Magnetic resonance imaging (MRI) of normal human placentae.

INTRODUCTION: The MRI appearances of the human placenta in the absence of maternal or fetal pathology have not been extensively studied, with only a few studies reporting findings in the uncomplicated pregnancy. The purpose of this study is to review the placental MRI appearances in low-risk pregnancies in a prospective study. METHODS: A prospective observational study of placental MRI in low-risk pregnancies was initially planned, however recruitment was terminated early due to the COVID19 pandemic. The protocol was subsequently modified to compare the placental appearances in the enrolled cohort with pregnancies having had MRI for non-placental pathologies. The data from the two groups were then pooled to assess the range of normal placental appearances. RESULTS: Eighty-three pregnancies were prospectively assessed with MRI at a median gestation of 29 weeks (range 14-39) from a mixed group of prospective cases (n = 28) and retrospectively recruited obstetric MRI (n = 55). Placental thickness in the third trimester ranged from 18 to 35 mm. T2 heterogeneity was seen in 75% (25/33) at second trimester and by the third trimester 50% (25/50) were moderately or markedly heterogenous. T2 dark bands (>6 mm) were seen in 9% (3/33) and 20% (10/50) of second and third trimester pregnancies, respectively. Undetectable myometrium or loss of the subplacental myometrial plane was present in 15% (5/33) of second and 38% (19/50) of third trimester placentae. CONCLUSION: This qualitative study of normal placental MRI appearances expands the current knowledge base by confirming they vary, evolve with gestation, and can overlap with signs of placenta accreta spectrum.

Filipino Nursing Students' Use of Low-cost Simulators During the COVID-19 Pandemic: A Summative Content Analysis of YouTube Videos.

Introduction: : This study examined Filipino nursing students' use of household materials as low-cost simulators and how they aid in online return demonstrations. Methods: : Summative content analysis guided this study. We collected uploaded YouTube videos (n=14) depicting Filipino nursing students using low-cost simulators in their skills demonstration. We used Bengtsson's approach to content analysis to analyze the data. Findings: : Four themes of low-cost simulators were identified: home and hardware, health and beauty, creative articles, and entertainment. The categories under home and hardware were tools, containers, furniture, and packaging. Health and beauty low-cost simulators were toiletries and medical supplies. Creative articles included fabrics, clothing accessories, and stationeries. Entertainment low-cost-simulators had toys and computer accessories. Discussion: : During the COVID-19 pandemic, our research uncovered home equipment employed as low-cost simulators to help nursing students' online simulation of skills demonstration. We recommend further investigation of whether students learned using low-cost simulators.

Autoantibodies are highly prevalent in non-SARS-CoV-2 respiratory infections and critical illness.

The widespread presence of autoantibodies in acute infection with SARS-CoV-2 is increasingly recognized, but the prevalence of autoantibodies in non-SARS-CoV-2 infections and critical illness has not yet been reported. We profiled IgG autoantibodies in 267 patients from 5 independent cohorts with non-SARS-CoV-2 viral, bacterial, and noninfectious critical illness. Serum samples were screened using Luminex arrays that included 58 cytokines and 55 autoantigens, many of which are associated with connective tissue diseases (CTDs). Samples positive for anti-cytokine antibodies were tested for receptor blocking activity using cell-based functional assays. Anti-cytokine antibodies were identified in > 50% of patients across all 5 acutely ill cohorts. In critically ill patients, anti-cytokine antibodies were far more common in infected versus uninfected patients. In cell-based functional assays, 11 of 39 samples positive for select anti-cytokine antibodies displayed receptor blocking activity against surface receptors for Type I IFN, GM-CSF, and IL-6. Autoantibodies against CTD-associated autoantigens were also commonly observed, including newly detected antibodies that emerged in longitudinal samples. These findings demonstrate that anti-cytokine and autoantibodies are common across different viral and nonviral infections and range in severity of illness.

