Rarely has scientific research been as solicited as in the past two years, as societies struggle to cope with the coronavirus [...]

Vial-based lyophilization for biopharmaceuticals has been an indispensable cornerstone process for over 50 years. However, the process is not without significant challenges. Capital costs to realize a lyophilized drug product facility, for example, are very high. Similarly, heat and mass transfer limitations inherent in lyophilization result in drying cycle on the order of several days while putting practical constraints on available formulation space, such as solute mass percentage or fill volume in a vial. Through collaboration with an external partner, we are exploring microwave vacuum drying (MVD) as a faster drying process to vial lyophilization wherein the heat transfer process occurs by microwave radiation instead of pure conduction from the vial. Drying using this radiative process demonstrates greater than 80% reduction in drying time over traditional freeze-drying times while maintaining product activity and stability. Such reduction in freeze-drying process times from days to several hours is a welcome change as it enables flexible manufacturing by being able to better react to changes either in terms of product volume for on-demand manufacturing scenarios or facilities for production (e.g., scale-out over scale-up). Additionally, by utilizing first-principle modeling coupled with experimental verification, a mechanism for faster drying times associated with MVD is proposed in this article. This research, to the best of our knowledge, forms the very first report of utilizing microwave vacuum drying for vaccines while utilizing the power of simplified models to understand drying principles associated with MVD.

Recent researches have showed that patients with COVID-19 pneumonia were often accompanied by pulmonary edema. Pulmonary edema is a manifestation of acute lung injury (ALI), and may progress to hypoxemia and potentially acute respiratory distress syndrome (ARDS), which have higher mortality. Precise classification of the degree of pulmonary edema in patients is of great significance for choosing the treatment plan and further improving the survival chance. In this paper, we proposed a deep learning neural network named non-local channel attention ResNet (NCA-ResNet) to analyze the lung ultrasound images and automatically score the degree of pulmonary edema in patients with COVID-19. The proposed method was designed by combining the ResNet with non-local module and the channel attention mechanism. The non-local module was used to extract the information of characteristics of A-lines and B-lines based on which the degree of pulmonary edema could be defined. The channel attention mechanism was used to assign weights to decisive channels. The data set contains 2220 lung ultrasound images provided by Huoshenshan Hospital in Wuhan, China, of which 2062 effective images with accurate scores given by two experienced clinicians were used in the experiment. The experimental results have demonstrated that our method achieved a high accuracy of classifying the degree of pulmonary edema in patients with COVID-19 by comparing with the previous deep learning methods, indicating its good potential to monitor the patients with COVID-19.

Cardiovascular diseases (CDVs) are still the leading cause of mortality in the developed world, despite the high number of deaths caused by the COVID pandemic of the last two years [...].

Background: Studies have shown that patients with ischemic stroke (IS) and concurrent COVID-19 have increased stroke severity. These analyses were limited by use of prepandemic era controls or by utilization of a sample from the early pandemic period when stroke care delivery was affected by lockdown. Studies on the severity of hemorrhagic stroke (HS) in patients with concurrent COVID-19 are few and limited by small sample sizes. Methods: Using the National Institute of Health (NIH) National COVID Cohort Collaborative (N3C) database, we identified patients diagnosed with stroke between Mar 1, 2020 - Feb 28, 2021. Hospitalized stroke patients with concurrent COVID-19 (stroke within 3 months after or one week prior to positive SARS-COV-2 PCR or AG lab test) were matched to all other hospitalized stroke patients in a 1:3 ratio. Nearest neighbor matching with a caliper of 0.25 was used for most clinical and demographic factors;exact matching for race/ethnicity and site. Within our matched sample, we used Poisson regression to calculate stroke severity incident rate ratio (IRR). Results: Our query identified 10,394 patients hospitalized with IS with available NIHSS scores upon admission (802 with concurrent COVID-19 and 9,592 without) and 2138 patients hospitalized with HS (181 with concurrent COVID-19 and 1957 without). Average NIHSS was greater in concurrent groups with both IS and HS (11.1 vs 7.68, p < 0.001 and 15.7 vs 11.7, p < 0.001 respectively). Propensity matched analysis also demonstrated that stroke patients with concurrent COVID-19 had increased initial NIHSS (IS: IRR = 1.4, 95% CI:1.3-1.5, p-value < 0.001;HS: IRR = 1.3, 95% CI:1.2- 1.5, p < 0.001). Average NIHSS in both IS and HS patients was greater in the Mar-Apr 2020 epoch than in all other 2 month epochs studied in these respective groups. Conclusions: This analysis suggests that the association between increased stroke severity and concurrent COVID-19 that was observed during the early pandemic was present throughout the pandemic as stroke care utilization normalized. Further work will center on the interaction between COVID-19 illness severity and stroke severity.

