Timing of Intubation in COVID-19: When It Is Too Early and When It Is Too Late.

The timing of initiating mechanical ventilation in patients with acute respiratory distress syndrome due to COVID-19 remains controversial. At the outset of the pandemic, "very early" intubation was recommended in patients requiring oxygen flows above 6 L per minute but was followed closely thereafter by avoidance of invasive mechanical ventilation (IMV) due to a perceived (yet over-estimated) risk of mortality after intubation. While the use of noninvasive methods of oxygen delivery, such as high-flow nasal oxygen (HFNO) or noninvasive positive pressure ventilation (NIV), can avert the need for mechanical ventilation in some, accumulating evidence suggests delayed intubation is also associated with an increased mortality in a subset of COVID-19 patients. Close monitoring is necessary in COVID-19 patients on HFNO or NIV to identify signs of noninvasive failure and ensure appropriate provision of IMV.

Adenosine deaminase augments SARS-CoV-2 specific cellular and humoral responses in aged mouse models of immunization and challenge.

Despite numerous clinically available vaccines and therapeutics, aged patients remain at increased risk for COVID-19 morbidity. Furthermore, various patient populations, including the aged can have suboptimal responses to SARS-CoV-2 vaccine antigens. Here, we characterized vaccine-induced responses to SARS-CoV-2 synthetic DNA vaccine antigens in aged mice. Aged mice exhibited altered cellular responses, including decreased IFNγ secretion and increased TNFα and IL-4 secretion suggestive of TH2-skewed responses. Aged mice exhibited decreased total binding and neutralizing antibodies in their serum but significantly increased TH2-type antigen-specific IgG1 antibody compared to their young counterparts. Strategies to enhance vaccine-induced immune responses are important, especially in aged patient populations. We observed that co-immunization with plasmid-encoded adenosine deaminase (pADA)enhanced immune responses in young animals. Ageing is associated with decreases in ADA function and expression. Here, we report that co-immunization with pADA enhanced IFNγ secretion while decreasing TNFα and IL-4 secretion. pADA expanded the breadth and affinity SARS-CoV-2 spike-specific antibodies while supporting TH1-type humoral responses in aged mice. scRNAseq analysis of aged lymph nodes revealed that pADA co-immunization supported a TH1 gene profile and decreased FoxP3 gene expression. Upon challenge, pADA co-immunization decreased viral loads in aged mice. These data support the use of mice as a model for age-associated decreased vaccine immunogenicity and infection-mediated morbidity and mortality in the context of SARS-CoV-2 vaccines and provide support for the use of adenosine deaminase as a molecular adjuvant in immune-challenged populations.

Feasibility Study of Cord Tissue Derived Mesenchymal Stromal Cells in COVID-19-Related Acute Respiratory Distress Syndrome.

BACKGROUND: Treatment options for patients with COVID-19-related acute respiratory distress syndrome (ARDS) are desperately needed. Allogeneic human umbilical cord derived mesenchymal stromal cells (hCT-MSCs) have potential therapeutic benefits in these critically ill patients, but feasibility and safety data are lacking. MATERIALS AND METHODS: In this phase I multisite study, 10 patients with COVID-19-related ARDS were treated with 3 daily intravenous infusions of hCT-MSCs (1 million cells/kg, maximum dose 100 million cells). The primary endpoint assessed safety. RESULTS: Ten patients (7 females, 3 males; median age 62 years (range 39-79)) were enrolled at 2 sites and received a total of 30 doses of study product. The average cell dose was 0.93 cells/kg (range 0.56-1.45 cells/kg and total dose range 55-117 million cells) with 5/30 (17%) of doses lower than intended dose. Average cell viability was 85% (range 63%-99%) with all but one meeting the >70% release criteria. There were no infusion-related reactions or study-related adverse events, 28 non-serious adverse events in 3 unique patients, and 2 serious adverse events in 2 unique patients, which were expected and unrelated to the study product. Five patients died: 3 by day 28 and 5 by day 90 of the study (median 27 days, range 7-76 days). All deaths were determined to be unrelated to the hCT-MSCs. CONCLUSION: We were able to collect relevant safety outcomes for the use of hCT-MSCs in patients with COVID-19-related ARDS. Future studies to explore their safety and efficacy are warranted.

