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Background: Mouse models that recapitulate key features of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection are important tools for understanding complex interactions between host genetics, immune responses, and SARS-CoV-2 pathogenesis. Little is known about how predominantly cellular (Th1 type) versus humoral (Th2 type) immune responses influence SARS-CoV-2 dynamics, including infectivity and disease course., Methods: We generated knock-in (KI) mice expressing human ACE2 (hACE2) and/or human TMPRSS2 (hTMPRSS2) on Th1-biased (C57BL/6; B6) and Th2-biased (BALB/c) genetic backgrounds. Mice were infected intranasally with SARS-CoV-2 Delta (B.1.617.2) or Omicron BA.1 (B.1.1.529) variants, followed by assessment of disease course, respiratory tract infection, lung histopathology, and humoral and cellular immune responses., Findings: In both B6 and BALB/c mice, hACE2 expression was required for infection of the lungs with Delta, but not Omicron BA.1. Disease severity was greater in Omicron BA.1-infected hTMPRSS2-KI and double-KI BALB/c mice compared with B6 mice, and in Delta-infected double-KI B6 and BALB/c mice compared with hACE2-KI mice. hACE2-KI B6 mice developed more severe lung pathology and more robust SARS-CoV-2-specific splenic CD8 T cell responses compared with hACE2-KI BALB/c mice. There were no notable differences between the two genetic backgrounds in plasma cell, germinal center B cell, or antibody responses to SARS-CoV-2., Interpretation: SARS-CoV-2 Delta and Omicron BA.1 infection, disease course, and CD8 T cell response are influenced by the host genetic background. These humanized mice hold promise as important tools for investigating the mechanisms underlying the heterogeneity of SARS-CoV-2-induced pathogenesis and immune response., Funding: This work was funded by NIH U19 AI142790-02S1, the GHR Foundation, the Arvin Gottleib Foundation, and the Overton family (to SS and EOS); Prebys Foundation (to SS); NIH R44 AI157900 (to KJ); and by an American Association of Immunologists Career Reentry Fellowship (FASB)., Competing Interests: Declaration of interests CC, NS, and KJ were employees of Synbal, Inc. DOC is employed by and holds stock in TransViragen Inc., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

Background: The Critical Care Societies Collaborative included not ordering diagnostic tests at regular intervals as one of their Choosing Wisely initiatives. A reduction in unnecessary chest radiographs (CXRs) can help reduce exposure to radiation and eliminate health care waste. We aimed to reduce daily screening CXRs in a pediatric ICU (PICU) by 20% from baseline within 4 months of implementation of CXR criteria., Methods: All intubated patients in the PICU were included in this quality improvement project. Patients with tracheostomies were excluded. We developed criteria delineating which patients were most likely to benefit from a daily screening CXR, and these criteria were discussed for each patient on rounds. Patients on extracorporeal membrane oxygenation, on high-frequency oscillatory ventilation, or on high support on conventional mechanical ventilation were included as needing a daily screening CXR. We tracked the percentage of intubated subjects receiving a screening CXR as an outcome measure. Unplanned extubations and the number of non-screening CXRs per intubated subject were followed as balancing measures., Results: The percentage of intubated subjects receiving a daily screening CXR was reduced from 79% to 31%. There was no increase in frequency of unplanned extubations or number of non-screening CXRs. With an estimated subject charge of roughly $270 and hospital cost of $54 per CXR, this project led to an estimated $300,000 in patient charge savings and $60,000 in hospital cost savings., Conclusions: Adopting criteria to delineate which patients are most likely to benefit from screening CXRs can lead to a reduction in the percentage of intubated patients receiving screening CXRs without appearing to increase harm., Competing Interests: The authors have disclosed no conflicts of interest., (Copyright © 2023 by Daedalus Enterprises.)

Therapeutic antibodies are an important tool in the arsenal against coronavirus infection. However, most antibodies developed early in the pandemic have lost most or all efficacy against newly emergent strains of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), particularly those of the Omicron lineage. Here, we report the identification of a panel of vaccinee-derived antibodies that have broad-spectrum neutralization activity. Structural and biochemical characterization of the three broadest-spectrum antibodies reveal complementary footprints and differing requirements for avidity to overcome variant-associated mutations in their binding footprints. In the K18 mouse model of infection, these three antibodies exhibit protective efficacy against BA.1 and BA.2 infection. This study highlights the resilience and vulnerabilities of SARS-CoV-2 antibodies and provides road maps for further development of broad-spectrum therapeutics., Competing Interests: Declaration of interests K.M.H, S.S.H., and E.O.S. have a patent pending for the antibodies described in this study., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

Although severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) initially infects the respiratory tract, it also directly or indirectly affects other organs, including the brain. However, little is known about the relative neurotropism of SARS-CoV-2 variants of concern (VOCs), including Omicron (B.1.1.529), which emerged in November 2021 and has remained the dominant pathogenic lineage since then. To address this gap, we examined the relative ability of Omicron, Beta (B.1.351), and Delta (B.1.617.2) to infect the brain in the context of a functional human immune system by using human angiotensin-converting enzyme 2 (hACE2) knock-in triple-immunodeficient NGC mice with or without reconstitution with human CD34 + stem cells. Intranasal inoculation of huCD34 + -hACE2-NCG mice with Beta and Delta resulted in productive infection of the nasal cavity, lungs, and brain on day 3 post-infection, but Omicron was surprisingly unique in its failure to infect either the nasal tissue or brain. Moreover, the same infection pattern was observed in hACE2-NCG mice, indicating that antiviral immunity was not responsible for the lack of Omicron neurotropism. In independent experiments, we demonstrate that nasal inoculation with Beta or with D614G, an ancestral SARS-CoV-2 with undetectable replication in huCD34 + -hACE2-NCG mice, resulted in a robust response by human innate immune cells, T cells, and B cells, confirming that exposure to SARS-CoV-2, even without detectable infection, is sufficient to induce an antiviral immune response. Collectively, these results suggest that modeling of the neurologic and immunologic sequelae of SARS-CoV-2 infection requires careful selection of the appropriate SARS-CoV-2 strain in the context of a specific mouse model., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