Expression of exogenous proteins in donor platelets treated with lipid nanoparticles encapsulating mRNA

Background: Platelets are transfused therapeutically for hemostasis, and are an integral part of hemorrhage management. However, transfusions can be ineffective in the most severe cases of hemorrhage. Platelets are also a potential cell therapy in other applications, but development has been hindered by inadequate methods to control which proteins are expressed by platelets. Currently, there are no methods to express exogenous proteins in transfusable platelets, which would expand their use to help treat the diseases they modulate. A method is therefore needed to modify transfusable platelets, and thus enhance their protein composition for specific applications. Aim(s): To produce engineered, transfusable platelets to enhance their natural coagulability and functional repertoire by directly transfecting donor-derived platelets with mRNA via lipid nanoparticle (LNP)-mediated delivery. The recent advances through the COVID-19 mRNA vaccines demonstrates the clinical safety and efficacy of LNP-mediated gene therapy, and thus offers a promising strategy to effectively engineer modified platelets. Method(s): Donor-derived platelets were washed and subsequently incubated with a systematic array of LNPs encapsulating Cy5-labeled mRNA encoding for nanoluciferase in comparison to commercial transfection reagents. LNP uptake and platelet activation via CD62p levels was assessed following 4 hours by flow cytometry, while luciferase expression was assessed by normalizing the luminescence intensity to the total protein content. Result(s): Platelets took up the mRNA through all conditions tested;nanoluciferase was only expressed, however, in platelets treated with LNPs and not commercial reagents. Systematically optimizing LNPs increased nanoluciferase expression nine-fold relative to pre-optimized LNPs. Exogenous protein expression did not appear to correlate with mRNA uptake nor platelet activation. Conclusion(s): Platelets transfected with LNPs can express exogenous protein. Further optimization can eventually lead to the creation of a platform technology that in the long-term will allow platelets to deliver therapeutic proteins and yield more effective platelet products.

Platelets Genetically Modified with mRNA-Lipid Nanoparticles Are Functionally Similar to Clinically Transfused Platelets in Vitro

Background/Case Studies: Platelet transfusions are an essential treatment for attenuating bleeding but are often ineffective in cases of intractable hemorrhage. Although anucleate, mature platelets synthesize protein de novo, making them amenable to mRNA gene therapy;however, there remains to be an effective transfection technique. Advancements in lipid nanoparticle (LNP) technology has enabled leading COVID vaccines and is an efficient method to deliver nucleic acids into target cells. Recently, a LNP approach to successfully express exogenous protein in donor platelets [unpublished data] has been developed, a first step towards demonstrating that donor platelet coagulability can be engineered. However, the effects of LNP treatment on platelet function has yet to be investigated. Study Design/Methods: Donated, pooled platelets were obtained from a regional blood for research centre. The hemostatic profiles of LNP-treated and clinical donor platelets were assessed using an adapted rotational thromboelastometry model of dilutional coagulopathy. Coagulability of whole blood (WB) and hemodiluted WB were assessed. Untreated and LNP-treated platelets were then supplemented into hemodiluted WB and activated using INTEM (ellagic acid) to generate a hemostatic profile. LNP-treated platelets were also stimulated with platelet agonists thrombin (0.1U/mL) and ADP (10 mM) and CD62p levels were evaluated to test if the activation response was similar to clinical platelets using flow cytometry. Statistical analysis was conducted by one-way ANOVA and significance defined by P < 0.05. Results/Findings: LNP-treated platelets have a comparable hemostatic profile to clinically transfused platelets and significantly contributed to clot strength when spiked into hemodiluted WB. After INTEM activation, the maximum clot firmness (MCF) of LNP-treated (45.67 +/-1.15) and untreated platelets (49.77 +/- 0.58) was significantly increased (P < 0.05) compared to diluted WB alone (35.00 +/- 1.00). No significant difference between untreated and LNP-treated donor platelets was observed although MCF trended down. No statistical difference in thrombin or ADP responsiveness, indicated by median fluorescent intensity of CD62p surface presentation, was observed between LNP treated and untreated platelets (P > 0.05). Conclusion(s): LNPs are an effective way to deliver exogenous nucleic acids into platelets;they do not significantly impair the platelet contribution to clot strength or responsiveness to agonists stimulation. The minimal effect of LNP exposure on in vitro platelet characteristics demonstrate that LNP engineering is a promising new approach to load platelets with nucleic acids encoding therapeutic protein to enhance their function.