Mouse hepatitis virus (MHV) utilizes a mouse biliary glycoprotein (Bgp) as a receptor. Co-cultivation of MHV-nonpermissive hamster BHK cells devoid of mouse Bgp with mouse DBT cells infected with MHV-A59 or JHMV induces syncytia formation on BHK cells (Bgp-independent fusion). This study shows the difference in Bgp-independent fusion activity among various MHV strains. Under a phase contrast microscopy, JHMV (cl-2, sp-4) induced the Bgp-independent syncytia on BHK cells similar to those observed on DBT cells, while such syncytia were not seen with the infection of other MHV strains (MHV-1, MHV-3, MHV-A59, MHV-S, srr7, srr11 and srr18). Tiny syncytia detectable only by immunofluorescence were produced with the latter MHV strains except for srr7 which failed to produce syncytia. MHVs except for srr7 grew in BHK cells after Bgp-independent infection. The Bgp-independent fusion by JHMV was inhibited either by anti-S1 or anti-S2 antibodies. These results showed that the JHMV spike protein had a remarkably high Bgp-independent fusion activity.

Coronavirus disease of 2019 (COVID-19) is responsible for many pulmonary and extrapulmonary complications. The main features of severe manifestations are hypoxia, thrombosis, microthrombi deposition, endothelial cell dysfunction, and cytokine storm. Since it is a new disease, there is not enough data on subacute and long-term complications, although there is compelling evidence for its occurrence. Such complications may be related to the disease itself, the combination of the disease with previous comorbidities, and also the treatment, including hospitalization, medications, and invasive procedures. The long-term impact of COVID-19 pandemic is not completely understood, but, extrapolating from studies about the impact of SARS in patients and their family caregivers, mental health issues are a big concern. Further research will be needed to assess the impact of COVID-19 for the whole society, related to its socioeconomic effects and the quarantine experience, as well as for health professionals who worked in the front line.

Endocytosis plays a particular role in the proteolytic activation of highly pathogenic henipaviruses Hendra (HeV) and Nipah virus (NiV) fusion (F) protein precursors. These proteins require endocytic uptake from the cell surface to be cleaved by cellular proteases within the endosomal compartment, followed by recycling to the plasma membrane for incorporation into budding virions or mediation of cell-cell fusion. This internalization largely depends on a tyrosine-based consensus motif for endocytosis present in the cytoplasmic tail of HeV and NiV F. Given the large number of tyrosine residues present in the F protein cytoplasmic domain of Cedar virus (CedV), a closely related but low pathogenic henipavirus, we aimed to investigate whether CedV F protein undergoes signal-mediated endocytosis from the cell surface controlled by tyrosine-based motifs present in its cytoplasmic tail and whether endocytosis is relevant for its biological activity. Therefore, tyrosine-based signals were mutated, and mutations were assessed for their effect on F cell surface expression, endocytosis, and biological activity. A membrane-proximal YXX&#934; motif and a C-terminal di-tyrosine motif are of particular importance for cell surface expression and endocytosis rate. Furthermore, our data strongly indicate the pivotal role of endocytosis for the biological activity of the CedV F protein.

The objective of this study was to test the effectiveness of ivermectin for the treatment of mouse hepatitis virus (MHV), a type 2 family RNA coronavirus similar to SARS-CoV-2. Female BALB/cJ mice were infected with 6,000 PFU of MHV-A59 (group infected, n = 20) or infected and then immediately treated with a single dose of 500 g/kg ivermectin (group infected + IVM, n = 20) or were not infected and treated with PBS (control group, n = 16). Five days after infection/treatment, the mice were euthanized and the tissues were sampled to assess their general health status and infection levels. Overall, the results demonstrated that viral infection induced typical MHV-caused disease, with the livers showing severe hepatocellular necrosis surrounded by a severe lymphoplasmacytic inflammatory infiltration associated with a high hepatic viral load (52,158 AU), while mice treated with ivermectin showed a better health status with a lower viral load (23,192 AU; p < 0.05), with only a few having histopathological liver damage (p < 0.05). No significant differences were found between the group infected + IVM and control group mice (P = NS). Furthermore, serum transaminase levels (aspartate aminotransferase and alanine aminotransferase) were significantly lower in the treated mice than in the infected animals. In conclusion, ivermectin diminished the MHV viral load and disease in the mice, being a useful model for further understanding this therapy against coronavirus diseases.