Generation and Characterization of a SARS-CoV-2-Susceptible Mouse Model Using Adeno-Associated Virus (AAV6.2FF)-Mediated Respiratory Delivery of the Human ACE2 Gene.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the aetiological agent of coronavirus disease 2019 (COVID-19) that has caused a pandemic with millions of human infections. There continues to be a pressing need to develop potential therapies and vaccines to inhibit SARS-CoV-2 infection to mitigate the ongoing pandemic. Epidemiological data from the current pandemic indicates that there may be sex-dependent differences in disease outcomes. To investigate these differences, we proposed to use common small animal species that are frequently used to model disease with viruses. However, common laboratory strains of mice are not readily infected by SARS-CoV-2 because of differences in the angiotensin-converting enzyme 2 (ACE2), the cellular receptor for the virus. To overcome this limitation, we transduced common laboratory accessible strains of mice of different sexes and age groups with a novel a triple AAV6 mutant, termed AAV6.2FF, encoding either human ACE2 or luciferase via intranasal administration to promote expression in the lung and nasal turbinates. Infection of AAV-hACE2-transduced mice with SARS-CoV-2 resulted in high viral titers in the lungs and nasal turbinates, establishment of an IgM and IgG antibody response, and modulation of lung and nasal turbinate cytokine profiles. There were insignificant differences in infection characteristics between age groups and sex-related differences; however, there were significant strain-related differences between BALB/c vs. C57BL/6 mice. We show that AAV-hACE2-transduced mice are a useful for determining immune responses and for potential evaluation of SARS-CoV-2 vaccines and antiviral therapies, and this study serves as a model for the utility of this approach to rapidly develop small-animal models for emerging viruses.

Universal admission laboratory screening for severe acute respiratory coronavirus virus 2 (SARS-CoV-2) asymptomatic infection across a large health system.

BACKGROUND: Admission laboratory screening for asymptomatic coronavirus disease 2019 (COVID-19) has been utilized to mitigate healthcare-associated severe acute respiratory coronavirus virus 2 (SARS-CoV-2) transmission. An understanding of the impact of such testing across a variety of patient populations is needed. METHODS: SARS-CoV-2 nucleic acid amplification admission testing results for all asymptomatic patients across 4 distinct inpatient facilities between April 20, 2020, and June 14, 2021, were analyzed. Positivity rates and the number needed to test (NNT) to identify 1 asymptomatic infected patient were calculated. Admission results were compared to COVID-19 community incidence rates for the system's surrounding metropolitan service area. Using a national survey of hospital epidemiologists, a clinically meaningful NNT of 1:100 was identified. RESULTS: In total, 51,187 tests were collected (positivity rate, 1.8%). During periods of high transmission, the NNT met the clinically relevant threshold in all populations. The NNT approached or met the threshold for most locations during periods of lower transmission. For all transmission levels, the NNT for fully vaccinated patients did not meet the threshold. CONCLUSIONS: Implementing an asymptomatic patient admission testing program can provide clinically relevant data based on the NNT, even during periods of lower transmission and among different patient populations. Limiting admission testing to non-fully vaccinated patients during periods of lower transmission may be a strategy to address resource concerns around this practice. Although the impact of such testing on healthcare-associated COVID-19 among patients and healthcare workers could not be clearly determined, these data provide important information as facilities weigh the costs and benefits of such testing.

