Interferon signaling in the nasal epithelium distinguishes among lethal and common cold respiratory viruses and is critical for viral clearance (preprint)

All respiratory viruses establish primary infections in the nasal epithelium, where efficient innate immune induction may prevent dissemination to the lower airway and thus minimize pathogenesis. Human coronaviruses (HCoVs) cause a range of pathologies, but the host and viral determinants of disease during common cold versus lethal HCoV infections are poorly understood. We model the initial site of infection using primary nasal epithelial cells cultured at air-liquid interface (ALI). HCoV-229E, HCoV-NL63 and human rhinovirus-16 are common cold-associated viruses that exhibit unique features in this model: early induction of antiviral interferon (IFN) signaling, IFN-mediated viral clearance, and preferential replication at nasal airway temperature (33C) which confers muted host IFN responses. In contrast, lethal SARS-CoV-2 and MERS-CoV encode antagonist proteins that prevent IFN-mediated clearance in nasal cultures. Our study identifies features shared among common cold-associated viruses, highlighting nasal innate immune responses as predictive of infection outcomes and nasally-directed IFNs as potential therapeutics.

SARS-CoV-2 nsp15 endoribonuclease antagonizes dsRNA-induced antiviral signaling (preprint)

Severe acute respiratory syndrome coronavirus (SARS-CoV)-2 has caused millions of deaths since emerging in 2019. Innate immune antagonism by lethal CoVs such as SARS-CoV-2 is crucial for optimal replication and pathogenesis. The conserved nonstructural protein 15 (nsp15) endoribonuclease (EndoU) limits activation of double-stranded (ds)RNA-induced pathways, including interferon (IFN) signaling, protein kinase R (PKR), and oligoadenylate synthetase/ribonuclease L (OAS/RNase L) during diverse CoV infections including murine coronavirus and Middle East respiratory syndrome (MERS)-CoV. To determine how nsp15 functions during SARS-CoV-2 infection, we constructed a mutant recombinant SARS-CoV-2 (nsp15mut) expressing a catalytically inactive nsp15. Infection with SARS-CoV-2 nsp15 mut led to increased activation of the IFN signaling and PKR pathways in lung-derived epithelial cell lines and primary nasal epithelial air-liquid interface (ALI) cultures as well as significant attenuation of replication in ALI cultures compared to wild-type (WT) virus. This replication defect was rescued when IFN signaling was inhibited with the Janus activated kinase (JAK) inhibitor ruxolitinib. Finally, to assess nsp15 function in the context of minimal (MERS-CoV) or moderate (SARS-CoV-2) innate immune induction, we compared infections with SARS-CoV-2 nsp15mut and previously described MERS-CoV nsp15 mutants. Inactivation of nsp15 had a more dramatic impact on MERS-CoV replication than SARS-CoV-2 in both Calu3 cells and nasal ALI cultures suggesting that SARS-CoV-2 can better tolerate innate immune responses. Taken together, SARS-CoV-2 nsp15 is a potent inhibitor of dsRNA-induced innate immune response and its antagonism of IFN signaling is necessary for optimal viral replication in primary nasal ALI culture. SIGNIFICANCESevere acute respiratory syndrome coronavirus (SARS-CoV)-2 causes a spectrum of respiratory disease ranging from asymptomatic infections to severe pneumonia and death. Innate immune responses during SARS-CoV-2 infection have been associated with clinical disease severity, with robust early interferon responses in the nasal epithelium reported to be protective. Thus, elucidating mechanisms through which SARS-CoV-2 induces and antagonizes host innate immune responses is crucial to understanding viral pathogenesis. CoVs encode various innate immune antagonists, including the conserved nonstructural protein 15 (nsp15) which contains an endoribonuclease (EndoU) domain. We demonstrate that SARS-CoV-2 EndoU is a crucial interferon antagonist, by providing further evidence for the role of the conserved CoV nsp15 in antagonizing innate immune activation, thereby optimizing CoV replication.

Infection of primary nasal epithelial cells differentiates among lethal and seasonal human coronaviruses.

