Search

Summary: Background: It is unknown if early COVID-19 monoclonal antibody (mAb) therapy can reduce risk of Long COVID. The mAbs amubarvimab/romlusevimab were previously demonstrated to reduce risk of hospitalization/death by 79%. This study assessed the impact of amubarvimab/romlusevimab on late outcomes, including Long COVID. Methods: Non-hospitalized high-risk adults within 10 days of COVID-19 symptom onset enrolled in a randomized, double-blind, placebo-controlled phase 2/3 trial of amubarvimab/romlusevimab for COVID-19 treatment. Late symptoms, assessed using a participant-completed symptom diary, were a pre-specified exploratory endpoint. The primary outcome for this analysis was the composite of Long COVID by participant self-report (presence of COVID-19 symptoms as recorded in the diary at week 36) or hospitalization or death by week 36. Inverse probability weighting (IPW) was used to address incomplete outcome ascertainment, giving weighted risk ratios (wRR) comparing amubarvimab/romlusevimab to placebo. Findings: Participants received amubarvimab/romlusevimab (n = 390) or placebo (n = 390) between January and July 2021. Median age was 49 years, 52% were female, 18% Black/African American, 49% Hispanic/Latino, and 9% COVID-19-vaccinated at entry. At week 36, 103 (13%) had incomplete outcome ascertainment, and 66 (17%) on amubarvimab/romlusevimab and 92 (24%) on placebo met the primary outcome (wRR = 0.70, 95% confidence interval (CI) 0.53–0.93). The difference was driven by fewer hospitalizations/deaths with amubarvimab/romlusevimab (4%) than placebo (13%). Among 652 participants with available diary responses, 53 (16%) on amubarvimab/romlusevimab and 44 (14%) on placebo reported presence of Long COVID. Interpretation: Amubarvimab/romlusevimab treatment, while highly effective in preventing hospitalizations/deaths, did not reduce risk of Long COVID. Additional interventions are needed to prevent Long COVID. Funding: National Institute of Allergy and Infectious Diseases of the National Institutes of Health. Amubarvimab and romlusevimab supplied by Brii Biosciences.

Background: In September 2022, UNC Hospitals was awarded a Regional Emerging Special Pathogens Treatment Center (RESPTC) grant by the U.S. Department of Health and Human Services Administration for Strategic Preparedness and Response (ASPR) to care for up to two patients with viral hemorrhagic fever, or similar pathogen, and up to ten patients with novel respiratory pathogens. Intensive infection prevention efforts and timely multidisciplinary commitment was required to develop the Space, Strategy, Staff, and Stuff needed to care for patients with a special pathogen. Methods: Multiple space needs assessments were undertaken to acquire spaces for the care of patients, simulation training, and a dedicated laboratory. Strategies for developing the response plan required collaboration with hospital executives, nursing leadership, public health leaders, and regional partners. Staff were recruited across various disciplines to join the response team and were provided hands-on skills training which was assessed by post-training surveys. Specialized ‘stuff’ (i.e., PPE, training equipment, and waste management devices) were researched and procured for use by the team. Results: Patient care and dedicated laboratory space was identified within existing infrastructure, and renovation plans were developed to adapt the space for these specialized activities. A waste management plan that benefits the hospital for routine waste and allows for Category A waste management was approved. Fifty-three staff members were recruited from 3 main disciplines (RNs, MDs, Paramedics), and across numerous settings (Medicine Acute Care & ICU, Pediatric ICU & Stepdown, Air Care/Transport, Burn ICU, Surgery Stepdown, Emergency Medicine, Infection Prevention, Infectious Disease) were trained during five 4-hour training sessions, culminating in an exercise involving transporting a rule–out Ebola patient to the hospital’s special pathogens unit. Post-training evaluations demonstrated a very high level of confidence (‘strongly agree’) in staffs’ knowledge about the RESPTC site (92.3%), special pathogens (80.8%), collaboration needed for managing patient care (80.8%), and in their comfort with special PPE donning and doffing (73.1%). Conclusions: Using a systematic approach to develop Space, Strategy, Staff, and Stuff, a large academic hospital readied itself to become a new RESPTC site. Key lessons learned include the importance of a multidisciplinary response team; local, state, and regional coordination for care planning and delivery; and early community partnership development. Logistical infrastructure and waste management challenges continue to require partnership with hospital leadership to optimize workflows and patient care. Holistic decision-making around infrastructure has led to changes that benefit all hospital patients and offer efficiencies to

