Acute respiratory distress syndrome (ARDS) in COVID‐19 is associated with high mortality. Mesenchymal stem cells are known to exert immunomodulatory and anti‐inflammatory effects and could yield beneficial effects in COVID‐19 ARDS. The objective of this study was to determine safety and explore efficacy of umbilical cord mesenchymal stem cell (UC‐MSC) infusions in subjects with COVID‐19 ARDS. A double‐blind, phase 1/2a, randomized, controlled trial was performed. Randomization and stratification by ARDS severity was used to foster balance among groups. All subjects were analyzed under intention to treat design. Twenty‐four subjects were randomized 1:1 to either UC‐MSC treatment (n = 12) or the control group (n = 12). Subjects in the UC‐MSC treatment group received two intravenous infusions (at day 0 and 3) of 100 ± 20 × 106 UC‐MSCs; controls received two infusions of vehicle solution. Both groups received best standard of care. Primary endpoint was safety (adverse events [AEs]) within 6 hours; cardiac arrest or death within 24 hours postinfusion). Secondary endpoints included patient survival at 31 days after the first infusion and time to recovery. No difference was observed between groups in infusion‐associated AEs. No serious adverse events (SAEs) were observed related to UC‐MSC infusions. UC‐MSC infusions in COVID‐19 ARDS were found to be safe. Inflammatory cytokines were significantly decreased in UC‐MSC‐treated subjects at day 6. Treatment was associated with significantly improved patient survival (91% vs 42%, P = .015), SAE‐free survival (P = .008), and time to recovery (P = .03). UC‐MSC infusions are safe and could be beneficial in treating subjects with COVID‐19 ARDS.

The immune system exerts antitumor activity via T cell-dependent recognition of tumor-specific antigens. Although the number of tumor neopeptides-peptides derived from somatic mutations-often correlates with immune activity and survival, most classically defined high-affinity neopeptides (CDNs) are not immunogenic, and only rare CDNs have been linked to tumor rejection. Thus, the rules of tumor antigen recognition remain incompletely understood. Here, we analyzed neopeptides, immune activity, and clinical outcome from 6,324 patients across 27 tumor types. We characterized a class of "alternatively defined neopeptides" (ADNs), which are mutant peptides predicted to bind MHC (class I or II) with improved affinity relative to their nonmutated counterpart. ADNs are abundant and molecularly distinct from CDNs. The load of ADNs correlated with intratumoral T-cell responses and immune suppression, and ADNs were also strong predictors of patient survival across tumor types. These results expand the spectrum of mutation-derived tumor antigens with potential clinical relevance.

Standardized protocols for wastewater-based surveillance (WBS) for the RNA of SARS-CoV-2, the virus responsible for the current COVID-19 pandemic, are being developed and refined worldwide for early detection of disease outbreaks. We report here on lessons learned from establishing a WBS program for SARS-CoV-2 integrated with a human surveillance program for COVID-19. We have established WBS at three campuses of a university, including student residential dormitories and a hospital that treats COVID-19 patients. Lessons learned from this WBS program address the variability of water quality, new detection technologies, the range of detectable viral loads in wastewater, and the predictive value of integrating environmental and human surveillance data. Data from our WBS program indicated that water quality was statistically different between sewer sampling sites, with more variability observed in wastewater coming from individual buildings compared to clusters of buildings. A new detection technology was developed based upon the use of a novel polymerase called V2G. Detectable levels of SARS-CoV-2 in wastewater varied from 10 2 to 10 6 genomic copies (gc) per liter of raw wastewater (L). Integration of environmental and human surveillance data indicate that WBS detection of 100 gc/L of SARS-CoV-2 RNA in wastewater was associated with a positivity rate of 4% as detected by human surveillance in the wastewater catchment area, though confidence intervals were wide (β ~ 8.99 ∗ ln(100); 95% CI = 0.90–17.08; p < 0.05). Our data also suggest that early detection of COVID-19 surges based on correlations between viral load in wastewater and human disease incidence could benefit by increasing the wastewater sample collection frequency from weekly to daily. Coupling simpler and faster detection technology with more frequent sampling has the potential to improve the predictive potential of using WBS of SARS-CoV-2 for early detection of the onset of COVID-19.

Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) in wastewater has been used to track community infections of coronavirus disease-2019 (COVID-19), providing critical information for public health interventions. Since levels in wastewater are dependent upon human inputs, we hypothesize that tracking infections can be improved by normalizing wastewater concentrations against indicators of human waste [Pepper Mild Mottle Virus (PMMoV), β-2 Microglobulin (B2M), and fecal coliform]. In this study, we analyzed SARS-CoV-2 and indicators of human waste in wastewater from two sewersheds of different scales: a University campus and a wastewater treatment plant. Wastewater data were combined with complementary COVID-19 case tracking to evaluate the efficiency of wastewater surveillance for forecasting new COVID-19 cases and, for the larger scale, hospitalizations. Results show that the normalization of SARS-CoV-2 levels by PMMoV and B2M resulted in improved correlations with COVID-19 cases for campus data using volcano second generation (V2G)-qPCR chemistry (r s = 0.69 without normalization, r s = 0.73 with normalization). Mixed results were obtained for normalization by PMMoV for samples collected at the community scale. Overall benefits from normalizing with measures of human waste depend upon qPCR chemistry and improves with smaller sewershed scale. We recommend further studies that evaluate the efficacy of additional normalization targets.

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