Key Points Question Does COVID-19 convalescent plasma (CCP), compared with placebo, improve the clinical status of hospitalized patients with COVID-19 requiring noninvasive supplemental oxygen? Findings In this randomized clinical trial including 941 patients, based on the World Health Organization 11-point Ordinal Scale for Clinical Improvement, CCP did not benefit 468 participants randomized to CCP compared with 473 randomized to placebo from April 2020 to March 2021. However, in exploratory analyses, CCP appeared to benefit those enrolled from April to June 2020, the period when most participants received high-titer CCP and were not receiving remdesivir and corticosteroids at randomization. Meaning In this trial, CCP did not meet prespecified outcomes for efficacy, but high-titer CCP may have benefited hospitalized patients with COVID-19 early in the pandemic when other treatments were not in use, suggesting a heterogenous treatment effect over time.

This study provides insight into the role of the virus strain, age, immunity, and URT flora on IAV shedding and transmission efficiency. Using the infant mouse model, we found that (i) differences in viral shedding of various IAV strains are dependent on specific hemagglutinin (HA) and/or neuraminidase (NA) proteins, (ii) host age plays a key role in the efficiency of IAV transmission, (iii) levels of IAV-specific immunoglobulins are necessary to limit infectiousness, transmission, and susceptibility to IAV, and (iv) expression of sialidases by colonizing S. pneumoniae antagonizes transmission by limiting the acquisition of IAV in recipient hosts. Our findings highlight the need for strategies that limit IAV shedding and the importance of understanding the function of the URT bacterial composition in IAV transmission. This work reinforces the significance of a tractable animal model to study both viral and host traits affecting IAV contagion and its potential for optimizing vaccines and therapeutics that target disease spread.

1 9 2 0 2 1 2 2 Word count: Abstract (368), Text (4692) 2 3 2 ABSTRACT 2 4 2 5The pandemic potential of influenza A viruses (IAV) depends on the infectivity of 2 6 the host, transmissibility of the virus, and susceptibility of the recipient. While virus traits 2 7 supporting IAV transmission have been studied in detail using ferret and guinea pig 2 8 models, there is limited understanding of host traits determining transmissibility and 2 9 susceptibility because current animal models of transmission are not sufficiently 3 0 tractable. Although mice remain the primary model to study IAV immunity and 3 1 pathogenesis, the efficiency of IAV transmission in adult mice has been inconsistent. 2Here we describe an infant mouse model which support efficient transmission of IAV. 3We demonstrate that transmission in this model requires young age, close contact, 3 4 shedding of virus particles from the upper respiratory tract (URT) of infected pups, the 3 5 use of a transmissible virus strain, and a susceptible recipient. We characterize 3 6shedding as a marker of infectiousness that predicts the efficiency of transmission 3 7 among different influenza virus strains. We also demonstrate that transmissibility and 3 8 susceptibility to IAV can be inhibited by humoral immunity via maternal-infant transfer of 3 9 IAV-specific immunoglobulins, and modifications to the URT milieu, via sialidase activity 4 0 of colonizing Streptococcus pneumoniae (Spn). Due to its simplicity and efficiency, this 4 1 model can be used to dissect the host's contribution to IAV transmission and explore 4 2 new methods to limit contagion.4 3 3 IMPORTANCE 4 4 4 5This study provides insight into the role of the virus strain, age, immunity, and 4 6 URT flora on IAV shedding and transmission efficiency. Using the infant mouse model, 4 7 we found that: (a) differences in viral shedding of various IAV strains is dependent on 4 8 specific hemagglutinin (HA) and/or neuraminidase (NA) proteins; (b) host age plays a 4 9 key role in the efficiency of IAV transmission; (c) levels of IAV-specific immunoglobulins 5 0 are necessary to limit infectiousness, transmission, and susceptibility to IAV; and (d) 5 1 expression of sialidases by colonizing Spn antagonize transmission by limiting the 5 2 acquisition of IAV in recipient hosts. Our findings highlight the need for strategies that 5 3 limit IAV shedding, and the importance of understanding the function of the URT 5 4 bacterial composition in IAV transmission. This work reinforces the significance of a 5 5tractable animal model to study both viral and host traits affecting IAV contagion, and its 5 6 potential for optimizing vaccines and therapeutics that target disease spread. 5 7 5 8 5 9

Objectives Our discussant’s thoughtful consideration of the patient’s case allows for review of three maxims of medicine: Occam’s razor (the simplest diagnosis is the most likely to be correct), Hickam’s dictum (multiple disease entities are more likely than one), and Crabtree’s bludgeon (the tendency to make data fit to an explanation we hold dear). Case presentation A 66-year-old woman with a history of hypertension presented to our hospital one day after arrival to the United States from Guinea with chronic daily vomiting, unintentional weight loss and progressive shoulder pain. Her labs are notable for renal failure, nephrotic range proteinuria and normocytic anemia while her shoulder X-ray shows osseous resorption in the lateral right clavicle. Multiple myeloma became the team’s working diagnosis; however, a subsequent shoulder biopsy was consistent with follicular thyroid carcinoma. Imaging suggested the patient’s renal failure was more likely a result of a chronic, unrelated process. Conclusions It is tempting to bludgeon diagnostic possibilities into Occam’s razor. Presumption that a patient’s signs and symptoms are connected by one disease process often puts us at a cognitive advantage. However, atypical presentations, multiple disease processes, and unique populations often lend themselves more to Hickam’s dictum than to Occam’s razor. Diagnostic aids include performing a metacognitive checklist, engaging analytic thinking, and acknowledging the imperfections of these axioms.