An inhaled bioadhesive hydrogel to shield non-human primates from SARS-CoV-2 infection.

The surge of fast-spreading SARS-CoV-2 mutated variants highlights the need for fast, broad-spectrum strategies to counteract viral infections. In this work, we report a physical barrier against SARS-CoV-2 infection based on an inhalable bioadhesive hydrogel, named spherical hydrogel inhalation for enhanced lung defence (SHIELD). Conveniently delivered via a dry powder inhaler, SHIELD particles form a dense hydrogel network that coats the airway, enhancing the diffusional barrier properties and restricting virus penetration. SHIELD's protective effect is first demonstrated in mice against two SARS-CoV-2 pseudo-viruses with different mutated spike proteins. Strikingly, in African green monkeys, a single SHIELD inhalation provides protection for up to 8 hours, efficiently reducing infection by the SARS-CoV-2 WA1 and B.1.617.2 (Delta) variants. Notably, SHIELD is made with food-grade materials and does not affect normal respiratory functions. This approach could offer additional protection to the population against SARS-CoV-2 and other respiratory pathogens.

A Modified Regimen of 21-day Nab-Paclitaxel Plus Gemcitabine in Locally Advanced or Metastatic Pancreatic Cancer: A Retrospective Real-World Study.

BACKGROUND: It is 1 of the standard treatment options for metastasis pancreatic cancer to receive nab-paclitaxel (125 mg/m2) plus gemcitabine (1000 mg/m2) on days 1, 8 and 15 every 28 days. Some patients showed intolerance and inconvenience to this therapeutic regimen. Thus, we conducted this retrospective real-world study to determine the efficacy and tolerability of a modified 21-day nab-paclitaxel plus gemcitabine (nab-P/Gem) regimen for the first-line treatment of locally advanced or metastatic pancreatic cancer. METHODS: Patients with locally advanced and metastatic pancreatic cancer treated with nab-paclitaxel (125 mg/m2) plus gemcitabine (1000 mg/m2) on days 1 and 8 every 21-day at West China Hospital and Shang Jin Hospital of Sichuan University from Mar 2018 to Dec 2021 were reviewed retrospectively. Clinical characteristics of patients were collected. The progression-free survival, overall survival, objective response rate, disease control rate, and toxicity were evaluated. RESULTS: A total of 113 patients who received the modified regimen of 21-day nab-P/Gem chemotherapy were included. The median overall survival was 9.3 months and the median progression-free survival was 4.4 months. The objective response rate and disease control rate were 18.6% and 56.7%, respectively. The median relative dose intensity for this modified regimen was 65%. The adverse events were mild to moderate, and the most common grade 3 or 4 treatment-related adverse events were neutropenia (21%) and leukopenia (16%). CONCLUSIONS: Our study showed that this modified regimen of 21-day nab-P/Gem for locally advanced and metastatic pancreatic cancer had comparable efficacy and tolerable toxicity. This treatment may provide a considerable option for pancreatic cancer patients who desire a modified schedule. The modified regimen of 21-day nab-P/Gem is also an option worth considering during the coronavirus disease 2019 pandemic for minimizing the number of visits and limiting the risk of exposure.

Inhalable dry powder mRNA vaccines based on extracellular vesicles.

Respiratory diseases are a global burden, with millions of deaths attributed to pulmonary illnesses and dysfunctions. Therapeutics have been developed, but they present major limitations regarding pulmonary bioavailability and product stability. To circumvent such limitations, we developed room-temperature-stable inhalable lung-derived extracellular vesicles or exosomes (Lung-Exos) as mRNA and protein drug carriers. Compared with standard synthetic nanoparticle liposomes (Lipos), Lung-Exos exhibited superior distribution to the bronchioles and parenchyma and are deliverable to the lungs of rodents and nonhuman primates (NHPs) by dry powder inhalation. In a vaccine application, severe acute respiratory coronavirus 2 (SARS-CoV-2) spike (S) protein encoding mRNA-loaded Lung-Exos (S-Exos) elicited greater immunoglobulin G (IgG) and secretory IgA (SIgA) responses than its loaded liposome (S-Lipo) counterpart. Importantly, S-Exos remained functional at room-temperature storage for one month. Our results suggest that extracellular vesicles can serve as an inhaled mRNA drug-delivery system that is superior to synthetic liposomes.

Exosomes decorated with a recombinant SARS-CoV-2 receptor-binding domain as an inhalable COVID-19 vaccine.

