A systematic review and meta-analysis of long COVID symptoms.

BACKGROUND: Ongoing symptoms or the development of new symptoms following a SARS-CoV-2 diagnosis has caused a complex clinical problem known as "long COVID" (LC). This has introduced further pressure on global healthcare systems as there appears to be a need for ongoing clinical management of these patients. LC personifies heterogeneous symptoms at varying frequencies. The most complex symptoms appear to be driven by the neurology and neuropsychiatry spheres. METHODS: A systematic protocol was developed, peer reviewed, and published in PROSPERO. The systematic review included publications from the 1st of December 2019-30th June 2021 published in English. Multiple electronic databases were used. The dataset has been analyzed using a random-effects model and a subgroup analysis based on geographical location. Prevalence and 95% confidence intervals (CIs) were established based on the data identified. RESULTS: Of the 302 studies, 49 met the inclusion criteria, although 36 studies were included in the meta-analysis. The 36 studies had a collective sample size of 11,598 LC patients. 18 of the 36 studies were designed as cohorts and the remainder were cross-sectional. Symptoms of mental health, gastrointestinal, cardiopulmonary, neurological, and pain were reported. CONCLUSIONS: The quality that differentiates this meta-analysis is that they are cohort and cross-sectional studies with follow-up. It is evident that there is limited knowledge available of LC and current clinical management strategies may be suboptimal as a result. Clinical practice improvements will require more comprehensive clinical research, enabling effective evidence-based approaches to better support patients.

Multi-bioinspired hierarchical integrated hydrogel for passive fog harvesting and solar-driven seawater desalination.

In recent years, with the outbreak and epidemic of the novel coronavirus in the world, how to obtain clean water from the limited resources has become an urgent issue of concern to all mankind. Atmospheric water harvesting technology and solar-driven interfacial evaporation technology have shown great potential in seeking clean and sustainable water resources. Here, inspired by a variety of organisms in nature, a multi-functional hydrogel matrix composed of polyvinyl alcohol (PVA), sodium alginate (SA) cross-linked by borax as well as doped with zeolitic imidazolate framework material 67 (ZIF-67) and graphene owning macro/micro/nano hierarchical structure has successfully fabricated for producing clean water. The hydrogel not only can reach the average water harvesting ratio up to 22.44 g g-1 under the condition of fog flow after 5 h, but also be capable of desorbing the harvested water with water release efficiency of 1.67 kg m-2 h-1 under 1 sun. In addition to excellent performance in passive fog harvesting, the evaporation rate over 1.89 kg m-2 h-1 is attained under 1 sun on natural seawater during long-term. This hydrogel indicates its potential in producing clean water resources in multiple scenarios in different dry or wet states, and which holds great promise for flexible electronic materials and sustainable sewage or wastewater treatment applications.

Design of an artificial transcriptional system for production of high levels of recombinant proteins in tobacco (Nicotiana benthamiana).

Plants have recently received much attention as a means of producing recombinant proteins because they are easy to grow at a low cost and at a large scale. Although many plant protein expression systems have been developed, there remains a need for improved systems that deliver high yields of recombinant proteins. Transcription of the recombinant gene is a key step in increasing the yield of recombinant proteins. However, revealed strong promoters, terminators, and transcription factors that have been identified do not necessarily lead to high level production of recombinant proteins. Thus, in this study, a robust expression system was designed to produce high levels of recombinant protein consisting of a novel hybrid promoter, FM'M-UD, coupled with an artificial terminator, 3PRt. FM'M-UD contained fragments from three viral promoters (the promoters of Mirabilis mosaic caulimovirus (MMV) full-length transcript, the MMV subgenomic transcript, and figwort mosaic virus subgenomic transcript) and two types of cis-acting elements (four GAL4 binding sites and two zinc finger binding sites). The artificial terminator, 3PRt, consisted of the PINII and 35S terminators plus RB7, a matrix attachment region. The FM'M-UD promoter increased protein levels of reporters GFP, RBD : SD1 (part of S protein from SARS-CoV-2), and human interleukin-6 (hIL6) by 4-6-fold, 2-fold, and 6-fold, respectively, relative to those of the same reporters driven by the CaMV 35S promoter. Furthermore, when the FM'M-UD/3PRt expression cassette was expressed together with GAL4/TAC3d2, an artificial transcription factor that bound the GAL4 binding sites in FM'M-UD, levels of hIL6 increased by 10.7-fold, relative to those obtained from the CaMV 35S promoter plus the RD29B terminator. Thus, this novel expression system led to the production of a large amount of recombinant protein in plants.