Age and Comorbidities Predict COVID-19 Outcome, Regardless of Innate Immune Response Severity: A Single Institutional Cohort Study

OBJECTIVES: The COVID-19 pandemic has claimed over eight hundred thousand lives in the United States alone, with older individuals and those with comorbidities being at higher risk of severe disease and death. Although severe acute respiratory syndrome coronavirus 2–induced hyperinflammation is one of the mechanisms underlying the high mortality, the association between age and innate immune responses in COVID-19 mortality remains unclear. DESIGN: Flow cytometry of fresh blood and multiplexed inflammatory chemokine measurements of sera were performed on samples collected longitudinally from our cohort. Aggregate impact of comorbid conditions was calculated with the Charlson Comorbidity Index, and association between patient factors and outcomes was calculated via Cox proportional hazard analysis and repeated measures analysis of variance. SETTING: A cohort of severely ill COVID-19 patients requiring ICU admission was followed prospectively. PATIENTS: In total, 67 patients (46 male, age 59 ± 14 yr) were included in the study. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Mortality in our cohort was 41.8%. We identified older age (hazard ratio [HR] 1.09 [95% CI 1.07–1.11];p = 0.001), higher comorbidity index (HR 1.24 [95% CI 1.14–1.35];p = 0.039), and hyponatremia (HR 0.90 [95% CI 0.82–0.99];p = 0.026) to each independently increase risk for death in COVID-19. We also found that neutrophilia (R = 0.2;p = 0.017), chemokine C-C motif ligand (CCL) 2 (R = 0.3;p = 0.043), and C-X-C motif chemokine ligand 9 (CXCL9) (R = 0.3;p = 0.050) were weakly but significantly correlated with mortality. Older age was associated with lower monocyte (R = –0.2;p = 0.006) and cluster of differentiation (CD) 16+ cell counts (R = –0.2;p = 0.002) and increased CCL11 concentration (R = 0.3;p = 0.050). Similarly, younger patients (< 65 yr) demonstrated a rise in CD4 (b-coefficient = 0.02;p = 0.036) and CD8 (0.01;p = 0.001) counts, as well as CCL20 (b-coefficient = 6.8;p = 0.036) during their ICU stay. This CD8 count rise was also associated with survival (b-coefficient = 0.01;p = 0.023). CONCLUSIONS: Age, comorbidities, and hyponatremia independently predict mortality in severe COVID-19. Neutrophilia and higher CCL2 and CXCL9 levels are also associated with higher mortality, while independent of age.

Relationship Between a State-Directed Lockdown on Non-COVID-19-related ICU Admissions and Mortality in a Multicenter Colorado Healthcare System.

Colorado issued a month long statewide lockdown on March 26, 2020, during the initial surge of the COVID-19 pandemic. The impact of this mandate on non-COVID-19 ICU admission rates and outcomes is unclear. DESIGN: We performed a retrospective analysis of all medical ICU admissions in the University of Colorado Health System in four predefined periods: 1) prepandemic (2 mo prior to lockdown period 1); 2) mandated lockdown from March 26 to April 26, 2020 (period 2); 3) between surges (period 3); and 4) nonmandated lockdown surge (between November 1, 2020, and March 31, 2021, period 4). SETTING: Nonsurgical ICU admissions at the University of Colorado Health Systems, including 10 hospitals throughout Colorado. SUBJECTS: All ICU admissions in four predefined time periods. MEASUREMENTS AND MAIN RESULTS: We included 13,787 patients who were admitted during the four study periods. The 28-day mortality rates for non-COVID-19 ICU admissions following index ICU admission were 13.6%, 18.0%, 13.5%, and 16.0% across periods 1-4, respectively. However, the increased odds in non-COVID-19 ICU mortality during the mandated lockdown period relative to prepandemic 1 (odds ratio [OR], 1.39; 95% CI, 1.11-1.72; p = 0.0.04) was attenuated and nonsignificant after adjustment for demographics, comorbidities, diagnosis flags, and severity (OR, 1.15; 95% CI, 0.89-1.48; p = 0.27). Similar results were found in time-to-event analyses. The most common diagnosis in each time period was acute respiratory failure (ARF), and we found it to have increased during lockdown (p < 0.001), whereas sepsis admissions increased during and decreased after lockdown (p = 0.004). Admissions for alcohol withdrawal syndrome (AWS) increased during lockdown and 6 months afterwards (p = 0.005). CONCLUSIONS: For non-COVID-19-related ICU admissions, mortality rate was similar before, during, and after Colorado's month long lockdown after confounder adjustment, including typical ICU admission flags. Primary admission diagnoses shifted throughout the predefined study periods with more admissions for severe critical diagnoses (i.e., ARF, sepsis, AWS) occurring during the mandated lockdown and nonmandated lockdown periods compared with the prepandemic and between surge period. This would suggest that the perceived increase in mortality during the lockdown for non-COVID-19 ICU admissions may be related to a shift inpatient demographics.