The first two mRNA vaccines against infection by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that were approved by regulators require a cold chain and were designed to elicit systemic immunity via intramuscular injection. Here we report the design and preclinical testing of an inhalable virus-like-particle as a COVID-19 vaccine that, after lyophilisation, is stable at room temperature for over three months. The vaccine consists of a recombinant SARS-CoV-2 receptor-binding domain (RBD) conjugated to lung-derived exosomes which, with respect to liposomes, enhance the retention of the RBD in both the mucus-lined respiratory airway and in lung parenchyma. In mice, the vaccine elicited RBD-specific IgG antibodies, mucosal IgA responses and CD4+ and CD8+ T cells with a Th1-like cytokine expression profile in the animals' lungs, and cleared them of SARS-CoV-2 pseudovirus after a challenge. In hamsters, two doses of the vaccine attenuated severe pneumonia and reduced inflammatory infiltrates after a challenge with live SARS-CoV-2. Inhalable and room-temperature-stable virus-like particles may become promising vaccine candidates.

Inhalable exosomes outperform liposomes as mRNA and protein drug carriers to the lung.

Respiratory diseases are among the leading causes of morbidity and mortality worldwide, coupled with the ongoing coronavirus disease 2019 (COVID-19) pandemic. mRNA lipid nanoparticle (LNP) vaccines have been developed, but their intramuscular delivery limits pulmonary bioavailability. Inhalation of nanoparticle therapeutics offers localized drug delivery that minimizes off targeted adverse effects and has greater patient compliance. However, LNP platforms require extensive reformulation for inhaled delivery. Lung-derived extracellular vesicles (Lung-Exo) offer a biological nanoparticle alternative that is naturally optimized for mRNA translation and delivery to pulmonary cells. We compared the biodistribution of Lung-Exo against commercially standard biological extracellular vesicles (HEK-Exo) and LNPs (Lipo), where Lung-Exo exhibited superior mRNA and protein cargo distribution to and retention in the bronchioles and parenchyma following nebulization administration. This suggests that inhaled Lung-Exo can deliver mRNA and protein drugs with enhanced pulmonary bioavailability and therapeutic efficacy.

Hofbauer Cells and COVID-19 in Pregnancy.

CONTEXT.­: SARS-CoV-2 can undergo maternal-fetal transmission, heightening interest in the placental pathology findings from this infection. Transplacental SARS-CoV-2 transmission is typically accompanied by chronic histiocytic intervillositis together with necrosis and positivity of syncytiotrophoblast for SARS-CoV-2. Hofbauer cells are placental macrophages that have been involved in viral diseases, including HIV and Zika virus, but their involvement in SARS-CoV-2 is unknown. OBJECTIVE.­: To determine whether SARS-CoV-2 can extend beyond the syncytiotrophoblast to enter Hofbauer cells, endothelium, and other villous stromal cells in infected placentas of liveborn and stillborn infants. DESIGN.­: Case-based retrospective analysis by 29 perinatal and molecular pathology specialists of placental findings from a preselected cohort of 22 SARS-CoV-2-infected placentas delivered to pregnant women testing positive for SARS-CoV-2 from 7 countries. Molecular pathology methods were used to investigate viral involvement of Hofbauer cells, villous capillary endothelium, syncytiotrophoblast, and other fetal-derived cells. RESULTS.­: Chronic histiocytic intervillositis and trophoblast necrosis were present in all 22 placentas (100%). SARS-CoV-2 was identified in Hofbauer cells from 4 of 22 placentas (18.2%). Villous capillary endothelial staining was positive in 2 of 22 cases (9.1%), both of which also had viral positivity in Hofbauer cells. Syncytiotrophoblast staining occurred in 21 of 22 placentas (95.5%). Hofbauer cell hyperplasia was present in 3 of 22 placentas (13.6%). In the 7 cases having documented transplacental infection of the fetus, 2 (28.6%) occurred in placentas with Hofbauer cell staining positive for SARS-CoV-2. CONCLUSIONS.­: SARS-CoV-2 can extend beyond the trophoblast into the villous stroma, involving Hofbauer cells and capillary endothelial cells, in a small number of infected placentas. Most cases of SARS-CoV-2 transplacental fetal infection occur without Hofbauer cell involvement.

Exosome therapeutics for COVID-19 and respiratory viruses.

Respiratory viral diseases are a leading cause of mortality in humans. They have proven to drive pandemic risk due to their complex transmission factors and viral evolution. However, the slow production of effective antiviral drugs and vaccines allows for outbreaks of these diseases, emphasizing a critical need for refined antiviral therapeutics. The delivery of exosomes, a naturally secreted extracellular vesicle, yields therapeutic effects for a variety of diseases, including viral infection. Exosomes and viruses utilize similar endosomal sorting pathways and mechanisms, providing exosomes with the potential to serve as a therapeutic that can target, bind, and suppress cellular uptake of various viruses including the novel severe acute respiratory syndrome coronavirus 2. Here, we review the relationship between exosomes and respiratory viruses, describe potential exosome therapeutics for viral infections, and summarize progress toward clinical translation for lung-derived exosome therapeutics.