The nasal epithelium is the initial entry portal and primary barrier to infection by all human coronaviruses (HCoVs). We utilize primary human nasal epithelial cells grown at air-liquid interface, which recapitulate the heterogeneous cellular population as well as mucociliary clearance functions of the in vivo nasal epithelium, to compare lethal [Severe acute respiratory syndrome (SARS)-CoV-2 and Middle East respiratory syndrome-CoV (MERS-CoV)] and seasonal (HCoV-NL63 and HCoV-229E) HCoVs. All four HCoVs replicate productively in nasal cultures, though replication is differentially modulated by temperature. Infections conducted at 33 °C vs. 37 °C (reflective of temperatures in the upper and lower airway, respectively) revealed that replication of both seasonal HCoVs (HCoV-NL63 and -229E) is significantly attenuated at 37 °C. In contrast, SARS-CoV-2 and MERS-CoV replicate at both temperatures, though SARS-CoV-2 replication is enhanced at 33 °C late in infection. These HCoVs also diverge significantly in terms of cytotoxicity induced following infection, as the seasonal HCoVs as well as SARS-CoV-2 cause cellular cytotoxicity as well as epithelial barrier disruption, while MERS-CoV does not. Treatment of nasal cultures with type 2 cytokine IL-13 to mimic asthmatic airways differentially impacts HCoV receptor availability as well as replication. MERS-CoV receptor DPP4 expression increases with IL-13 treatment, whereas ACE2, the receptor used by SARS-CoV-2 and HCoV-NL63, is down-regulated. IL-13 treatment enhances MERS-CoV and HCoV-229E replication but reduces that of SARS-CoV-2 and HCoV-NL63, reflecting the impact of IL-13 on HCoV receptor availability. This study highlights diversity among HCoVs during infection of the nasal epithelium, which is likely to influence downstream infection outcomes such as disease severity and transmissibility.

Severe Increase in Nursing Labor Cost and Effect on Surgical Department Financial Margins at an Academic, Tertiary Medical Center.

BACKGROUND: A pre-existing nationwide nursing shortage drastically worsened during the pandemic, causing a significant increase in nursing labor costs. We examined the financial impact of these changes on department of surgery financial margins. STUDY DESIGN: Operating room, inpatient, and outpatient financial metrics were analyzed. Monthly averages from a 14-month control cohort, January 2019 to February 2020 (pre-COVID-19), were compared with a 21-month cohort, March 2020 to November 2021 (COVID-19). True revenue and cost data from hospital accounting records, not estimates or administrative projections, were analyzed. Statistics were performed with standard Student's t -test and the Anderson-Darling normality test. RESULTS: Monthly surgical nursing costs increased significantly, with concomitant significant decreases in departmental contribution to margin. No significant change was observed in case volume per month, length of stay per case, or surgical acuity, as standardized by the US Centers for Medicare & Medicaid Services Case Mix Index. To obviate insurance payor mix as a variable and standardize cost data, surgical nursing expense per relative value unit was analyzed, demonstrating a significant increase. Hospital-wide agency nursing costs increased from $5.1 to $13.5 million per month (+165%) in 2021. CONCLUSIONS: Our results demonstrate a significant increase in surgical nursing labor costs with a resultant erosion of department of surgery financial margins. Use of real-time accounting data instead of commonly touted administrative approximations or Medicare projections increases both the accuracy and generalizability of the data. The long-term impact of both direct costs from supply chain interruption and indirect costs, such as limited operating room and ICU access, will require further study. Clearly this ominous trend is not viable, and fiscal recovery will require sustained, strategic workforce allocation.

Associations Among Postpartum Posttraumatic Stress Disorder Symptoms and COVID-19 Pandemic-Related Stressors.

INTRODUCTION: Coronavirus disease 2019 (COVID-19) pandemic-related stressors (eg, exposure, infection worry, self-quarantining) can result in heightened levels of distress and symptoms of postpartum posttraumatic stress disorder (PTSD). METHODS: Using a cross-sectional descriptive design, we collected survey data from a convenience sample of 670 postpartum persons who gave birth to a newborn during the first 6 months of the COVID-19 pandemic in the United States. The presence of PTSD symptoms was measured using the 21-item Birth Memories And Recall Questionnaire (BirthMARQ) and defined as an affirmative rating for each item (score of 5 to 7 on a 1 to 7 agreement scale). Symptoms counts were computed for each of the 6 BirthMARQ domains, 2 symptom clusters (intrusive; mood and cognition alterations), and the total number of symptoms. Symptom counts were analyzed using descriptive statistics. We explored associations among COVID-19 experiences (self-quarantine behaviors, infection worry, exposure) and counts of PTSD symptoms using negative binomial regression models while controlling for postpartum depression screening scores, neonatal intensive care unit admissions, number of weeks postpartum, race, and marital status. RESULTS: Almost 99% of participants reported experiencing at least one of 21 PTSD symptoms (mean, 8.32; SD, 3.63). Exposure to COVID-19 was associated with a 34% greater risk for experiencing intrusive symptoms, specifically, symptoms of reliving the birthing experience as if it were happening now (47% greater risk). Worry surrounding COVID-19 infection was associated with a 26% increased risk for experiencing intrusive recall symptoms in which birth memories came up unexpectantly. COVID-19 quarantining behaviors were not significantly related to increasing PTSD symptoms. Many of the demographic variables included were associated with increasing PTSD symptoms. DISCUSSION: Screening perinatal persons for PTSD is critically important, especially during public health crises like the COVID-19 pandemic. The integration of comprehensive mental health screening, including specific screening for trauma and symptoms of PTSD, across health care settings can help improve delivery of quality, patient-centered care to postpartum persons.