The origins of COVID-19 pandemic: A brief overview.

The novel coronavirus disease (COVID-19) outbreak that emerged at the end of 2019 has now swept the world for more than 2 years, causing immeasurable damage to the lives and economies of the world. It has drawn so much attention to discovering how the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) originated and entered the human body. The current argument revolves around two contradictory theories: a scenario of laboratory spillover events and human contact with zoonotic diseases. Here, we reviewed the transmission, pathogenesis, possible hosts, as well as the genome and protein structure of SARS-CoV-2, which play key roles in the COVID-19 pandemic. We believe the coronavirus was originally transmitted to human by animals rather than by a laboratory leak. However, there still needs more investigations to determine the source of the pandemic. Understanding how COVID-19 emerged is vital to developing global strategies for mitigating future outbreaks.

Therapeutic Polypeptides and Peptidomimetics: Powerful Tools for COVID-19 Treatment.

The coronavirus disease 2019 (COVID-19) pandemic has swept the whole world and brought about a public health crisis of unprecedented proportions. To combat the rapid transmission and possible deaths due to the disease, researchers and companies around the world are developing all possible strategies. Due to the advantages of safety, specificity, and fewer adverse effects, polypeptide and peptidomimetic drugs are considered promising strategies. This review comprehensively summarizes and discusses the progress in development of peptide drugs for use in the treatment of COVID-19. Based on the latest results in this field, we divided them into clinically approved drugs, clinical trial drugs, and clinically ineffective drugs, and outlined the molecular targets and mechanisms of action one by one to reveal their feasibility as promising therapeutic agents for COVID-19. Notably, monoclonal antibodies have shown beneficial effects in the early stages of infection, while Paxlovid can significantly reduce hospitalization and mortality among non-vaccinated patients. Among clinical experimental drugs, both the interleukin-1 receptor antagonist anakinra and the bradykinin B2 receptor antagonist icatibant are well tolerated and effective in patients with COVID-19, but long-term trials are needed to confirm the durability of efficacy.

The prevalence of mental ill-health in women during pregnancy and after childbirth during the Covid-19 pandemic: a systematic review and Meta-analysis.

BACKGROUND: This systematic review aims to explore the prevalence of the impact of the COVID-19, MERS, and SARS pandemics on the mental health of pregnant women. METHODS: All COVID-19, SARS and MERS studies that evaluated the mental health of pregnant women with/without gynaecological conditions that were reported in English between December 2000 - July 2021 were included. The search criteria were developed based upon the research question using PubMed, Science Direct, Ovid PsycINFO and EMBASE databases. A wide search criterion was used to ensure the inclusion of all pregnant women with existing gynaecological conditions. The Newcastle-Ottawa-Scale was used to assess the risk of bias for all included studies. Random effects model with restricted maximum-likelihood estimation method was applied for the meta-analysis and I-square statistic was used to evaluate heterogeneity across studies. The pooled prevalence rates of symptoms of anxiety, depression, PTSD, stress, and sleep disorders with 95% confidence interval (CI) were computed. RESULTS: This systematic review identified 217 studies which included 638,889 pregnant women or women who had just given birth. There were no studies reporting the mental health impact due to MERS and SARS. Results showed that women who were pregnant or had just given birth displayed various symptoms of poor mental health including those relating to depression (24.9%), anxiety (32.8%), stress (29.44%), Post Traumatic Stress Disorder (PTSD) (27.93%), and sleep disorders (24.38%) during the COVID-19 pandemic. DISCUSSION: It is important to note that studies included in this review used a range of outcome measures which does not allow for direct comparisons between findings. Most studies reported self-reported measure of symptoms without clinical diagnoses so conclusions can be made for symptom prevalence rather than of mental illness. The importance of managing mental health during pregnancy and after-delivery improves the quality of life and wellbeing of mothers hence developing an evidence-based approached as part of pandemic preparedness would improve mental health during challenging times. OTHER: The work presented in this manuscript was not funded by any specific grants. A study protocol was developed and published in PROSPERO (CRD42021235356) to explore several key objectives.