Objective: To determine whether dogs can be trained to utilize olfaction to differentiate between saliva samples from dogs with cancer and those from healthy control dogs., Sample: Canine patient saliva samples were collected (October 2020 to July 2022) from 139 dogs diagnosed with malignant tumors and from 161 healthy dogs (control samples) for use during training and testing of the dog detection team. Samples from canine patients were collected prior to treatment with radiation therapy or chemotherapy., Procedures: Six pet dogs (mean ± SD age, 5.4 ± 1.9 years) were trained for odor discrimination between healthy control and malignant tumor samples. Training of the dogs, using a reward-based positive reinforcement method, took place 1 to 3 times per week for a period of 6 months (January to June 2022). After training was complete, a subset of samples not utilized during the training sessions were selected for use during odor discrimination testing of the dog team., Results: The trained dogs could accurately distinguish between samples from cancer patients versus control dogs with a mean sensitivity of 90% and mean specificity of 98%, and with mean positive and negative predictive values of 95%., Clinical Relevance: This study serves as preliminary evidence that dogs can be trained to detect differences in scent between saliva samples from cancer and normal patients. Further studies should expand upon these results with a larger sample, varied tumor types, use of non-cancer diseases as controls, and exploration of this technique in feline patients.

Background: Adult critical care and radiographical societies have recommended changing practice from routine screening radiographs to on-demand chest radiographs (CXRs) for stable mechanically ventilated adult patients. There are no similar recommendations for patients in the pediatric ICU. Reducing the frequency with which unneeded CXRs are obtained can decrease radiation exposure and reduce waste, a substantial contributor to rising health care costs. We aimed to reduce unneeded daily screening CXRs in a pediatric cardiovascular ICU (CICU) by 20% in 6 months., Methods: Criteria delineating which subjects in the CICU required daily screening CXRs were created and added to the daily rounding sheet for discussion for each subject. The primary goal of this study was to reduce CXRs in mechanically ventilated subjects as our previous practice had been to order daily CXRs. Respiratory therapists increased the frequency of evaluating and documenting endotracheal tube positioning prior to the initiation of this project. The outcome measure was the percentage subjects who received a daily screening CXR. The ratio of daily screening CXRs to the number of total CXRs ordered and unplanned extubations were followed as balancing measures., Results: The number of subjects who received a daily screening CXR decreased from a baseline of 67% to 44% over the course of this project. There was no change in the ratio of daily screening CXRs to the number of total CXRs ordered or an increase in unplanned extubations. With an estimated cost of $268 per CXR, a reduction of 33% in routine screening CXRs saves an estimated $250,000 annually., Conclusions: A decrease in daily screening CXRs can be sustained through the development of specific criteria to determine which patients need screening radiographs. This can be achieved without an increase in CXRs obtained at other times throughout the day or an increase in unplanned extubations. This eliminates unneeded health care expenditures, improves resource allocation for radiology technicians, and decreases disruptive interventions for patients., Competing Interests: The authors have disclosed no conflicts of interest., (Copyright © 2023 by Daedalus Enterprises.)

Background: This study was conducted to determine the association between fluid balance metrics and mortality and other postoperative outcomes after neonatal cardiac operation in a contemporary multicenter cohort., Methods: This was an observational cohort study across 22 hospitals in neonates (≤30 days) undergoing cardiac operation. We explored overall percentage fluid overload, postoperative day 1 percentage fluid overload, peak percentage fluid overload, and time to first negative daily fluid balance. The primary outcome was in-hospital mortality. Secondary outcomes included postoperative duration of mechanical ventilation and intensive care unit (ICU) and hospital length of stay. Multivariable logistic or negative binomial regression was used to determine independent associations between fluid overload variables and each outcome., Results: The cohort included 2223 patients. In-hospital mortality was 3.9% (n = 87). Overall median peak percentage fluid overload was 4.9% (interquartile range, 0.4%-10.5%). Peak percentage fluid overload and postoperative day 1 percentage fluid overload were not associated with primary or secondary outcomes. Hospital resource utilization increased on each successive day of not achieving a first negative daily fluid balance and was characterized by longer duration of mechanical ventilation (incidence rate ratio, 1.11; 95% CI, 1.08-1.14), ICU length of stay (incidence rate ratio, 1.08; 95% CI, 1.03-1.12), and hospital length of stay (incidence rate ratio, 1.09; 95% CI, 1.05-1.13)., Conclusions: Time to first negative daily fluid balance, but not percentage fluid overload, is associated with improved postoperative outcomes in neonates after cardiac operation. Specific treatments to achieve an early negative fluid balance may decrease postoperative care durations., (Copyright © 2022 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.)