Divergent SARS-CoV-2 variant emerges in white-tailed deer with deer-to-human transmission.

Wildlife reservoirs of broad-host-range viruses have the potential to enable evolution of viral variants that can emerge to infect humans. In North America, there is phylogenomic evidence of continual transmission of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) from humans to white-tailed deer (Odocoileus virginianus) through unknown means, but no evidence of transmission from deer to humans. We carried out an observational surveillance study in Ontario, Canada during November and December 2021 (n = 300 deer) and identified a highly divergent lineage of SARS-CoV-2 in white-tailed deer (B.1.641). This lineage is one of the most divergent SARS-CoV-2 lineages identified so far, with 76 mutations (including 37 previously associated with non-human mammalian hosts). From a set of five complete and two partial deer-derived viral genomes we applied phylogenomic, recombination, selection and mutation spectrum analyses, which provided evidence for evolution and transmission in deer and a shared ancestry with mink-derived virus. Our analysis also revealed an epidemiologically linked human infection. Taken together, our findings provide evidence for sustained evolution of SARS-CoV-2 in white-tailed deer and of deer-to-human transmission.

SARS-CoV-2 viremia but not respiratory viral load is associated with ventilator complications (preprint)

COVID-19 can cause acute respiratory distress syndrome (ARDS) associated with high morbidity and mortality. Previous studies have shown an association between plasma viral load (VL) of severe acute respiratory distress (SARS-Cov2) and disease severity. This study is one of the first to measure endotracheal aspirate (ETA) VL in addition to plasma VL in patients admitted to the medical intensive care unit with COVID-19. Viral load from both plasma and ETA decreased over time. Subjects with high plasma VL experienced a greater number of adverse events, including ventilator-associated pneumonia (VAP), increased number of days on mechanical ventilation, and increased number of days in hospital. There was no association between ETA VL and adverse events.

Singleplex, multiplex and pooled sample real-time RT-PCR assays for detection of SARS-CoV-2 in an occupational medicine setting.

For workplaces which cannot operate as telework or remotely, there is a critical need for routine occupational SARS-CoV-2 diagnostic testing. Although diagnostic tests including the CDC 2019-Novel Coronavirus (2019-nCoV) Real-Time RT-PCR Diagnostic Panel (CDC Diagnostic Panel) (EUA200001) were made available early in the pandemic, resource scarcity and high demand for reagents and equipment necessitated priority of symptomatic patients. There is a clearly defined need for flexible testing methodologies and strategies with rapid turnaround of results for (1) symptomatic, (2) asymptomatic with high-risk exposures and (3) asymptomatic populations without preexisting conditions for routine screening to address the needs of an on-site work force. We developed a distinct SARS-CoV-2 diagnostic assay based on the original CDC Diagnostic Panel (EUA200001), yet, with minimum overlap for currently employed reagents to eliminate direct competition for limited resources. As the pandemic progressed with testing loads increasing, we modified the assay to include 5-sample pooling and amplicon target multiplexing. Analytical sensitivity of the pooled and multiplexed assays was rigorously tested with contrived positive samples in realistic patient backgrounds. Assay performance was determined with clinical samples previously assessed with an FDA authorized assay. Throughout the pandemic we successfully tested symptomatic, known contact and travelers within our occupational population with a ~ 24-48-h turnaround time to limit the spread of COVID-19 in the workplace. Our singleplex assay had a detection limit of 31.25 copies per reaction. The three-color multiplexed assay maintained similar sensitivity to the singleplex assay, while tripling the throughput. The pooling assay further increased the throughput to five-fold the singleplex assay, albeit with a subtle loss of sensitivity. We subsequently developed a hybrid 'multiplex-pooled' strategy to testing to address the need for both rapid analysis of samples from personnel at high risk of COVID infection and routine screening. Herein, our SARS-CoV-2 assays specifically address the needs of occupational healthcare for both rapid analysis of personnel at high-risk of infection and routine screening that is essential for controlling COVID-19 disease transmission. In addition to SARS-CoV-2 and COVID-19, this work demonstrates successful flexible assays developments and deployments with implications for emerging highly transmissible diseases and future pandemics.

