The Effect of Language on Access to Timely COVID-19 Vaccination of Solid Abdominal Organ Transplant Recipients.

In dynamic healthcare environments including the COVID-19 pandemic, it is paramount to communicate health recommendations expediently and clearly. Research has shown social determinants of health affect the impact of COVID-19 on abdominal transplant recipients, but there has been less research on the effect of language proficiency. This is a cohort study of time to first COVID-19 vaccination among abdominal organ transplant recipients in an academic medical center in Boston, MA between 18 December 2020, and 15 February 2021. Cox proportional hazards analysis of time to vaccination by preferred language were adjusted for race, age group, insurance, and transplanted organ. Among 3001 patients, 53% were vaccinated during the study period. Language preference other than English was independently associated with delay to vaccination (0.64, p = 0.001), on adjusted analysis. In addition, Black, Hispanic and other race patients were less likely to be vaccinated than white patients (0.58, 0.67, 0.68 vs. reference, all p < 0.03). Language preference other than English is an independent barrier to solid abdominal organ transplant recipients' access to timely COVID-19 vaccination. Equity in care should be improved by providing targeted services to minority language speakers.

Differential effects of macrophage subtypes on SARS-CoV-2 infection in a human pluripotent stem cell-derived model.

Dysfunctional immune responses contribute critically to the progression of Coronavirus Disease-2019 (COVID-19), with macrophages as one of the main cell types involved. It is urgent to understand the interactions among permissive cells, macrophages, and the SARS-CoV-2 virus, thereby offering important insights into effective therapeutic strategies. Here, we establish a lung and macrophage co-culture system derived from human pluripotent stem cells (hPSCs), modeling the host-pathogen interaction in SARS-CoV-2 infection. We find that both classically polarized macrophages (M1) and alternatively polarized macrophages (M2) have inhibitory effects on SARS-CoV-2 infection. However, M1 and non-activated (M0) macrophages, but not M2 macrophages, significantly up-regulate inflammatory factors upon viral infection. Moreover, M1 macrophages suppress the growth and enhance apoptosis of lung cells. Inhibition of viral entry using an ACE2 blocking antibody substantially enhances the activity of M2 macrophages. Our studies indicate differential immune response patterns in distinct macrophage phenotypes, which could lead to a range of COVID-19 disease severity.

Cytoplasmic Tail Truncation of SARS-CoV-2 Spike Protein Enhances Titer of Pseudotyped Vectors but Masks the Effect of the D614G Mutation.

The high pathogenicity of SARS-CoV-2 requires it to be handled under biosafety level 3 conditions. Consequently, Spike protein-pseudotyped vectors are a useful tool to study viral entry and its inhibition, with retroviral, lentiviral (LV), and vesicular stomatitis virus (VSV) vectors the most commonly used systems. Methods to increase the titer of such vectors commonly include concentration by ultracentrifugation and truncation of the Spike protein cytoplasmic tail. However, limited studies have examined whether such a modification also impacts the protein's function. Here, we optimized concentration methods for SARS-CoV-2 Spike-pseudotyped VSV vectors, finding that tangential flow filtration produced vectors with more consistent titers than ultracentrifugation. We also examined the impact of Spike tail truncation on transduction of various cell types and sensitivity to convalescent serum neutralization. We found that tail truncation increased Spike incorporation into both LV and VSV vectors and resulted in enhanced titers but had no impact on sensitivity to convalescent serum. In addition, we analyzed the effect of the D614G mutation, which became a dominant SARS-CoV-2 variant early in the pandemic. Our studies revealed that, similar to the tail truncation, D614G independently increases Spike incorporation and vector titers, but this effect is masked by also including the cytoplasmic tail truncation. Therefore, the use of full-length Spike protein, combined with tangential flow filtration, is recommended as a method to generate high titer pseudotyped vectors that retain native Spike protein functions. IMPORTANCE Pseudotyped viral vectors are useful tools to study the properties of viral fusion proteins, especially those from highly pathogenic viruses. The Spike protein of SARS-CoV-2 has been investigated using pseudotyped lentiviral and VSV vector systems, where truncation of its cytoplasmic tail is commonly used to enhance Spike incorporation into vectors and to increase the titers of the resulting vectors. However, our studies have shown that such effects can also mask the phenotype of the D614G mutation in the ectodomain of the protein, which was a dominant variant arising early in the COVID-19 pandemic. To better ensure the authenticity of Spike protein phenotypes when using pseudotyped vectors, we recommend using full-length Spike proteins, combined with tangential flow filtration methods of concentration if higher-titer vectors are required.