The COVID-19 pandemic verifies the preparation of medical care in individual countries in terms of the fluent of guaranteed medical services provided to the people in need. Due to the easy spread of SARS-CoV-2 virus when in direct contact with the patients, health care workers are at an increased risk of infection. Nurses and auxiliary staff, as well as medical doctors, were most frequently infected. The prevalence of infection depends on the adopted reporting method, including the diagnostic test used to recognize the infection, the nature of the work performed, but also on the gender, knowledge, and individual behavior of employees while performing their professional duties. It ranges from 5-30% depending on the country and the occupational group, and the highest rates were recorded in the initial phase of the pandemic. A review of the literature shows the lack of a uniform, transparent system of reporting infections in health care workers, which makes a reliable assessment of the epidemiological situation in this area difficult.

Asthma in pregnancy is a health issue of great concern. Physiological changes and drug compliance during pregnancy can affect asthma control in varying degrees, and the control level of asthma and the side effects of asthma medications are closely related to the adverse perinatal outcomes of mother and fetus. This article provides an update on the available literature regarding the alleviating or aggravating mechanism of asthma in pregnancy, diagnosis, disease assessment, and systematic management, to provide a new guidance for physician, obstetric joint doctor, and health care practitioner.

Perillyl alcohol (POH) has been extensively studied for the treatment of peripheral and primary brain tumors. The intranasal route of administration has been preferred for dosing POH in early-stage clinical trials associated with promising outcomes in primary brain cancer. However, it is unclear how intranasal POH targets brain tumors in these patients. Multiple studies indicate that intranasally applied large molecules may enter the brain and cerebrospinal fluid (CSF) through direct olfactory and trigeminal nerve-associated pathways originating in the nasal mucosa that bypass the blood-brain barrier. It is unknown whether POH, a small molecule subject to extensive nasal metabolism and systemic absorption, may also undergo direct transport to brain or CSF from the nasal mucosa. Here, we compared CSF and plasma concentrations of POH and its metabolite, perillic acid (PA), following intranasal or intravascular POH application. Samples were collected over 70 min and assayed by high-performance liquid chromatography. Intranasal administration resulted in tenfold higher CSF-to-plasma ratios for POH and tenfold higher CSF levels for PA compared to equal dose intravascular administration. Our preclinical results demonstrate POH undergoes direct transport from the nasal mucosa to the CSF, a finding with potential significance for its efficacy as an intranasal chemotherapeutic for brain cancer.

The highly pathogenic virus SARS-CoV-2 has shattered the healthcare system of the world causing the COVID-19 pandemic since first detected in Wuhan, China. Therefore, scrutinizing the genome structure and tracing the transmission of the virus has gained enormous interest in designing appropriate intervention strategies to control the pandemic. In this report, we examined 4622 sequences from Bangladesh and found that they belonged to thirty-five major PANGO lineages, while Delta alone accounted for 39%, and 78% were from just four primary lineages. Our research has also shown Dhaka to be the hub of viral transmission and observed the virus spreading back and forth across the country at different times by building a transmission network. The analysis resulted in 7659 unique mutations, with an average of 24.61 missense mutations per sequence. Moreover, our analysis of genetic diversity and mutation patterns revealed that eight genes were under negative selection pressure to purify deleterious mutations, while three genes were under positive selection pressure. ImportanceWith 29,122 deaths, 1.95 million infections and a shattered healthcare system from SARS-CoV-2 in Bangladesh, the only way to avoid further complications is to break the transmission network of the virus. Therefore, it is vital to shedding light on the transmission, divergence, mutations, and emergence of new variants using genomic data analyses and surveillance. Here, we present the geographic and temporal distribution of different SARS-CoV-2 variants throughout Bangladesh over the past two years, and their current prevalence. Further, we have developed a transmission network of viral spreads, which in turn will help take intervention measures. Then we analyzed all the mutations that occurred and their effect on evolution as well as the currently present mutations that could trigger a new variant of concern. In short, together with an ongoing genomic surveillance program, these data will help to better understand SARS-CoV-2, its evolution, and pandemic characteristics in Bangladesh.