A humanized nanobody phage display library yields potent binders of SARS CoV-2 spike.

Neutralizing antibodies targeting the SARS-CoV-2 spike protein have shown a great preventative/therapeutic potential. Here, we report a rapid and efficient strategy for the development and design of SARS-CoV-2 neutralizing humanized nanobody constructs with sub-nanomolar affinities and nanomolar potencies. CryoEM-based structural analysis of the nanobodies in complex with spike revealed two distinct binding modes. The most potent nanobody, RBD-1-2G(NCATS-BL8125), tolerates the N501Y RBD mutation and remains capable of neutralizing the B.1.1.7 (Alpha) variant. Molecular dynamics simulations provide a structural basis for understanding the neutralization process of nanobodies exclusively focused on the spike-ACE2 interface with and without the N501Y mutation on RBD. A primary human airway air-lung interface (ALI) ex vivo model showed that RBD-1-2G-Fc antibody treatment was effective at reducing viral burden following WA1 and B.1.1.7 SARS-CoV-2 infections. Therefore, this presented strategy will serve as a tool to mitigate the threat of emerging SARS-CoV-2 variants.

Differential chromatin accessibility in peripheral blood mononuclear cells underlies COVID-19 disease severity prior to seroconversion.

SARS-CoV-2 infection triggers profound and variable immune responses in human hosts. Chromatin remodeling has been observed in individuals severely ill or convalescing with COVID-19, but chromatin remodeling early in disease prior to anti-spike protein IgG seroconversion has not been defined. We performed the Assay for Transposase-Accessible Chromatin using sequencing (ATAC-seq) and RNA-seq on peripheral blood mononuclear cells (PBMCs) from outpatients with mild or moderate symptom severity at different stages of clinical illness. Early in the disease course prior to IgG seroconversion, modifications in chromatin accessibility associated with mild or moderate symptoms were already robust and included severity-associated changes in accessibility of genes in interleukin signaling, regulation of cell differentiation and cell morphology. Furthermore, single-cell analyses revealed evolution of the chromatin accessibility landscape and transcription factor motif accessibility for individual PBMC cell types over time. The most extensive remodeling occurred in CD14+ monocytes, where sub-populations with distinct chromatin accessibility profiles were observed prior to seroconversion. Mild symptom severity was marked by upregulation of classical antiviral pathways, including those regulating IRF1 and IRF7, whereas in moderate disease, these classical antiviral signals diminished, suggesting dysregulated and less effective responses. Together, these observations offer novel insight into the epigenome of early mild SARS-CoV-2 infection and suggest that detection of chromatin remodeling in early disease may offer promise for a new class of diagnostic tools for COVID-19.

High risk and low prevalence diseases: Acute chest syndrome in sickle cell disease.