Cell-mimicking nanodecoys neutralize SARS-CoV-2 and mitigate lung injury in a non-human primate model of COVID-19.

Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has grown into a global pandemic, and only a few antiviral treatments have been approved to date. Angiotensin-converting enzyme 2 (ACE2) plays a fundamental role in SARS-CoV-2 pathogenesis because it allows viral entry into host cells. Here we show that ACE2 nanodecoys derived from human lung spheroid cells (LSCs) can bind and neutralize SARS-CoV-2 and protect the host lung cells from infection. In mice, these LSC-nanodecoys were delivered via inhalation therapy and resided in the lungs for over 72 h post-delivery. Furthermore, inhalation of the LSC-nanodecoys accelerated clearance of SARS-CoV-2 mimics from the lungs, with no observed toxicity. In cynomolgus macaques challenged with live SARS-CoV-2, four doses of these nanodecoys delivered by inhalation promoted viral clearance and reduced lung injury. Our results suggest that LSC-nanodecoys can serve as a potential therapeutic agent for treating COVID-19.

Frontispiece: Exosome therapeutics for COVID-19 and respiratory viruses (View 3/2021)

In article number 20200186, Ke Cheng, Phuong-Uyen C. Dinh, Kristen Popowski and their co-workers describe the relationship between nanoparticles and respiratory viruses, to emphasize the clinical translation of exosome therapeutics for diseases such as SARS-CoV-2 infection. A naturally occurring extracellular vesicle, exosomes utilize similar endosomal sorting pathways and uptake mechanisms as viruses. In this cover, the gears represent the parallels between nanoparticle and viral mechanisms within the lung and how these biological systems can be utilized to enhance drug delivery and efficacy.

Initial Development of a National Survey on Remote Learning in Early Childhood During COVID-19: Establishing Content Validity and Reporting Successes and Barriers.

This article describes the development and administration of a survey to identify early childhood educators' successes and barriers when delivering remote instruction (e.g., online whole or small group instruction) during the COVID-19 pandemic to children 2-5 years old. The survey was developed using procedures outlined by the commonly accepted stages of an instrument development process. Content validity was established using four approaches: (a) identification of the purpose of the survey, (b) creation of a blueprint of items, (c) cognitive interviews, and (d) expert panel review. A total of 1,053 early childhood educators began the survey, with 808 (77%) of the responses included because educators met the inclusion criteria of working in the United States and responding to at least one question related to remote instruction. The survey contained 37 closed-ended and six open-ended items covering eight domains: (a) demographic information; (b) preparation, guidelines, and materials for remote learning; (c) caregiver communication and engagement; (d) assessment; (e) instruction; (f) educators' levels of confidence before and after remote learning; (g) access to services (i.e., wraparound and/or special education); and (h) planning for the return to face-to-face instruction. Both quantitative (descriptive, t-test, regression, ANOVA, and Chi-square tests) and consensual qualitative research analyses were applied to summarize the survey results. Findings from this survey indicated that even with limited or no guidance from administrators, educators successfully adapted to remote instruction and their levels of confidence increased over time. Ongoing improvements need to be made to sustain regular communication with all families, to offer access to technology (i.e., devices and internet), to administer assessments or universal screeners, and to provide cohesive guidelines and expectations. Results from this study begin to shed light on early childhood educators' adaptation to remote instruction as a result of COVID-19. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s10643-021-01216-y.

Inhibition of HECT E3 ligases as potential therapy for COVID-19.

SARS-CoV-2 is responsible for the ongoing world-wide pandemic which has already taken more than two million lives. Effective treatments are urgently needed. The enzymatic activity of the HECT-E3 ligase family members has been implicated in the cell egression phase of deadly RNA viruses such as Ebola through direct interaction of its VP40 Protein. Here we report that HECT-E3 ligase family members such as NEDD4 and WWP1 interact with and ubiquitylate the SARS-CoV-2 Spike protein. Furthermore, we find that HECT family members are overexpressed in primary samples derived from COVID-19 infected patients and COVID-19 mouse models. Importantly, rare germline activating variants in the NEDD4 and WWP1 genes are associated with severe COVID-19 cases. Critically, I3C, a natural NEDD4 and WWP1 inhibitor from Brassicaceae, displays potent antiviral effects and inhibits viral egression. In conclusion, we identify the HECT family members of E3 ligases as likely novel biomarkers for COVID-19, as well as new potential targets of therapeutic strategy easily testable in clinical trials in view of the established well-tolerated nature of the Brassicaceae natural compounds.