SARS-CoV-2 spike trimer vaccine expressed in Nicotiana benthamiana adjuvanted with Alum elicits protective immune responses in mice.

The ongoing coronavirus disease 2019 (COVID-19) pandemic has spurred rapid development of vaccines as part of the public health response. However, the general strategy used to construct recombinant trimeric severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike (S) proteins in mammalian cells is not completely adaptive to molecular farming. Therefore, we generated several constructs of recombinant S proteins for high expression in Nicotiana benthamiana. Intramuscular injection of N. benthamiana-expressed Sct vaccine (NSct Vac) into Balb/c mice elicited both humoral and cellular immune responses, and booster doses increased neutralizing antibody titres. In human angiotensin-converting enzyme knock-in mice, two doses of NSct Vac induced anti-S and neutralizing antibodies, which cross-neutralized Alpha, Beta, Delta and Omicron variants. Survival rates after lethal challenge with SARS-CoV-2 were up to 80%, without significant body weight loss, and viral titres in lung tissue fell rapidly, with no infectious virus detectable at 7-day post-infection. Thus, plant-derived NSct Vac could be a candidate COVID-19 vaccine.

Mental health impact of the Middle East respiratory syndrome, SARS, and COVID-19: A comparative systematic review and meta-analysis.

BACKGROUND: Over the last few decades, 3 pathogenic pandemics have impacted the global population; severe acute respiratory syndrome coronavirus (SARS-CoV), Middle East respiratory syndrome coronavirus (MERS-CoV) and SARS-CoV-2. The global disease burden has attributed to millions of deaths and morbidities, with the majority being attributed to SARS-CoV-2. As such, the evaluation of the mental health (MH) impact across healthcare professionals (HCPs), patients and the general public would be an important facet to evaluate to better understand short, medium and long-term exposures. AIM: To identify and report: (1) MH conditions commonly observed across all 3 pandemics; (2) Impact of MH outcomes across HCPs, patients and the general public associated with all 3 pandemics; and (3) The prevalence of the MH impact and clinical epidemiological significance. METHODS: A systematic methodology was developed and published on PROSPERO (CRD42021228697). The databases PubMed, EMBASE, ScienceDirect and the Cochrane Central Register of Controlled Trials were used as part of the data extraction process, and publications from January 1, 1990 to August 1, 2021 were searched. MeSH terms and keywords used included Mood disorders, PTSD, Anxiety, Depression, Psychological stress, Psychosis, Bipolar, Mental Health, Unipolar, Self-harm, BAME, Psychiatry disorders and Psychological distress. The terms were expanded with a 'snowballing' method. Cox-regression and the Monte-Carlo simulation method was used in addition to I 2 and Egger's tests to determine heterogeneity and publication bias. RESULTS: In comparison to MERS and SARS-CoV, it is evident SAR-CoV-2 has an ongoing MH impact, with emphasis on depression, anxiety and post-traumatic stress disorder. CONCLUSION: It was evident MH studies during MERS and SARS-CoV was limited in comparison to SARS-CoV-2, with much emphasis on reporting symptoms of depression, anxiety, stress and sleep disturbances. The lack of comprehensive studies conducted during previous pandemics have introduced limitations to the "know-how" for clinicians and researchers to better support patients and deliver care with limited healthcare resources.

Sars-Cov-2 Spike Protein-Induced Damage of hiPSC-Derived Cardiomyocytes.

Sars-Cov-2 may trigger molecular and functional alterations of cardiomyocytes (CMs) of the heart due to the presence of receptor angiotensin-converting enzyme 2 (ACE2) of the host cells. While the endocytic itinerary of the virus via cleavage of the spike protein of Sars-Cov-2 is well understood, the role of the remaining part of the spike protein subunit and ACE2 complex is still elusive. Herein, the possible effects of this complex are investigated by using synthetic spike proteins of Sars-Cov-2, human-induced pluripotent stem cells (hiPSC), and a culture device made of an arrayed monolayer of cross-linked nanofibers. hiPSCs are first differentiated into CMs that form cardiac tissue-like constructs with regular beating and expression of both ACE2 and gap junction protein Connexin 43. When incubated with the spike proteins, the hiPSC-CMs undergo a rhythmic fluctuation with overstretched sarcomere structures and dispersed gap junction proteins. When incubated with the spike proteins and supplementary angiotensin II, the damage of the spike protein on hiPSC-CMs is enhanced due to downregulated ACE2, chromatin margination, altered Connexin 43 expression, sarcomere disruption, and beating break. This discovery may imply latent effects of the spike proteins on the heart.