Expression of Exogenous Proteins in Donor Platelets Treated with Lipid Nanoparticles Encapsulating mRNA

Background/Case Studies: Platelets are transfused therapeutically for hemostasis and are an integral part of hemorrhage management. Transfusions, however, can be ineffective in the most severe cases of hemorrhage. Platelets are also a potential cell therapy in other applications, but development has been hindered by inadequate methods to control which proteins are expressed by platelets. Currently, there are no methods to express exogenous proteins in transfusable platelets, which would expand their use to help treat the diseases they modulate. A method is therefore needed to modify transfusable platelets, and thus enhance their protein composition for specific applications. Lipid nanoparticles (LNPs) represent the most clinically advanced system for non-viral gene delivery, and can potentially be used to transfect donor-derived platelets with mRNA to produce transfusable platelets with an enhanced functional repertoire. The recent advances through the COVID-19 mRNA vaccines demonstrates the clinical safety and efficacy of LNP-mediated gene therapy, and thus offers a promising strategy to effectively engineer modified platelets. Study Design/Methods: Donor-derived platelets were washed and subsequently incubated with a systematic array of LNPs encapsulating Cy5-labeled mRNA encoding for nanoluciferase in comparison to the commercial transfection reagents, lipofectamine and Ribojuice. LNP uptake and platelet activation via CD62p levels was assessed following 4 h by flow cytometry, while nanoluciferase expression was assessed by normalizing the luminescence intensity (RLU) to the total protein content. Data was analyzed via a one-way unpaired Student or Welch's t-test or one-way analysis of variance (ANOVA) as appropriate. A p-value < 0.05 was considered significant. Results/Findings: Platelets internalized the mRNA through all conditions tested, with Ribojuice yielding the highest significant increase in Cy5 median fluorescence intensity relative to the LNP (59815 +/- 6466 A.U. vs. 1253 +/- 44 A.U., respectively, p = 0.002). Nanoluciferase was only expressed, however, in platelets treated with LNPs, yielding a normalized luminescence signal of 62 +/- 17 RLU/mug protein, and not with either of the commercial reagents. Systematically optimizing LNPs increased nanoluciferase expression nine-fold to 589 +/- 241 RLU/mug protein relative to pre-optimized LNPs (p = 0.031). A Pearson correlation analysis revealed that the expression of exogenous protein expression did not appear to correlate with the mRNA uptake (Pearson correlation coefficient, r = -0.35) nor platelet activation (r = -0.07). Conclusion(s): Transfecting platelets with LNPs containing mRNA enable the expression of exogenous protein. Further optimization can eventually lead to the creation of a platform technology that in the long-term will allow platelets to deliver therapeutic proteins and yield more effective platelet products.

Diagnostic value of determination of plasma CRP, PCT and IL-6 levels in patients with COVID-19

The article's objective was to assess the clinical diagnostic utility of plasma levels of CRP, PCT, and IL-6 in individuals with COVID-19 both alone and in combination. Results showed that according to the ROC curve, PCT and CRP were highly valuable in the diagnosis of COVID-19, and CRP was most valuable in the evaluation of patients with severe and critical COVID-19. The combined detection of the three indexes might increase the evaluation's effectiveness. When evaluating COVID-19 patients who were in severe condition, IL-6 demonstrated a strong predictive value. Therefore, combining the three indicators may increase the diagnostic efficiency and provide crucial reference values for the clinical diagnosis and treatment of COVID-19. CRP, PCT, and IL-6 levels may be potential biomarkers for the diagnosis of COVID-19 and can be used to determine the severity of COVID-19.

The human disease gene LYSET is essential for lysosomal enzyme transport and viral infection.

Lysosomes are key degradative compartments of the cell. Transport to lysosomes relies on GlcNAc-1-phosphotransferase-mediated tagging of soluble enzymes with mannose 6-phosphate (M6P). GlcNAc-1-phosphotransferase deficiency leads to the severe lysosomal storage disorder mucolipidosis II (MLII). Several viruses require lysosomal cathepsins to cleave structural proteins and thus depend on functional GlcNAc-1-phosphotransferase. We used genome-scale CRISPR screens to identify lysosomal enzyme trafficking factor (LYSET, also named TMEM251) as essential for infection by cathepsin-dependent viruses including severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). LYSET deficiency resulted in global loss of M6P tagging and mislocalization of GlcNAc-1-phosphotransferase from the Golgi complex to lysosomes. Lyset knockout mice exhibited MLII-like phenotypes, and human pathogenic LYSET alleles failed to restore lysosomal sorting defects. Thus, LYSET is required for correct functioning of the M6P trafficking machinery and mutations in LYSET can explain the phenotype of the associated disorder.