Accelerating COVID-19 Treatment Interventions and Vaccines (ACTIV) was initiated by the US government to rapidly develop and test vaccines and therapeutics against COVID-19 in 2020. The ACTIV Therapeutics-Clinical Working Group selected ACTIV trial teams and clinical networks to expeditiously develop and launch master protocols based on therapeutic targets and patient populations. The suite of clinical trials was designed to collectively inform therapeutic care for COVID-19 outpatient, inpatient, and intensive care populations globally. In this report, we highlight challenges, strategies, and solutions around clinical protocol development and regulatory approval to document our experience and propose plans for future similar healthcare emergencies.

Summary: Background: With the emergence of SARS-CoV-2 variants resistant to monoclonal antibody therapies and limited global access to therapeutics, the evaluation of novel therapeutics to prevent progression to severe COVID-19 remains a critical need. Methods: Safety, clinical and antiviral efficacy of inhaled interferon-β1a (SNG001) were evaluated in a phase II randomized controlled trial on the ACTIV-2/A5401 platform (ClinicalTrials.gov NCT04518410). Adult outpatients with confirmed SARS-CoV-2 infection within 10 days of symptom onset were randomized and initiated either orally inhaled nebulized SNG001 given once daily for 14 days (n = 110) or blinded pooled placebo (n = 110) between February 10 and August 18, 2021. Findings: The proportion of participants reporting premature treatment discontinuation was 9% among SNG001 and 13% among placebo participants. There were no differences between participants who received SNG001 or placebo in the primary outcomes of treatment emergent Grade 3 or higher adverse events (3.6% and 8.2%, respectively), time to symptom improvement (median 13 and 9 days, respectively), or proportion with unquantifiable nasopharyngeal SARS-CoV-2 RNA at days 3 (28% [26/93] vs. 39% [37/94], respectively), 7 (65% [60/93] vs. 66% [62/94]) and 14 (91% [86/95] vs. 91% [83/81]). There were fewer hospitalizations with SNG001 (n = 1; 1%) compared with placebo (n = 7; 6%), representing an 86% relative risk reduction (p = 0.07). There were no deaths in either arm. Interpretation: In this trial, SNG001 was safe and associated with a non-statistically significant decrease in hospitalization for COVID-19 pneumonia. Funding: The ACTIV-2 platform study is funded by the NIH. Research reported in this publication was supported by the National Institute of Allergy and Infectious Diseases of the National Institutes of Health under Award Number UM1 AI068634, UM1 AI068636 and UM1 AI106701. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

In April 2021, Eli Lilly voluntarily asked the FDA to revoke the Emergency Use Authorization for the monoclonal antibody bamlanivimab due to reduced susceptibility in vitro to SARS-CoV-2 variants, not for safety. In this work, authors carry out a placebo-controlled phase 2 evaluation of bamlanivimab in non-hospitalized adults with COVID-19, to determine safety and efficacy.

Abstract Germline pathogenic TP53 variants predispose individuals to a high lifetime risk of developing multiple cancers and are the hallmark feature of Li-Fraumeni syndrome (LFS). Our group has previously shown that LFS patients harbor shorter plasma cell-free DNA fragmentation; independent of cancer status. To understand the functional underpinning of cfDNA fragmentation in LFS, we conducted a fragmentomic analysis of 199 cfDNA samples from 82 TP53 mutation carriers and 30 healthy TP53-wildtype controls. We find that LFS individuals exhibit an increased prevalence of A/T nucleotides at fragment ends, dysregulated nucleosome positioning at p53 binding sites, and loci-specific changes in chromatin accessibility at development-associated transcription factor binding sites and at cancer-associated open chromatin regions. Machine learning classification resulted in robust differentiation between TP53 mutant versus wildtype cfDNA samples (AUC-ROC = 0.710–1.000) and intra-patient longitudinal analysis of ctDNA fragmentation signal enabled early cancer detection. These results suggest that cfDNA fragmentation may be a useful diagnostic tool in LFS patients and provides an important baseline for cancer early detection.