Advancing rapid adaptation for urgent public health crises: Using implementation science to facilitate effective and efficient responses.

Responding rapidly to emerging public health crises is vital to reducing their escalation, spread, and impact on population health. These responses, however, are challenging and disparate processes for researchers and practitioners. Researchers often develop new interventions that take significant time and resources, with little exportability. In contrast, community-serving systems are often poorly equipped to properly adopt new interventions or adapt existing ones in a data-driven way during crises' onset and escalation. This results in significant delays in deploying evidence-based interventions (EBIs) with notable public health consequences. This prolonged timeline for EBI development and implementation results in significant morbidity and mortality that is costly and preventable. As public health emergencies have demonstrated (e.g., COVID-19 pandemic), the negative consequences often exacerbate existing health disparities. Implementation science has the potential to bridge the extant gap between research and practice, and enhance equity in rapid public health responses, but is underutilized. For the field to have a greater "real-world" impact, it needs to be more rapid, iterative, participatory, and work within the timeframes of community-serving systems. This paper focuses on rapid adaptation as a developing implementation science area to facilitate system responses during public health crises. We highlight frameworks to guide rapid adaptation for optimizing existing EBIs when responding to urgent public health issues. We also explore the economic implications of rapid adaptation. Resource limitations are frequently a central reason for implementation failure; thus, we consider the economic impacts of rapid adaptation. Finally, we provide examples and propose directions for future research and application.

Drastic increase in hospital labor costs led to a sustained financial loss for an academic vascular surgery division during the coronavirus disease 2019 pandemic.

OBJECTIVE: The financial effects of the coronavirus disease 2019 (COVID-19) pandemic have fundamentally changed the healthcare environment, with hospitals expected to have lost billions in 2021. A preexisting nationwide nursing shortage became drastically worse during the pandemic amid dramatically increasing labor costs. We examined the evolution and financial effects of these changes during repeated pandemic surges within a vascular surgery division at a tertiary medical center. METHODS: Operating room, inpatient unit, and outpatient clinic financial data were examined retrospectively. The monthly averages for a 14-month control cohort before COVID-19 (January 2019 to February 2020) were compared to the averages for seven interval groups of sequential, 3-month cohorts from March 2020 through November 2021 (groups 1-7). RESULTS: The monthly relative value unit (RVU) generation had returned to the mean before the COVID-19 pandemic (2520 RVUs) after an isolated decrease early in the pandemic (group 1; 1734 RVUs). The RVUs ranged from 2540 to 2863 per month for groups 2 to 5, with a slight decline in groups 6 and 7. The average monthly RVUs in the COVID-19 period (2437 RVUs) were nearly equivalent (P = .93) to those for the pre-COVID-19 cohort. An analysis of payor mix demonstrated an increase in commercial and Medicaid payors, with a respective decrease in Medicare payors, during COVID-19. The contribution to indirect, or profit, from inpatient hospital and outpatient clinical revenue showed a drastic decrease in group 1, followed by a swift rebound when the government restrictions were eased (group 2). The total monthly vascular nursing unit expense demonstrated a marked increase with each sequential group during COVID-19, with an average monthly upsurge of +$82,171 (+47%; P < .001). An increase in the nursing labor expenses of +$884 per vascular case (from $1630 to $2514; +54%; P < .001) was observed in the COVID-19 era. The nursing labor costs per patient day had increased from $580 to $852 (+$272; +53%; P < .001). The nursing labor cost per RVU had increased from $69.5 to $107.7 (+$38.2; +55%; P < .001). On a system-wide level, the agency-related nursing costs had increased from $4.9 million to $13.6 million per month (+178%; P < .001) in 2021 compared with 2020. CONCLUSIONS: The COVID-19 pandemic has had severe, nationwide effects on healthcare delivery, exacerbating the deleterious effects of an existing, critical nursing shortage. To the best of our knowledge, the present study is the first detailed analysis of this phenomenon and its effects on a surgical division. Our results have demonstrated a progressive, drastic increase in nursing labor costs during the pandemic, with a resultant sustained erosion of financial margins despite a level of clinical productivity, as measured in RVUs, equal to the prepandemic standards. This precarious trend is not sustainable and will require increased, targeted government funding.