A randomized trial in the investigation of anxiety and depression in patients with coronavirus disease 2019 (COVID-19).

BACKGROUND: In March 2020, the World Health Organization (WHO) declared COVID-19 a public health emergency of international concern. A small proportion of patients infected with COVID-19 go on to develop pneumonia. We speculated that COVID-19 may be likely to result in psychological disorders such as anxiety and depression. In this study, we conducted an investigation of anxiety and depression in patients with COVID-19. METHODS: Sixty-five COVID-19 patients were randomly enrolled into this study. Anxiety and depression among participants were measured through the completion of anonymous Chinese-language Zung self-rating anxiety scale and self-rating depression scale questionnaires. Data were analyzed using independent samples t-tests, Mann-Whitney U-tests, and χ2 tests. RESULTS: The questionnaire results showed that 26.15% and 41.54% of participants suffered from anxiety and depression, respectively, although there was no significantly statistical difference between the proportions of COVID-19 patients with anxiety and depression. Statistically significant differences in employment status, partial pressure of oxygen, and corticosteroid application existed between moderate- and severe COVID-19 patients (P<0.05). In particular, the partial pressure of oxygen was significantly lower in severe COVID-19 patients than in their moderate counter parts (71.31±23.54 vs. 101.06±34.43, U=156, P=0.006). Total lymphocytes was lower in severe group than in moderate group [1.659±0.643 vs. 0.745 (0.645, 0.928), U=109, P=0.000]. Also, a higher proportion of female than male patients had anxiety (χ2=5.388, P=0.02). COVID-19 patients who received antiviral medications also displayed a higher rate of anxiety (χ2=4.481, P=0.034). Total lymphocytes between the non-anxiety and anxiety had statistical difference (U=321, P=0.019). Meanwhile, total lymphocytes between the non-depression and depression also had statistical difference (U=389.5, P=0.01). CONCLUSIONS: Among patients with COVID-19, females and those treated with antiviral medications were more likely to experience anxiety. In addition, our findings reflected the effect of anxiety and depression on immune system.

Advanced Nanobiomedical Approaches to Combat Coronavirus Disease of 2019.

New infectious diseases are making themselves known as the human population grows, expands into new regions, and becomes more dense, increasing contact with each other and animal populations. Ease of travel has also increased infectious disease transmission and has now culminated into a global pandemic. The emergence of the novel coronavirus severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in December 2019 has already infected over 83.7 million people and caused over 1.8 million deaths. While there have been vaccine candidates produced and supportive care implemented, the world is impatiently waiting for a commercially approved vaccine and treatment for the coronavirus disease of 2019 (COVID-19). The different vaccine types investigated for the prevention of COVID-19 all have great promise but face safety obstacles that must be first addressed. Some vaccine candidates of key interest are whole inactivated viruses, adeno-associated viruses, virus-like particles, and lipid nanoparticles. This review examines nanobiomedical techniques for combatting COVID-19 in terms of vaccines and therapeutics.

Histologic and Immunohistochemical Evaluation of 65 Placentas From Women With Polymerase Chain Reaction-Proven Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Infection.

CONTEXT.­: Coronavirus disease 2019 (COVID-19) has been shown to have effects outside of the respiratory system. Placental pathology in the setting of maternal severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection remains a topic of great interest because earlier studies have shown mixed results. OBJECTIVE.­: To ascertain whether maternal SARS-CoV-2 infection is associated with any specific placental histopathology, and to evaluate the virus's propensity for direct placental involvement. DESIGN.­: Placentas from 65 women with polymerase chain reaction-proven SARS-CoV-2 infection underwent histologic evaluation using Amsterdam consensus group criteria and terminology. Another 85 placentas from women without SARS-CoV-2 constituted the negative control group. A total of 64 of the placentas from the SARS-CoV-2-positive group underwent immunohistochemical staining for SARS-CoV-2 nucleocapsid protein. RESULTS.­: Pathologic findings were divided into maternal vascular malperfusion, fetal vascular malperfusion, chronic inflammatory lesions, amniotic fluid infection sequence, increased perivillous fibrin, intervillous thrombi, increased subchorionic fibrin, meconium-laden macrophages (M-LMs) within fetal membranes, and chorangiosis. There was no statistically significant difference in prevalence of any specific placental histopathology between the SARS-CoV-2-positive and SARS-CoV-2-negative groups. There was no immunohistochemical evidence of SARS-CoV-2 virus in any of the 64 placentas that underwent staining for viral nucleocapsid protein. CONCLUSIONS.­: Our study results and a literature review suggest that there is no characteristic histopathology in most placentas from women with SARS-CoV-2 infection. Likewise, direct placental involvement by SARS-CoV-2 is a rare event.