Summary: Background: Glucocorticoids (GCs) are widely applied anti-inflammatory drugs that are associated with adverse metabolic effects including insulin resistance and weight gain. Previous research indicates that GCs may negatively impact brown adipose tissue (BAT) activity in rodents and humans. Methods: We performed a randomised, double-blinded cross-over trial in 16 healthy men (clinicaltrials.gov NCT03269747). Participants received 40 mg of prednisone per day for one week or placebo. After a washout period of four weeks, participants crossed-over to the other treatment arm. Primary endpoint was the increase in resting energy expenditure (EE) in response to a mild-cold stimulus (cold-induced thermogenesis, CIT). Secondary outcomes comprised mean 18F-FDG uptake into supraclavicular BAT (SUVmean) as determined by FDG-PET/CT, volume of the BAT depot as well as fat content determined by MRI. The plasma metabolome and the transcriptome of supraclavicular BAT and of skeletal muscle biopsies after each treatment period were analysed. Findings: Sixteen participants were recruited to the trial and completed it successfully per protocol. After prednisone treatment resting EE was higher both during warm and cold conditions. However, CIT was similar, 153 kcal/24 h (95% CI 40–266 kcal/24 h) after placebo and 186 kcal/24 h (95% CI 94–277 kcal/24 h, p = 0.38) after prednisone. SUVmean of BAT after cold exposure was not significantly affected by prednisone (3.36 g/ml, 95% CI 2.69–4.02 g/ml, vs 3.07 g/ml, 95% CI 2.52–3.62 g/ml, p = 0.28). Results of plasma metabolomics and BAT transcriptomics corroborated these findings. RNA sequencing of muscle biopsies revealed higher expression of genes involved in calcium cycling. No serious adverse events were reported and adverse events were evenly distributed between the two treatments. Interpretation: Prednisone increased EE in healthy men possibly by altering skeletal muscle calcium cycling. Cold-induced BAT activity was not affected by GC treatment, which indicates that the unfavourable metabolic effects of GCs are independent from thermogenic adipocytes. Funding: Grants from Swiss National Science Foundation (PZ00P3_167823), Bangerter-Rhyner Foundation and from Nora van der Meeuwen-Häfliger Foundation to MJB. A fellowship-grant from the Swiss National Science Foundation (SNF211053) to WS. Grants from German Research Foundation (project number: 314061271-TRR 205) and Else Kröner-Fresenius (grant support 2012_A103 and 2015_A228) to MR.

ObjectiveHyperthyroidism is a common endocrine disorder which leads to higher resting energy expenditure (REE). Increased activity of brown adipose tissue (BAT) contributes to elevated REE in hyperthyroid patients. For rapid control of hyperthyroid symptoms, the non-selective β-blocker propranolol is widely used. While, long-term treatment with propranolol reduces REE it is currently unclear whether it can also acutely diminish REE.DesignIn the present prospective interventional trial we investigated the effect of propranolol on REE in hyperthyroid patients.MethodsNineteen patients with overt primary hyperthyroidism were recruited from the endocrine outpatient clinic. REE was measured by indirect calorimetry before and after an acute dose of 80mg propranolol and during a control period, respectively. Additionally, skin temperature was recorded at eleven predefined locations during each study visit, vital signes and heart rate (HR) were measured before and after administration of propranolol.ResultsMean REE decreased slightly after acute administration of 80mg propranolol (p= 0.03) from 1639 ± 307 kcal/24h to 1594 ± 283 kcal/24h. During the control visit REE did not change significantly. HR correlated significantly with the level of free T3 (R2 = 0.38, p=0.029) free T4 (R2 = 0.39, p=0.026). HR decreased 81 ± 12 bpm to 67 ± 7.6 bpm 90 minutes after oral administration of propranolol (p