An effective volunteer community-based COVID-19 response program: the Vashon, WA Medical Reserve Corp experience (preprint)

BackgroundVashon, WA is a rural community at risk from COVID-19 due to advanced age and limited access to acute care. Medical Reserve Corps are a national network of 800 volunteer healthcare organizations that have contributed to the pandemic response in many communities. Here we evaluate the effectiveness of the Vashon Medical Reserve Corps (VMRC) volunteer, community-based COVID-19 response program that integrated public engagement, SARS-CoV2 testing, contact tracing, vaccination and material support in reducing COVID-19 transmission and severe disease. MethodsThis observational cross-sectional study compares cumulative COVID-19 case, hospitalization and death rates on Vashon with other King County zip codes and the county at large from February 2020 through November 2021. We developed multiple linear regression models of COVID-19 rates using metrics of age, race/ethnicity, wealth and educational attainment across King County zip codes. Effectiveness of contact tracing was evaluated by timeliness and success of case investigations, and identification and testing of named contacts. Vaccination effectiveness was estimated by comparing time to reach vaccination milestones. We examined vehicle traffic on Vashon ferries and King County highways to understand whether reduced mobility contributed to Vashons reduced COVID-19 rates. ResultsVashons cumulative COVID-19 case rate was 29% that of King County overall and was lower across all age groups and races/ethnicities (both p<.01). A multiple linear regression model showed Vashon to be a significant outlier among King County zip codes with an observed rate 38% of predicted (p<.05), the lowest of any King County zip code. Vashons observed COVID-19 hospitalization and death rates were 22% and 32% of those predicted by parallel regression models. Hence, Vashons demographics do not explain its reduced COVID rates. Traffic reductions on King County highways and Vashon ferries were nearly identical throughout the study period suggesting altered mobility also does not explain Vashons low COVID-19 rates. Effectiveness of VMRCs COVID-19 response program was demonstrated by 1) highly effective contact tracing that rapidly interviewed 93% of cases and subsequently tested 96% of named contacts, and 2) attainment of vaccination milestones 1-4 months earlier than comparable King County zip codes (p<.01). ConclusionVMRCs volunteer, COVID-19 response program was associated with significantly fewer COVID-19 cases than predicted from its demographics. VMRCs contact tracing and vaccination efforts were highly successful and likely contributed to reduced COVID-19 rates. The VMRC experience suggests that a decentralized community-based public health program can be highly effective in implementing epidemic control strategies when focused on an at-risk community. We suggest that MRCs can be particularly effective in extending the reach of county public health departments and should be included in ongoing pandemic planning.

MERS-CoV endoribonuclease and accessory proteins jointly evade host innate immunity during infection of lung and nasal epithelial cells.

Middle East respiratory syndrome coronavirus (MERS-CoV) emerged into humans in 2012, causing highly lethal respiratory disease. The severity of disease may be, in part, because MERS-CoV is adept at antagonizing early innate immune pathways­interferon (IFN) production and signaling, protein kinase R (PKR), and oligoadenylate synthetase/ribonuclease L (OAS/RNase L)­activated in response to viral double-stranded RNA (dsRNA) generated during genome replication. This is in contrast to severe acute respiratory syndrome CoV-2 (SARS-CoV-2), which we recently reported to activate PKR and RNase L and, to some extent, IFN signaling. We previously found that MERS-CoV accessory proteins NS4a (dsRNA binding protein) and NS4b (phosphodiesterase) could weakly suppress these pathways, but ablation of each had minimal effect on virus replication. Here we investigated the antagonist effects of the conserved coronavirus endoribonuclease (EndoU), in combination with NS4a or NS4b. Inactivation of EndoU catalytic activity alone in a recombinant MERS-CoV caused little if any effect on activation of the innate immune pathways during infection. However, infection with recombinant viruses containing combined mutations with inactivation of EndoU and deletion of NS4a or inactivation of the NS4b phosphodiesterase promoted robust activation of dsRNA-induced innate immune pathways. This resulted in at least tenfold attenuation of replication in human lung­derived A549 and primary nasal cells. Furthermore, replication of these recombinant viruses could be rescued to the level of wild-type MERS-CoV by knockout of host immune mediators MAVS, PKR, or RNase L. Thus, EndoU and accessory proteins NS4a and NS4b together suppress dsRNA-induced innate immunity during MERS-CoV infection in order to optimize viral replication.