INTRODUCTION: Acute chest syndrome (ACS) in sickle cell disease (SCD) is a serious condition that carries with it a high rate of morbidity and mortality. OBJECTIVE: This review highlights the pearls and pitfalls of ACS in SCD, including diagnosis and management in the emergency department (ED) based on current evidence. DISCUSSION: ACS is defined by respiratory symptoms and/or fever and a new radiodensity on chest imaging in a patient with SCD. There are a variety of inciting causes, including infectious and non-infectious etiologies. Although ACS is more common in those with homozygous SCD, clinicians should consider ACS in all SCD patients, as ACS is a leading cause of death in SCD. Patients typically present with or develop respiratory symptoms including fever, cough, chest pain, and shortness of breath, which can progress to respiratory failure requiring mechanical ventilation in 20% of adult patients. However, the initial presentation can vary. While the first line imaging modality is classically chest radiograph, lung ultrasound has demonstrated promise. Further imaging to include computed tomography may be necessary. Management focuses on analgesia, oxygen supplementation, incentive spirometry, bronchodilators, rehydration, antibiotics, consideration for transfusion, and specialist consultation. Empiric antibiotics that cover atypical pathogens are necessary along with measures to increase oxygen-carrying capacity in those with hypoxemia such as simple transfusion or exchange transfusion. CONCLUSIONS: An understanding of ACS can assist emergency clinicians in diagnosing and managing this potentially deadly disease.

Effects of a pharmacy-driven medication history program on patient outcomes.

PURPOSE: Obtaining an accurate medication history is a vital component of medication reconciliation upon admission to the hospital. Despite the importance of this task, medication histories are often inaccurate and/or incomplete. We evaluated the association of a pharmacy-driven medication history initiative on clinical outcomes of patients admitted to the general medicine service of an academic medical center. METHODS: Comparing patients who received a pharmacy-driven medication history to those who did not, a retrospective stabilized inverse probability treatment weighting propensity score analysis was used to estimate the average treatment effect of the intervention on general medical patients. Fifty-two patient baseline characteristics including demographic, operational, and clinical variables were controlled in the propensity score model. Hospital length of stay, 7-day and 30-day unplanned readmissions, and in-hospital mortality were evaluated. RESULTS: Among 11,576 eligible general medical patients, 2,234 (19.30%) received a pharmacy-driven medication history and 9,342 (80.70%) patients did not. The estimated average treatment effect of receiving a pharmacy-driven medication history was a shorter length of stay (mean, 5.88 days vs 6.53 days; P = 0.0002) and a lower in-hospital mortality rate (2.34% vs 3.72%, P = 0.001), after adjustment for differences in patient baseline characteristics. No significant difference was found for 7-day or 30-day all-cause readmission rates. CONCLUSION: Pharmacy-driven medication histories reduced length of stay and in-hospital mortality in patients admitted to the general medical service at an academic medical center but did not change 7-day and 30-day all-cause readmission rates. Further research via a large, multisite randomized controlled trial is needed to confirm our findings.

The Expert Next Door: Interactions With Friends and Family During the COVID-19 Pandemic.

The coronavirus disease 2019 (COVID-19) pandemic thrust the field of public health into the spotlight. For many epidemiologists, biostatisticians, and other public health professionals, this caused the professional aspects of our lives to collide with the personal, as friends and family reached out with concerns and questions. Learning how to navigate this space was new for many of us and required refining our communication style depending on context, setting, and audience. Some of us took to social media, utilizing our existing personal accounts to share information after sorting through and summarizing the rapidly emerging literature to keep loved ones safe. However, those in our lives sometimes asked unanswerable questions, or began distancing themselves when we suggested more stringent guidance than they had hoped for, causing additional stress during an already traumatic time. We often had to remind ourselves that we were also individuals experiencing this pandemic and that our time-intensive efforts were meaningful, relevant, and impactful. As this pandemic and other public health crises continue, we encourage members of our discipline to consider how we can best use shared lessons from this period and to recognize that our professional knowledge, when used in our personal lives, can promote, protect, and bolster confidence in public health.

Combining Heparin and a FX/Xa Aptamer to Reduce Thrombin Generation in Cardiopulmonary Bypass and COVID-19.