TMEM41B and VMP1 modulate cellular lipid and energy metabolism for facilitating dengue virus infection.

Transmembrane Protein 41B (TMEM41B) and Vacuole Membrane Protein 1 (VMP1) are two ER-associated lipid scramblases that play a role in autophagosome formation and cellular lipid metabolism. TMEM41B is also a recently validated host factor required by flaviviruses and coronaviruses. However, the exact underlying mechanism of TMEM41B in promoting viral infections remains an open question. Here, we validated that both TMEM41B and VMP1 are essential host dependency factors for all four serotypes of dengue virus (DENV) and human coronavirus OC43 (HCoV-OC43), but not chikungunya virus (CHIKV). While HCoV-OC43 failed to replicate entirely in both TMEM41B- and VMP1-deficient cells, we detected diminished levels of DENV infections in these cell lines, which were accompanied by upregulation of the innate immune dsRNA sensors, RIG-I and MDA5. Nonetheless, this upregulation did not correspondingly induce the downstream effector TBK1 activation and Interferon-beta expression. Despite low levels of DENV replication, classical DENV replication organelles were undetectable in the infected TMEM41B-deficient cells, suggesting that the upregulation of the dsRNA sensors is likely a consequence of aberrant viral replication rather than a causal factor for reduced DENV infection. Intriguingly, we uncovered that the inhibitory effect of TMEM41B deficiency on DENV replication, but not HCoV-OC43, can be partially reversed using exogenous fatty acid supplements. In contrast, VMP1 deficiency cannot be rescued using the metabolite treatment. In line with the observed phenotypes, we found that both TMEM41B- and VMP1-deficient cells harbor higher levels of compromised mitochondria, especially in VMP1 deficiency which results in severe dysregulations of mitochondrial beta-oxidation. Using a metabolomic profiling approach, we revealed distinctive global dysregulations of the cellular metabolome, particularly lipidome, in TMEM41B- and VMP1-deficient cells. Our findings highlight a central role for TMEM41B and VMP1 in modulating multiple cellular pathways, including lipid mobilization, mitochondrial beta-oxidation, and global metabolic regulations, to facilitate the replication of flaviviruses and coronaviruses.

Genome-wide bidirectional CRISPR screens identify mucins as host factors modulating SARS-CoV-2 infection.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes a range of symptoms in infected individuals, from mild respiratory illness to acute respiratory distress syndrome. A systematic understanding of host factors influencing viral infection is critical to elucidate SARS-CoV-2-host interactions and the progression of Coronavirus disease 2019 (COVID-19). Here, we conducted genome-wide CRISPR knockout and activation screens in human lung epithelial cells with endogenous expression of the SARS-CoV-2 entry factors ACE2 and TMPRSS2. We uncovered proviral and antiviral factors across highly interconnected host pathways, including clathrin transport, inflammatory signaling, cell-cycle regulation, and transcriptional and epigenetic regulation. We further identified mucins, a family of high molecular weight glycoproteins, as a prominent viral restriction network that inhibits SARS-CoV-2 infection in vitro and in murine models. These mucins also inhibit infection of diverse respiratory viruses. This functional landscape of SARS-CoV-2 host factors provides a physiologically relevant starting point for new host-directed therapeutics and highlights airway mucins as a host defense mechanism.

Déjà vu all over again: racial, ethnic and age disparities in mortality from influenza 1918-19 and COVID-19 in the United States.