Intermedia Agenda Setting amid the Pandemic: A Computational Analysis of China's Online News.

Based on Intermedia Agenda Setting (IAS), the current study examines how official media and semi-privatized commercial media on the Weibo platform covered the COVID-19 pandemic in China. Both supervised machine learning and time series analysis were employed to analyze 350,059 Weibo posts released by 3,883 news sources between December 2019 and April 2020. Our results indicated that, in this nonwestern state-regulated China media environment, official and semi-privatized commercial media had a significant reciprocal relationship in news coverage. Both of them focused on "treatment on patients," "work resumption," and "propaganda and mobilization." Importantly, this paper sheds light on the value of the fine-grained level of agenda in IAS research. Using a fine-grained analysis, we separately investigated the effects of official and semi-privatized commercial media on predicting the pandemic prevalence, referring to the number of confirmed cases reported in real time. Implications and future directions were further discussed.

The Multi-Modal Risk Analysis and Medical Prevention of Lumbar Degeneration, Fatigue, and Injury Based on FEM/BMD for Elderly Chinese Women Who Act as Stay-Home Grandchildren Sitters.

Background: An increasing number of Chinese elderly women stay at home and act as grandchildren sitters. In consequence of the frequent load-bearing, chronic lumbar fatigue probably caused a higher risk of lumbar degeneration, fatigue, and injury which has become one of the most important aging and health problems in China. In this study, a multi-mode lumbar finite element model (FEM) with specific bone mineral density (BMD) were developed and validated for further spine injury prevention and control. Methods: The material properties of lumbar vertebra were modified according to degenerated bone mineral density, and geometry was adjusted based on intervertebral disc height. The motion of lifting children was simulated by a 76 year-old Chinese women's FEM, and the stress distribution was calculated and predicted. Results: The pressure of L5-S intervertebral disc in the bending 3-year-old dummy lifting posture was significantly higher than the same posture without lifting, the maximum effective stress of endplate cartilage in the upright child lifting posture was 1.6 times that of the bending without lifting posture. And the fatigue risk limitation frequency of the upright with dummy posture was predicted with the functional equation of fatigue and stress which was deduced by genetic algorithm, which combined with the effective stress of lumbar vertebrae spongy bone calculated from FEM. Conclusions: The child-lifting motion could increase the risk of lumbar degeneration, fatigue, and injury in elderly women, and they should keep below the frequency limit of the motion of lifting children in their daily life. This study could put forward scientific injury prevention guidance to Chinese elderly women who lift children in daily life frequently.

Activation of Tenofovir Alafenamide and Sofosbuvir in the Human Lung and Its Implications in the Development of Nucleoside/Nucleotide Prodrugs for Treating SARS-CoV-2 Pulmonary Infection.

ProTide technology is a powerful tool for the design of nucleoside/nucleotide analog prodrugs. ProTide prodrug design improves cell permeability and enhances intracellular activation. The hydrolysis of the ester bond of a ProTide is a determinant of the intracellular activation efficiency and final antiviral efficacy of the prodrug. The hydrolysis is dictated by the catalytic activity and abundance of activating enzymes. The antiviral agents tenofovir alafenamide (TAF) and sofosbuvir (SBV) are typical ProTides. Both TAF and SBV have also been proposed to treat patients with COVID-19. However, the mechanisms underlying the activation of the two prodrugs in the lung remain inconclusive. In the present study, we profiled the catalytic activity of serine hydrolases in human lung S9 fractions using an activity-based protein profiling assay. We evaluated the hydrolysis of TAF and SBV using human lung and liver S9 fractions and purified enzymes. The results showed that CatA and CES1 were involved in the hydrolysis of the two prodrugs in the human lung. More specifically, CatA exhibited a nearly 4-fold higher hydrolytic activity towards TAF than SBV, whereas the CES1 activity on hydrolyzing TAF was slightly lower than that for SBV. Overall, TAF had a nearly 4-fold higher hydrolysis rate in human lung S9 than SBV. We further analyzed protein expression levels of CatA and CES1 in the human lung, liver, and primary cells of the two tissues using proteomics data extracted from the literature. The relative protein abundance of CatA to CES1 was considerably higher in the human lung and primary human airway epithelial cells than in the human liver and primary human hepatocytes. The findings demonstrated that the high susceptivity of TAF to CatA-mediated hydrolysis resulted in efficient TAF hydrolysis in the human lung, suggesting that CatA could be utilized as a target activating enzyme when designing antiviral ester prodrugs for the treatment of respiratory virus infection.