Known limitations of unfractionated heparin (UFH) have encouraged the evaluation of anticoagulant aptamers as alternatives to UFH in highly procoagulant settings such as cardiopulmonary bypass (CPB). Despite progress, these efforts have not been totally successful. We take a different approach and explore whether properties of an anticoagulant aptamer can complement UFH, rather than replace it, to address shortcomings with UFH use. Combining RNA aptamer 11F7t, which targets factor X/Xa, with UFH (or low molecular weight heparin) yields a significantly enhanced anticoagulant cocktail effective in normal and COVID-19 patient blood. This aptamer-UFH combination (1) supports continuous circulation of human blood through an ex vivo membrane oxygenation circuit, as is required for patients undergoing CPB and COVID-19 patients requiring extracorporeal membrane oxygenation, (2) allows for a reduced level of UFH to be employed, (3) more effectively limits thrombin generation compared to UFH alone, and (4) is rapidly reversed by the administration of protamine sulfate, the standard treatment for reversing UFH clinically following CPB. Thus, the combination of factor X/Xa aptamer and UFH has significantly improved anticoagulant properties compared to UFH alone and underscores the potential of RNA aptamers to improve medical management of acute care patients requiring potent yet rapidly reversible anticoagulation.

Differential chromatin accessibility in peripheral blood mononuclear cells underlies COVID-19 disease severity prior to seroconversion (preprint)

SARS-CoV-2 infection triggers profound and variable immune responses in human hosts. Chromatin remodeling has been observed in individuals severely ill or convalescing with COVID-19, but chromatin remodeling early in disease prior to anti-spike protein IgG seroconversion has not been defined. We performed the Assay for Transposase-Accessible Chromatin using sequencing (ATAC-seq) and RNA-seq on peripheral blood mononuclear cells (PBMCs) from outpatients with mild or moderate symptom severity at different stages of clinical illness. Early in the disease course prior to IgG seroconversion, modifications in chromatin accessibility associate with mild or moderate symptoms are already robust and include severity-associated changes in accessibility of genes in interleukin signaling, regulation of cell differentiation and cell morphology. Furthermore, single-cell analyses revealed evolution of the chromatin accessibility landscape and transcription factor motif accessibility for individual PBMC cell types over time. The most extensive remodeling occurred in CD14+ monocytes, where sub-populations with distinct chromatin accessibility profiles were observed prior to seroconversion. Mild symptom severity is marked by upregulation classical antiviral pathways including those regulating IRF1 and IRF7, whereas in moderate disease these classical antiviral signals diminish suggesting dysregulated and less effective responses. Together, these observations offer novel insight into the epigenome of early mild SARS-CoV-2 infection and suggest that detection of chromatin remodeling in early disease may offer promise for a new class of diagnostic tools for COVID-19. 

New York City jails: COVID discharge policy, data transparency, and reform.

During the early stages of the COVID-19 pandemic in 2020, Mayor Bill de Blasio ordered the release of individuals incarcerated in New York City jails who were at high risk of contracting the disease and at low risk of committing criminal reoffense. Using public information, we construct and analyze a database of nearly 350,000 incarceration episodes in the city jail system from 2014-2020, paying special attention to what happened during the week of March 23-29, 2020, immediately following the mayor's order. In concordance with de Blasio's stated policy, we find that being discharged during this focus week is associated with a lower probability of readmission as compared to being discharged during the same calendar week in previous years. Furthermore, comparing the individuals discharged during the focus week of 2020 to those discharged during the same calendar week in previous years, we find that the former group was, on average, slightly older than the latter group, although the difference is not large. Additionally, the individuals in the former group had spent substantially longer in jail than those in the latter group. With the release of long-serving individuals demonstrated to be feasible, we also examine how the jail population would have looked over the past six years had caps in incarceration been in place. With a cap of one year, the system would experience a 15% decrease in incarceration. With a cap of 100 days, the reduction would be over 50%. Because our results are only as accurate as New York City's public-facing jail data, we discuss numerous challenges with this data and suggest improvements related to the incarcerated individual's age, gender, race, and more. Finally, we discuss the policy implications of our work, highlight some opportunities and challenges posed by incarceration caps, and suggest key areas for reform. One such reform might involve identifying and discharging low-risk individuals sooner in general, which might be feasible given the de Blasio administration's actions during the early stages of COVID-19.