Background: Examination of the mortality patterns in the United States among racial, ethnic, and age groups attributed to the 1918-19 influenza pandemic revealed stark disparities, causes for which could have been addressed and rectified this past century. However, these disparities have been amplified during the current COVID-19 pandemic.We have ignored the lessons of the past, and were destined to repeat its failings. Objectives: Compare and contrast mortality patterns by age, race, and ethnicity attributable to the 1918-19 influenza pandemic in the United States with corresponding patterns during the COVID-19 pandemic. Methods: This is a retrospective study, establishing mortality rates according to age, race and ethnicity attributable to the 1918-19 influenza pandemic in the United States and to the current COVID-19 pandemic, using mortality data published by the U.S. Public Health Service and the Centers for Disease Control and Prevention. Negative binomial regression models were used to establish rate ratios, that is, ratios of mortality rates across the various racial/ethnic groups, and associated 95% confidence intervals. Results: Mortality patterns by age differ significantly between the 1918-19 influenza pandemic and the COVID-19 pandemic: with infant and young adult (25-40 years old) mortality substantially higher in the former. Disparities in mortality between racial and ethnic groups are amplified in the COVID-19 pandemic compared to the 1918-19 experience. Conclusions: As we evaluate our nation's response to COVID-19 and design public policy to prepare better for coming pandemics, we cannot ignore the stark disparities in mortality rates experienced by different racial and ethnic groups. This will require a sustained resolve by society and government to delineate and remedy the causative factors, through science devoid of political interpretation and exploitation.

Platelets genetically modified with mRNA-lipid nanoparticles are functionally similar to clinically transfused platelets in vitro

Background: Platelet transfusions are an essential treatment for attenuating bleeding but are often ineffective in cases of intractable haemorrhage. Although anucleate, mature platelets synthesize protein de novo, making them amenable to mRNA gene therapy;however, there remains to be an effective transfection technique. Advancements in lipid nanoparticle technology has enabled leading COVID vaccines and is an efficient method to deliver nucleic acids into target cells. Recently, we developed a LNP approach to successfully express exogenous protein in platelets [unpublished data], a first step towards demonstrating that donor platelet coagulability can be engineered. However, the effects of LNP treatment on platelet function has yet to be investigated. Aims: To determine whether LNP-treated donor platelets are functionally similar, or better, in vitro, than platelets currently transfused clinically as a next step to establish LNP engineered platelets as a new cell therapy. Methods: The hemostatic profiles of LNP-treated and clinical donor platelets were assessed using an adapted rotational thromboelastometry model of dilutional coagulopathy. LNP-treated platelets were also stimulated with conventional platelet agonists to test if responsiveness is similar, or better than clinical platelets using flow cytometry. Results: LNP-treated platelets have a comparable hemostatic profile to clinically transfused platelets and significantly improved clotting dynamics when spiked into hemodiluted whole blood in an in vitro transfusion simulation. LNP-treated platelets also respond comparably, and in some cases more potently to agonist simulation compared to untreated platelets as indicated by similar p-selectin surface presentation. Summary/Conclusions: LNPs are an effective way to deliver exogenous nucleic acids into platelets;they do not significantly change platelet coagulability or responsiveness to agonists. LNP platelet engineering is a promising new approach to load platelets with procoagulant protein to enhance their function.

Significant Impact of Coronavirus Disease 2019 (COVID-19) on Human Immunodeficiency Virus (HIV) Care in Hospitals Affecting the First Pillar of the HIV Care Continuum.

During COVID-19 lockdown, the in-hospital number of HIV indicator conditions decreased disproportionally compared with other non-COVID-19 diseases, which was accompanied by reduced HIV testing rates, number and proportion of positive HIV tests, and new HIV referrals, with more late presentation after lockdown cessation, indicating a significantly impacted HIV care continuum.

[Infection fatality rate (IFR) during the course of COVID-19 pandemic in Upper Silesia Metropolitan Area (Poland) in 2020]. / Wskaznik smiertelnosci infekcji (IFR) w przebiegu pandemii COVID-19 w Aglomeracji Górnoslaskiej w 2020 r.

