work needs to be done to establish the long-term effectiveness of this flexible, learner-specific curriculum.

Mindfulness in Motion: A Mindfulness Based Intervention in Pulmonary Rehabilitation to Improve Self-Efficacy in Chronic Respiratory Disease

Rationale: Patients with chronic lung disease experience dyspnea and other symptoms that significantly affect quality of life and can result in elevated rates of depression and anxiety. Concomitant anxiety and depression can often result in poorer outcomes in these patients and can hinder their confidence in self-management of their disease. Mindfulness involves non-judgmental attention to a person's surroundings and experiences cultivates the ability to be aware of the present moment. A formal mindfulness-based intervention developed at Ohio State University called Mindfulness in Motion offered within the established structure of a pulmonary rehabilitation program was implemented in both virtual and in-person format to promote disease self-efficacy, reduce stress and improve symptoms of anxiety and depression that often accompany chronic symptomatic lung disease. Methods: This is a prospective feasibility/pilot study pre/post-test design with an intervention and control wait list groups. All new adult patients enrolling in pulmonary rehabilitation were eligible. Mindfulness in Motion (MIM) is a Mindfulness Based Intervention that is offered in a group format for 1hr/week/8 weeks combined with 10-20 online audio and video programs to facilitate individual mindfulness practice. The Mindfulness in Motion program relaced one of the usual 1 hour pulmonary rehabilitation education sessions. One round of the intervention was done virtually via Microsoft Teams due to the restrictions of the Covid-19 pandemic and an additional in-person round of this program is currently ongoing. The primary outcome is the PROMIS Self-Efficacy for Managing Chronic Conditions-Symptoms. Breath counts pre and post intervention are of interest as well. Secondary outcomes are: PROMIS Percieved Stress Scale, PROMIS Anxiety Short Form, PROMIS Depression short form and Respiratory Rate. These measures were collected pre-intervention, post-intervention, 6 months and 1 year. Results: Data collection and analysis of primary and secondary endpoints is currently ongoing. However, early analysis shows a decrease in respiratory rate immediately post-intervention. In initial 4 subjects in which respiratory rate data was recorded, 3 out of 4 patients showed significant consistent reduction in respiratory rate from the beginning to the end of each session in the 7 weeks of the intervention already completed (see Table 1). Conclusion: Mindfulness in Motion is a mindfulness intervention that is implementable within the existing structure of pulmonary rehabilitation. Further, it may be effective at slowing breathing rate in these patients prior to exercising which may be beneficial to participation. Further investigation with a larger randomized control trial would be feasible and warranted for further study. (Table Presented).

THE COST OF IN-PERSON VERSUS TELEHEALTH PAP INITIATION FOR PATIENTS WITH SLEEP APNEA

Introduction: Telehealth has been widely integrated into healthcare systems during the COVID-19 pandemic and is likely to remain a part of routine clinical care. At the VA Greater Los Angeles Healthcare System (VAGLAHS), positive airway pressure (PAP) set-up visits transitioned from in person to telehealth for newly diagnosed sleep apnea patients during the pandemic. The telehealth pathway included mailing of PAP machines to patients with follow-up video/phone education by respiratory therapists (RTs). As part of a larger study examining the clinical outcomes resulting from telehealth versus in-person PAP initiation, we performed a cost analysis of these two treatment pathways within VAGLAHS. Methods: We examined the total variable direct cost of telehealth versus in-person PAP initiation for patients newly diagnosed with sleep apnea at VAGLAHS between March and October 2021 (n = 2,662 PAP set-ups) using a bottom-up analysis. There was an average of 16 PAP set-ups per day with 11 set-ups (68.7%) via telehealth and 5 set-ups (31.3%) in person. Results: The total variable direct cost of telehealth PAP initiation was $98.87 per patient. The total variable direct cost of in-person PAP initiation was $50.58 per patient. For telehealth, there was an additional cost of mailing the PAP machine and 31.2% more RT time spent on educating patients compared to the in-person pathway. After the initial PAP set-up visit, a larger subset of patients required additional troubleshooting help from RTs about proper PAP use after telehealth compared to in-person set-ups (5% versus 1%). Conclusion: The telehealth PAP initiation pathway was nearly two times the cost of in-person PAP initiation. This resulted from the additional cost of mailing the PAP machine, more RT time spent on education, and a greater need for troubleshooting after the visit. Telehealth visits may need to be supplemented by written educational materials or web-based resources to reduce the need for additional support after the initial visit.