RBD-homodimer, a COVID-19 subunit vaccine candidate, elicits immunogenicity and protection in rodents and nonhuman primates.

The pandemic of COVID-19 caused by SARS-CoV-2 has raised a new challenges to the scientific and industrious fields after over 1-year spread across different countries. The ultimate approach to end the pandemic is the timely application of vaccines to achieve herd immunity. Here, a novel SARS-CoV-2 receptor-binding domain (RBD) homodimer was developed as a SARS-CoV-2 vaccine candidate. Formulated with aluminum adjuvant, RBD dimer elicited strong immune response in both rodents and non-human primates, and protected mice from SARS-CoV-2 challenge with significantly reducing viral load and alleviating pathological injury in the lung. In the non-human primates, the vaccine could prevent majority of the animals from SARS-CoV-2 infection in the respiratory tract and reduce lung damage. In addition, antibodies elicited by this vaccine candidate showed cross-neutralization activities to SARS-CoV-2 variants. Furthermore, with our expression system, we provided a high-yield RBD homodimer vaccine without additional biosafety or special transport device supports. Thus, it may serve as a safe, effective, and low-cost SARS-CoV-2 vaccine candidate.

Sequential non-invasive following short-term invasive mechanical ventilation in the treatment of tuberculosis with respiratory failure: a randomized controlled study.

BACKGROUND: Invasive and non-invasive mechanical ventilation (MV) have been combined as sequential MV in the treatment of respiratory failure. However, the effectiveness remains unclear. Here, we performed a randomized controlled study to assess the efficacy and safety of sequential MV in the treatment of tuberculosis with respiratory failure. METHODS: Forty-four tuberculosis patients diagnosed with respiratory failure were randomly divided into sequential MV group (n = 24) and conventional MV group (n = 20). Initially, the patients in both groups received invasive positive pressure ventilation. When the patients' conditions were relieved, the ventilation modality in sequential MV group was switched to oronasal face mask continuous positive airway pressure until weaning. RESULTS: After treatment, the patients in sequential MV group had similar respiratory rate, heart rate, oxygenation index, alveolo-arterial oxygen partial pressure difference (A-aDO2), blood pH, PaCO2 to those in conventional MV group (all P value > 0.05). There was no significant difference in ventilation time and ICU stay between the two groups (P > 0.05), but sequential MV group significantly reduced the time of invasive ventilation (mean difference (MD): - 36.2 h, 95% confidence interval (CI) - 53.6, - 18.8 h, P < 0.001). Sequential MV group also reduced the incidence of ventilator-associated pneumonia (VAP; relative risk (RR): 0.44, 95% CI 0.24, 0.83, P = 0.006) and atelectasis (RR:0.49, 95% CI 0.24,1.00, P = 0.040). CONCLUSIONS: Sequential MV was effective in treating tuberculosis with respiratory failure. It showed advantages in reducing invasive ventilation time and ventilator-associated adverse events. REGISTRATION NUMBER FOR CLINICAL TRIAL: Chinese Clinical Trial Registry ChiCTR2000032311, April 21st, 2020.

Meta-analysis with zero-event studies: a comparative study with application to COVID-19 data.

BACKGROUND: Meta-analysis is a statistical method to synthesize evidence from a number of independent studies, including those from clinical studies with binary outcomes. In practice, when there are zero events in one or both groups, it may cause statistical problems in the subsequent analysis. METHODS: In this paper, by considering the relative risk as the effect size, we conduct a comparative study that consists of four continuity correction methods and another state-of-the-art method without the continuity correction, namely the generalized linear mixed models (GLMMs). To further advance the literature, we also introduce a new method of the continuity correction for estimating the relative risk. RESULTS: From the simulation studies, the new method performs well in terms of mean squared error when there are few studies. In contrast, the generalized linear mixed model performs the best when the number of studies is large. In addition, by reanalyzing recent coronavirus disease 2019 (COVID-19) data, it is evident that the double-zero-event studies impact the estimate of the mean effect size. CONCLUSIONS: We recommend the new method to handle the zero-event studies when there are few studies in a meta-analysis, or instead use the GLMM when the number of studies is large. The double-zero-event studies may be informative, and so we suggest not excluding them.