BACKGROUND: During the course of COVID-19 pandemic, a wide range of scientific projects was implemented worldwide, including studies focusing on infection fatality rate (IFR). The value of IFR depends on the number of COVID-19 deaths in a population in a given period and the number of infected people in this population, usually provided by seropepidemiological studies (anti-SARS-CoV-2 IgG in the case of COVID-19). The objective of our study was to estimate IFR in the course of COVID-19 pandemic in 2020, in the general population of Upper Silesia Metropolitan Area (USMA). MATERIAL AND METHODS: The seroepidemiological study was conducted in October-November 2020. Among randomly selected inhabitants of Katowice, Gliwice, and Sosnowiec (N = 1167), the presence of SARS-CoV-2 virus infection was assessed based on a positive IgG test result performed with the ELISA method. Data on deaths due to COVID-19 were obtained from the Registry Offices of each city. The infection fatality rate was calculated using the formula IFR (%) = [number of deaths/number of infected] × 100. RESULTS: Results of our study showed the prevalence of infection at 11.4% (95% CI: 9.5-13.2). In three examined towns, in the period January-November 2020, there was a total of 516 COVID-19 deaths. The resulting crude IFR was 0.65% (95% CI: 0.56-0.78). The IgG test had 88% sensitivity and 99% specificity and these figures were used to adjust IFR. The adjusted IFR value was similar to the crude value: IFR = 0.62% (95% CI: 0.53-0.74). CONCLUSIONS: The value of IFR estimated for the USMA population was similar to average values obtained in other countries and can be used as the background for monitoring the course and impact of COVID-19 pandemic in the Upper Silesian Industrial Area. Med Pr. 2021;72(6):671-6.

Efficacy of interferon beta-1a plus remdesivir compared with remdesivir alone in hospitalised adults with COVID-19: a double-bind, randomised, placebo-controlled, phase 3 trial.

BACKGROUND: Functional impairment of interferon, a natural antiviral component of the immune system, is associated with the pathogenesis and severity of COVID-19. We aimed to compare the efficacy of interferon beta-1a in combination with remdesivir compared with remdesivir alone in hospitalised patients with COVID-19. METHODS: We did a double-blind, randomised, placebo-controlled trial at 63 hospitals across five countries (Japan, Mexico, Singapore, South Korea, and the USA). Eligible patients were hospitalised adults (aged ≥18 years) with SARS-CoV-2 infection, as confirmed by a positive RT-PCR test, and who met one of the following criteria suggestive of lower respiratory tract infection: the presence of radiographic infiltrates on imaging, a peripheral oxygen saturation on room air of 94% or less, or requiring supplemental oxygen. Patients were excluded if they had either an alanine aminotransferase or an aspartate aminotransferase concentration more than five times the upper limit of normal; had impaired renal function; were allergic to the study product; were pregnant or breast feeding; were already on mechanical ventilation; or were anticipating discharge from the hospital or transfer to another hospital within 72 h of enrolment. Patients were randomly assigned (1:1) to receive intravenous remdesivir as a 200 mg loading dose on day 1 followed by a 100 mg maintenance dose administered daily for up to 9 days and up to four doses of either 44 µg interferon beta-1a (interferon beta-1a group plus remdesivir group) or placebo (placebo plus remdesivir group) administered subcutaneously every other day. Randomisation was stratified by study site and disease severity at enrolment. Patients, investigators, and site staff were masked to interferon beta-1a and placebo treatment; remdesivir treatment was given to all patients without masking. The primary outcome was time to recovery, defined as the first day that a patient attained a category 1, 2, or 3 score on the eight-category ordinal scale within 28 days, assessed in the modified intention-to-treat population, defined as all randomised patients who were classified according to actual clinical severity. Safety was assessed in the as-treated population, defined as all patients who received at least one dose of the assigned treatment. This trial is registered with ClinicalTrials.gov, NCT04492475. FINDINGS: Between Aug 5, 2020, and Nov 11, 2020, 969 patients were enrolled and randomly assigned to the interferon beta-1a plus remdesivir group (n=487) or to the placebo plus remdesivir group (n=482). The mean duration of symptoms before enrolment was 8·7 days (SD 4·4) in the interferon beta-1a plus remdesivir group and 8·5 days (SD 4·3) days in the placebo plus remdesivir group. Patients in both groups had a time to recovery of 5 days (95% CI not estimable) (rate ratio of interferon beta-1a plus remdesivir group vs placebo plus remdesivir 0·99 [95% CI 0·87-1·13]; p=0·88). The Kaplan-Meier estimate of mortality at 28 days was 5% (95% CI 3-7%) in the interferon beta-1a plus remdesivir group and 3% (2-6%) in the placebo plus remdesivir group (hazard ratio 1·33 [95% CI 0·69-2·55]; p=0·39). Patients who did not require high-flow oxygen at baseline were more likely to have at least one related adverse event in the interferon beta-1a plus remdesivir group (33 [7%] of 442 patients) than in the placebo plus remdesivir group (15 [3%] of 435). In patients who required high-flow oxygen at baseline, 24 (69%) of 35 had an adverse event and 21 (60%) had a serious adverse event in the interferon beta-1a plus remdesivir group compared with 13 (39%) of 33 who had an adverse event and eight (24%) who had a serious adverse event in the placebo plus remdesivir group. INTERPRETATION: Interferon beta-1a plus remdesivir was not superior to remdesivir alone in hospitalised patients with COVID-19 pneumonia. Patients who required high-flow oxygen at baseline had worse outcomes after treatment with interferon beta-1a compared with those given placebo. FUNDING: The National Institute of Allergy and Infectious Diseases (USA).