Powder characterisation: A critical tool for the evolution of inhaled drug delivery

In this article, Jamie Clayton, Operations Director at Freeman Technology, and Joana Pinto, PhD, Senior Scientist, and Sarah Zellnitz, PhD, Senior Scientist, both of Research Center Pharmaceutical Engineering’s Area II – Advanced Products & Delivery section, discuss the benefits of multi-faceted powder characterisation in dry powder inhalation formulations and how it can support efforts to achieve net zero emissions.

Postpartum depression and associated risk factors during the COVID-19 pandemic.

OBJECTIVE: To describe postpartum depression and associated risk factors among postpartum patients in the United States (US) between February and July 2020. This study used a cross-sectional descriptive design to collect survey data from a convenience sample of postpartum patients who lived in the US and delivered a live infant after the US declared COVID-19 a public health emergency. RESULTS: Our sample included 670 postpartum patients who completed an online survey inclusive of the Edinburgh Postnatal Depression Scale (EPDS) and selected demographic items (e.g. NICU admission status, infant gestational age, infant feeding method). In our sample, 1 in 3 participants screened positive for postpartum depression and 1 in 5 had major depressive symptoms. Participants who fed their infants formula had 92% greater odds of screening positive for postpartum depression and were 73% more likely to screen positive for major depressive symptoms compared to those who breastfed or bottle-fed with their own human milk. Participants with infants admitted to a NICU had 74% greater odds of screening positive. Each 1 week increase in weeks postpartum increased the odds of screening positive by 4%. Participants who worried about themselves and their infants contracting COVID-19 had 71% greater odds of screening positive.

Management of hyperglycaemia in patients treated with dexamethasone for COVID-19

Background: The use of dexamethasone has resulted in lower mortality for patients receiving oxygen or invasive mechanical ventilation. It is a first-line treatment for coronavirus disease 209 (COVID-19). However, COVID-19 and dexamethasone both increase the risk of hyperglycaemia (shown to increase COVID-19 morbidity and mortality) and increase the risk of hyperglycaemic emergencies. Aim: To improve management of hyperglycaemia secondary to COVID-19 and dexamethasone use in patients with and without pre-existing diabetes by implementing the Concise Advice on Inpatient Diabetes guidelines at a tertiary centre. Methods: 111 patients from respiratory wards were included in a quality improvement project (QIP) over a period of 0 weeks. Outcome measures included frequency of blood glucose monitoring, appropriate ketone assessment and guideline-concordant management of hyperglycaemia. Plan-Do-Study-Act methodology was used, and interventions included posters, education of nursing staff and junior doctors, and discussion at the departmental meeting. Results: By the end of the QIP there was a 33% increase from baseline in individuals having 6-hourly capillary blood glucose monitoring in the first 48 hours. Management of hyperglycaemia also improved with a 40% increase from baseline in individuals receiving acute correction with insulin and a 2 % increase from baseline in individuals having regular insulin started or adjusted. Conclusion: Both COVID-19 and its treatment increase the risk of hyperglycaemia with consequent morbidity and mortality implications. This QIP improved hyperglycaemia management through guideline implementation. This shows that guideline compliance can enable better patient care. Further system-wide work is required for sustainability.

"Mourning the Experience of What Should Have Been": Experiences of Peripartum Women During the COVID-19 Pandemic.