Tissue-Specific Proteomics Analysis of Anti-COVID-19 Nucleoside and Nucleotide Prodrug-Activating Enzymes Provides Insights into the Optimization of Prodrug Design and Pharmacotherapy Strategy.

Nucleoside and nucleotide analogs are an essential class of antivirals for COVID-19 treatment. Several nucleoside/nucleotide analogs have shown promising effects against SARS-CoV-2 in vitro; however, their in vivo efficacy is limited. Nucleoside/nucleotide analogs are often formed as ester prodrugs to improve pharmacokinetics (PK) performance. After entering cells, the prodrugs undergo several enzymatic metabolism steps to form the active metabolite triphosphate nucleoside (TP-Nuc); prodrug activation is therefore associated with the abundance and catalytic activity of the corresponding activating enzymes. Having the activation of nucleoside/nucleotide prodrugs occur at the target site of action, such as the lung, is critical for anti-SARS-CoV-2 efficacy. Herein, we conducted an absolute quantitative proteomics study to determine the expression of relevant activating enzymes in human organs related to the PK and antiviral efficacy of nucleoside/nucleotide prodrugs, including the lung, liver, intestine, and kidney. The protein levels of prodrug-activating enzymes differed significantly among the tissues. Using catalytic activity values reported previously for individual enzymes, we calculated prodrug activation profiles in these tissues. The prodrugs evaluated in this study include nine McGuigan phosphoramidate prodrugs, two cyclic monophosphate prodrugs, two l-valyl ester prodrugs, and one octanoate prodrug. Our analysis showed that most orally administered nucleoside/nucleotide prodrugs were primarily activated in the liver, suggesting that parenteral delivery routes such as inhalation and intravenous infusion could be better options when these antiviral prodrugs are used to treat COVID-19. The results also indicated that the l-valyl ester prodrug design can plausibly improve drug bioavailability and enhance effects against SARS-CoV-2 intestinal infections. This study further revealed that an octanoate prodrug could provide a long-acting antiviral effect targeting SARS-CoV-2 infections in the lung. Finally, our molecular docking analysis suggested several prodrug forms of favipiravir and GS-441524 that are likely to exhibit favorable PK features over existing prodrug forms. In sum, this study revealed the activation mechanisms of various nucleoside/nucleotide prodrugs relevant to COVID-19 treatment in different organs and shed light on the development of more effective anti-COVID-19 prodrugs.

Immunoglobulin fragment F(ab')2 against RBD potently neutralizes SARS-CoV-2 in vitro.

COVID-19, which is caused by the emerging human coronavirus SARS-CoV-2, has become a global pandemic that poses a serious threat to human health. To date, no vaccines or specific antiviral drugs have been approved for the treatment of this disease in clinic. Herein, therapeutic antibodies for SARS-CoV-2 were obtained from hyperimmune equine plasma. First, a recombinant SARS-CoV-2 spike protein receptor-binding domain (RBD) was obtained in gram-level quantities through high-cell density fermentation of Chinese hamster ovary cells. Then, the binding of the RBD to the SARS-CoV-2 receptor, human angiotensin-converting enzyme 2, was verified by several biochemical methods. The efficacy of the RBD in triggering antibody response in vivo was subsequently tested in both mice and equines, and the results showed that the RBD triggered high-titer neutralizing antibody production in vivo. Immunoglobulin F(ab')2 fragments were prepared from equine antisera via removal of the Fc region from the immunoglobulins. Finally, a neutralization test with live virus demonstrated that RBD-specific F(ab')2 inhibited SARS-CoV-2 with an EC50 of 0.07 µg/ml and an EC80 of 0.18 µg/ml, showing a potent inhibitory effect on SARS-CoV-2. These results highlight RBD-specific equine immunoglobulin F(ab')2 fragment as a candidate for the treatment of SARS-CoV-2.