Mitigation of SARS-CoV-2 Transmission at a Large Public University (preprint)

In the Fall of 2020, many universities saw extensive transmission of SARS-CoV-2 among their populations, threatening the health of students, faculty and staff, the viability of in-person instruction, and the health of surrounding communities.1, 2 Here we report that a multimodal "SHIELD: Target, Test, and Tell" program mitigated the spread of SARS-CoV-2 at a large public university, prevented community transmission, and allowed continuation of in-person classes amidst the pandemic. The program combines epidemiological modelling and surveillance (Target); fast and frequent testing using a novel and FDA Emergency Use Authorized low-cost and scalable saliva-based RT-qPCR assay for SARS-CoV-2 that bypasses RNA extraction, called covidSHIELD (Test); and digital tools that communicate test results, notify of potential exposures, and promote compliance with public health mandates (Tell). These elements were combined with masks, social distancing, and robust education efforts. In Fall 2020, we performed more than 1,000,000 covidSHIELD tests while keeping classrooms, laboratories, and many other university activities open. Generally, our case positivity rates remained less than 0.5%, we prevented transmission from our students to our faculty and staff, and data indicate that we had no spread in our classrooms or research laboratories. During this fall semester, we had zero COVID-19-related hospitalizations or deaths amongst our university community. We also prevented transmission from our university community to the surrounding Champaign County community. Our experience demonstrates that multimodal transmission mitigation programs can enable university communities to achieve such outcomes until widespread vaccination against COVID-19 is achieved, and provides a roadmap for how future pandemics can be addressed.

A Review of Aerosol Generation Mitigation in International Dental Guidance.

INTRODUCTION: The coronavirus disease 2019 (COVID-19) led to the worldwide closure of dental practices or reduction of dental services. By the end of April 2020, governments and professional organisations were publishing recommendations or guidance for the reopening/restructuring of dental services. The aim of this study was to assess how dental aerosol-generating procedures (AGPs) were defined in international dental guidelines, what mitigation processes were advised, and whether they were linked to COVID-19 epidemiology. METHODS: Electronic searches of a broad range of databases, along with grey literature searches, without language restriction were conducted up to 13 July 2020. Recommendations for the use of face masks and fallow times with patients without COVID-19 were assessed against the deaths per 1 million population in the included countries and country income level using Pearson Chi-squared statistics. RESULTS: Sixty-three guidance documents were included. Most (98%) indicated that AGPs can be performed with patients without COVID-19 with caveats, including advice to restrict AGPs where possible, with 21% only recommending AGPs for dental emergencies. Face masks were recommended by most documents (94%), with 91% also specifying the use of goggles or face shields. Fallow periods for patients without COVID-19 were mentioned in 48% of documents, ranging from 2 to 180 minutes. There were no significant differences in recommendations for face masks or fallow time in patients without COVID-19 by country death rate (P = .463 and P = .901) or World Bank status (P = .504 and P = .835). Most documents recommended procedural or environmental mitigations such as preprocedural mouthwash (82%) and general ventilation (52%). Few documents provided underpinning evidence for their recommendations. CONCLUSIONS: While the amount of high-quality direct evidence related to dentistry and COVID-19 remains limited, it is important to be explicit about the considered judgements for recommendations as well as generate new evidence to face this challenge.