OBJECTIVES: The ongoing COVID-19 pandemic may significantly affect the peripartum experience; however, little is known about the perceptions of women who gave birth during the COVID-19 pandemic. Thus, the purpose of our study was to describe the peripartum experiences of women who gave birth during the COVID-19 pandemic in the United States. METHODS: Using a cross-sectional design, we collected survey data from a convenience sample of postpartum women recruited through social media. Participants were 18 years of age or older, lived in the United States, gave birth after February 1, 2020, and could read English. This study was part of the COVID-19 Maternal Attachment, Mood, Ability, and Support study, which was a larger study that collected survey data describing maternal mental health and breastfeeding during the COVID-19 pandemic. This paper presents findings from the two free-text items describing peripartum experiences. Using the constant comparative method, responses were thematically analyzed to identify and collate major and minor themes. RESULTS: 371 participants responded to at least one free-text item. Five major themes emerged: (1) Heightened emotional distress; (2) Adverse breastfeeding experiences; (3) Unanticipated hospital policy changes shifted birthing plans; (4) Expectation vs. reality: "mourning what the experience should have been;" and (5) Surprising benefits of the COVID-19 pandemic to the delivery and postpartum experience. CONCLUSIONS FOR PRACTICE: Peripartum women are vulnerable to heightened stress induced by COVID-19 pandemic sequalae. During public health crises, peripartum women may need additional resources and support to improve their mental health, wellbeing, and breastfeeding experiences.

Parents' pandemic NICU experience in the United States: a qualitative study.

BACKGROUND: Prior to the COVID-19 pandemic, parents of infants in the Neonatal Intensive Care Unit (NICU) frequently reported high levels of stress, uncertainty, and decreased parenting confidence. Early research has demonstrated that parents have had less access to their infants in the hospital due to restrictions on parental presence secondary to the pandemic. It is unknown how parents have perceived their experiences in the NICU since the beginning of the COVID-19 pandemic. The purpose of this study was to describe the lived experience of parents who had an infant in the NICU in the context of the COVID-19 pandemic to inform healthcare providers and policy makers for future development of policies and care planning. METHODS: The study design was a qualitative description of the impact of the COVID-19 pandemic on parents' experiences of having an infant in the NICU. Free-text responses to open-ended questions were collected as part of a multi-method study of parents' experiences of the NICU during the first six months of the pandemic. Participants from the United States were recruited using social media platforms between the months of May and July of 2020. Data were analyzed using a reflexive thematic approach. FINDINGS: Free-text responses came from 169 parents from 38 different states in the United States. Three broad themes emerged from the analysis: (1) parents' NICU experiences during the COVID-19 pandemic were emotionally isolating and overwhelming, (2) policy changes restricting parental presence created disruptions to the family unit and limited family-centered care, and (3) interactions with NICU providers intensified or alleviated emotional distress felt by parents. A unifying theme of experiences of emotional distress attributed to COVID-19 circumstances ran through all three themes. CONCLUSIONS: Parents of infants in the NICU during the first six months of the COVID-19 pandemic experienced emotional struggles, feelings of isolation, lack of family-centered care, and deep disappointment with system-level decisions. Moving forward, parents need to be considered essential partners in the development of policies concerning care of and access to their infants.

Low-dose in vivo protection and neutralization across SARS-CoV-2 variants by monoclonal antibody combinations.

Prevention of viral escape and increased coverage against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants of concern require therapeutic monoclonal antibodies (mAbs) targeting multiple sites of vulnerability on the coronavirus spike glycoprotein. Here we identify several potent neutralizing antibodies directed against either the N-terminal domain (NTD) or the receptor-binding domain (RBD) of the spike protein. Administered in combinations, these mAbs provided low-dose protection against SARS-CoV-2 infection in the K18-human angiotensin-converting enzyme 2 mouse model, using both neutralization and Fc effector antibody functions. The RBD mAb WRAIR-2125, which targets residue F486 through a unique heavy-chain and light-chain pairing, demonstrated potent neutralizing activity against all major SARS-CoV-2 variants of concern. In combination with NTD and other RBD mAbs, WRAIR-2125 also prevented viral escape. These data demonstrate that NTD/RBD mAb combinations confer potent protection, likely leveraging complementary mechanisms of viral inactivation and clearance.

Resilient Real Estate

The editors of the special real estate issue introduce the articles contained in the issue and relate them to the concept of resiliency in real estate investments. COVID-19 had a major impact on returns to real estate. However, the resilience of property returns to COVID-19 varied significantly by location, by sector, and even across individual assets of the same property type in the same city. Resilient investments are those able to withstand the effect of not only acute disruptions in the market but also chronic longer-term threats. For real estate, these threats include pandemics, climate change, changing demographics, changes in tenant preferences, changes in technology, and even factors that are unknown and unpredictable at the moment but that may become important in the future. As some of these threats may not be insurable and may not be diversifiable, much of the work of risk management in creating resilient real estate portfolios will need to be at the property level. A number of approaches can be implemented to increase resilience at a property, but flexibility in building design may be among the most important.