The Risk of Postoperative Complications After Major Elective Surgery in Active or Resolved COVID-19 in the United States.

OBJECTIVE: To assess the association between the timing of surgery relative to the development of Covid-19 and the risks of postoperative complications. SUMMARY BACKGROUND DATA: It is unknown whether patients who recovered from Covid-19 and then underwent a major elective operation have an increased risk of developing postoperative complications. METHODS: The risk of postoperative complications for patients with Covid-19 undergoing 18 major types of elective operations in the Covid-19 Research Database was evaluated using multivariable logistic regression. Patients were grouped by time of surgery relative to SARS-CoV-2 infection; that is, surgery performed: (1) before January 1, 2020 ("pre-Covid-19"), (2) 0 to 4 weeks after SARS-CoV-2 infection ("peri-Covid-19"), (3) 4 to 8 weeks after infection ("early post-Covid-19"), and (4) ≥8 weeks after infection ("late post-Covid-19"). RESULTS: Of the 5479 patients who met study criteria, patients with peri-Covid-19 had an elevated risk of developing postoperative pneumonia [adjusted odds ratio (aOR), 6.46; 95% confidence interval (CI): 4.06-10.27], respiratory failure (aOR, 3.36; 95% CI: 2.22-5.10), pulmonary embolism (aOR, 2.73; 95% CI: 1.35-5.53), and sepsis (aOR, 3.67; 95% CI: 2.18-6.16) when compared to pre-Covid-19 patients. Early post-Covid-19 patients had an increased risk of developing postoperative pneumonia when compared to pre-Covid-19 patients (aOR, 2.44; 95% CI: 1.20-4.96). Late post-Covid-19 patients did not have an increased risk of postoperative complications when compared to pre-Covid-19 patients. CONCLUSIONS: Major, elective surgery 0 to 4 weeks after SARS-CoV-2 infection is associated with an increased risk of postoperative complications. Surgery performed 4 to 8 weeks after SARS-CoV-2 infection is still associated with an increased risk of postoperative pneumonia, whereas surgery 8 weeks after Covid-19 diagnosis is not associated with increased complications.

Modeling COVID-19 with Human Pluripotent Stem Cell-Derived Cells Reveals Synergistic Effects of Anti-inflammatory Macrophages with ACE2 Inhibition Against SARS-CoV-2.

Dysfunctional immune responses contribute critically to the progression of Coronavirus Disease-2019 (COVID-19) from mild to severe stages including fatality, with pro-inflammatory macrophages as one of the main mediators of lung hyper-inflammation. Therefore, there is an urgent need to better understand the interactions among SARS-CoV-2 permissive cells, macrophage, and the SARS-CoV-2 virus, thereby offering important insights into new therapeutic strategies. Here, we used directed differentiation of human pluripotent stem cells (hPSCs) to establish a lung and macrophage co-culture system and model the host-pathogen interaction and immune response caused by SARS-CoV-2 infection. Among the hPSC-derived lung cells, alveolar type II and ciliated cells are the major cell populations expressing the viral receptor ACE2 and co-effector TMPRSS2, and both were highly permissive to viral infection. We found that alternatively polarized macrophages (M2) and classically polarized macrophages (M1) had similar inhibitory effects on SARS-CoV-2 infection. However, only M1 macrophages significantly up-regulated inflammatory factors including IL-6 and IL-18, inhibiting growth and enhancing apoptosis of lung cells. Inhibiting viral entry into target cells using an ACE2 blocking antibody enhanced the activity of M2 macrophages, resulting in nearly complete clearance of virus and protection of lung cells. These results suggest a potential therapeutic strategy, in that by blocking viral entrance to target cells while boosting anti-inflammatory action of macrophages at an early stage of infection, M2 macrophages can eliminate SARS-CoV-2, while sparing lung cells and suppressing the dysfunctional hyper-inflammatory response mediated by M1 macrophages.