The association between household and neighborhood characteristics and COVID-19 related ICU admissions.

Introduction: Approaches to COVID-19 mitigation can be more efficiently delivered with a more detailed understanding of where the severe cases occur. Our objective was to assess which demographic, housing and neighborhood characteristics were independently and collectively associated with differing rates of severe COVID-19. Methods: A cohort of patients with SARS-CoV-2 in a single health system from March 1, 2020 to February 15, 2021 was reviewed to determine whether demographic, housing, or neighborhood characteristics are associated with higher rates of severe COVID-19 infections and to create a novel scoring index. Characteristics included proportion of multifamily homes, essential workers, and ages of the homes within neighborhoods. Results: There were 735 COVID-19 ICU admissions in the study interval which accounted for 61 percent of the state's ICU admissions for COVID-19. Compared to the general population of the state those admitted to the ICU with COVID-19 were disproportionately older, male sex, and were more often Black, Indigenous, People of Color. Patients disproportionately resided in neighborhoods with three plus unit multifamily homes, homes built before 1940, homes with more than one person to a room, homes of lower average value, and in neighborhoods with a greater proportion of essential workers. From this our COVID-19 Neighborhood Index value was comparatively higher for the ICU patients (61.1) relative to the population of Rhode Island (49.4). Conclusion: COVID-19-related ICU admissions are highly related to demographic, housing and neighborhood-level factors. This may guide more nuanced and targeted vaccine distribution plans and public health measures for future pandemics.

Identification and Mechanistic Basis of non-ACE2 Blocking Neutralizing Antibodies from COVID-19 Patients with Deep RNA Sequencing and Molecular Dynamics Simulations (preprint)

Variants of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) continue to cause disease and impair the effectiveness of treatments. The therapeutic potential of convergent neutralizing antibodies (NAbs) from fully recovered patients has been explored in several early stages of novel drugs. Here, we identified initially elicited NAbs (Ig Heavy, Ig lambda, Ig kappa) in response to COVID-19 infection in patients admitted to the intensive care unit at a single center with deep RNA sequencing (>100 million reads) of peripheral blood as a diagnostic tool for predicting the severity of the disease and as a means to pinpoint specific compensatory NAb treatments. Clinical data were prospectively collected at multiple time points during ICU admission, and amino acid sequences for the NAb CDR3 segments were identified. Patients who survived severe COVID-19 had significantly more of a Class 3 antibody (C135) to SARS-CoV-2 compared to non-survivors (16,315 reads vs 1,412 reads, p=0.02). In addition to highlighting the utility of RNA sequencing in revealing unique NAb profiles in COVID-19 patients with different outcomes, we provided a physical basis for our findings via atomistic modeling combined with molecular dynamics simulations. We established the interactions of the Class 3 NAb C135 with the SARS-CoV-2 spike protein, proposing a mechanistic basis for inhibition via multiple conformations that can effectively prevent ACE2 from binding to the spike protein, despite C135 not directly blocking the ACE2 binding motif. Overall, we demonstrate that deep RNA sequencing combined with structural modeling offers the new potential to identify and understand novel therapeutic(s) NAbs in individuals lacking certain immune responses due to their poor endogenous production. Our results suggest a possible window of opportunity for administration of such NAbs when their full sequence becomes available. A method involving rapid deep RNA sequencing of patients infected with SARS-CoV-2 or its variants at the earliest infection time could help to develop personalized treatments using the identified specific NAbs.