Where Do We Go From Here? A Framework for Using Susceptible-Infectious-Recovered Models for Policy Making in Emerging Infectious Diseases.

OBJECTIVES: Throughout the coronavirus disease 2019 pandemic, susceptible-infectious-recovered (SIR) modeling has been the preeminent modeling method to inform policy making worldwide. Nevertheless, the usefulness of such models has been subject to controversy. An evolution in the epidemiological modeling field is urgently needed, beginning with an agreed-upon set of modeling standards for policy recommendations. The objective of this article is to propose a set of modeling standards to support policy decision making. METHODS: We identify and describe 5 broad standards: transparency, heterogeneity, calibration and validation, cost-benefit analysis, and model obsolescence and recalibration. We give methodological recommendations and provide examples in the literature that employ these standards well. We also develop and demonstrate a modeling practices checklist using existing coronavirus disease 2019 literature that can be employed by readers, authors, and reviewers to evaluate and compare policy modeling literature along our formulated standards. RESULTS: We graded 16 articles using our checklist. On average, the articles met 6.81 of our 19 categories (36.7%). No articles contained any cost-benefit analyses and few were adequately transparent. CONCLUSIONS: There is significant room for improvement in modeling pandemic policy. Issues often arise from a lack of transparency, poor modeling assumptions, lack of a system-wide perspective in modeling, and lack of flexibility in the academic system to rapidly iterate modeling as new information becomes available. In anticipation of future challenges, we encourage the modeling community at large to contribute toward the refinement and consensus of a shared set of standards for infectious disease policy modeling.

Genome-wide, bidirectional CRISPR screens identify mucins as critical host factors modulating SARS-CoV-2 infection (preprint)

SARS-CoV-2 can cause a range of symptoms in infected individuals, from mild respiratory illness to acute respiratory distress syndrome. A systematic understanding of the host factors mediating viral infection or restriction is critical to elucidate SARS-CoV-2 host-pathogen interactions and the progression of COVID-19. To this end, we conducted genome-wide CRISPR knockout and activation screens in human lung epithelial cells with endogenous expression of the SARS-CoV-2 entry factors ACE2 and TMPRSS2. These screens uncovered proviral and antiviral host factors across highly interconnected host pathways, including components implicated in clathrin transport, inflammatory signaling, cell cycle regulation, and transcriptional and epigenetic regulation. Mucins, a family of high-molecular weight glycoproteins and the main constituent of mucus, are central components of a prominent viral restriction pathway that we identified. We demonstrate that multiple membrane-anchored mucins are critical inhibitors of SARS-CoV-2 entry and are upregulated in response to viral infection. This functional landscape of SARS-CoV-2 host factors provides a physiologically relevant starting point for new host-directed therapeutics and suggests interactions between SARS-CoV-2 and airway mucins of COVID-19 patients as a host defense mechanism.

COVID-19-related risk of in-hospital death in Silesia, Poland.

INTRODUCTION: The situation regarding COVID­19 in Poland is rapidly evolving. Because of this, it is important to investigate COVID­19 mortality and its predictors in one of the most densely populated regions of the country, Silesia Province. OBJECTIVES: The goals of this study were to assess in­hospital mortality due to COVID­19 and the impact of sex, age, and coexisting diseases on the risk of death. PATIENTS AND METHODS: The data analysis was based on discharge reports of patients with COVID­19 hospitalized between March and June 2020 in all hospitals in the region. Age, sex, hospital discharge status, and the presence of coexisting diseases were abstracted from the charts. RESULTS: In a group of 2830 in­patients with COVID­19, 325 died during hospitalization. COVID­19 deaths were associated with male sex (odds ratio [OR], 1.52; 95% CI, 1.17-1.96), older age (OR, 6.11; 95% CI, 4.5-8.31), and the presence of 3 or more coexisting diseases (OR, 4.78; 95% CI, 3.52-6.49). The most prevalent comorbidities were chronic cardiovascular and respiratory diseases. CONCLUSIONS: The estimated in­hospital fatality rate for COVID­19 was 11.5%, which is lower than the average COVID­19 fatality rate in other European countries. The risk of in­hospital death was associated with sex, age, and the number of coexisting diseases, such as chronic cardiovascular and respiratory diseases.