SARS-CoV-2 infection, which is responsible for the current COVID-19 pandemic, can cause life-threatening pneumonia, respiratory failure and even death. Characterizing SARS-CoV-2 pathogenesis in primary human target cells and tissues is crucial for developing vaccines and therapeutics. However, given the limited access to clinical samples from COVID-19 patients, there is a pressing need for in vitro/in vivo models to investigate authentic SARS-CoV-2 infection in primary human lung cells or tissues with mature structures. The present study was designed to evaluate a humanized mouse model carrying human lung xenografts for SARS-CoV-2 infection in vivo. Methods: Human fetal lung tissue surgically grafted under the dorsal skin of SCID mice were assessed for growth and development after 8 weeks. Following SARS-CoV-2 inoculation into the differentiated lung xenografts, viral replication, cell-type tropism and histopathology of SARS-CoV-2 infection, and local cytokine/chemokine expression were determined over a 6-day period. The effect of IFN-&#945; treatment against SARS-CoV-2 infection was tested in the lung xenografts. Results: Human lung xenografts expanded and developed mature structures closely resembling normal human lung. SARS-CoV-2 replicated and spread efficiently in the lung xenografts with the epithelial cells as the main target, caused severe lung damage, and induced a robust pro-inflammatory response. IFN-&#945; treatment effectively inhibited SARS-CoV-2 replication in the lung xenografts. Conclusions: These data support the human lung xenograft mouse model as a useful and biological relevant tool that should facilitate studies on the pathogenesis of SARS-CoV-2 lung infection and the evaluation of potential antiviral therapies.

During the recent outbreak of Ebola virus disease (EVD) in west Africa, we established an Ebola treatment center (ETC) with improved ward architecture. The ETC was built with movable prefabricated boards according to infectious disease unit standard requirements. The clinical staff ensured their own security while providing patients with effective treatment. Of the 180 admissions to the ETC, 10 cases were confirmed with EVD of which six patients survived. None of the clinical staff was infected. We hope that our experience will enable others to avoid unnecessary risks while delivering EVD care.

We describe the results of two vaccinations of a self-experimenting healthy volunteer with SARS-CoV-2-derived peptides performed in March and April 2020, respectively The first set of peptides contained eight peptides predicted to bind to the individuals HLA molecules The second set consisted of ten peptides predicted to bind promiscuously to several HLA-DR allotypes The vaccine formulation contained the new TLR 1/2 agonist XS15 and was administered as an emulsion in Montanide as a single subcutaneous injection Peripheral blood mononuclear cells isolated from blood drawn before and after vaccinations were assessed using Interferon- ELISpot assays and intracellular cytokine staining We detected vaccine-induced CD4 T cell responses against six out of 11 peptides predicted to bind to HLA-DR after 19 days, following vaccination, for one peptide already at day 12 We used these results to support the design of a T-cell-inducing vaccine for application in high-risk patients, with weakened lymphocyte performance Meanwhile, an according vaccine, incorporating T cell epitopes predominant in convalescents, is undergoing clinical trial testing

SARS-CoV-2 infection results in highly heterogeneous outcomes, from cure without symptoms to acute respiratory distress and death. While immunological correlates of disease severity have been identified, how they act together to determine the outcomes is unknown. Here, using a new mathematical model of within-host SARS-CoV-2 infection, we analyze diverse clinical datasets and predict that a subtle interplay between innate and CD8 T-cell responses underlies disease heterogeneity. Our model considers essential features of these immune arms and immunopathology from cytokines and effector cells. Model predictions provided excellent fits to patient data and, by varying the strength and timing of the immune arms, quantitatively recapitulated viral load changes in mild, moderate, and severe disease, and death. Additionally, they explained several confounding observations, including viral recrudescence after symptom loss, prolonged viral positivity before cure, and mortality despite declining viral loads. Together, a robust conceptual understanding of COVID-19 outcomes emerges, bearing implications for interventions.

In recent times, social prescribing has been introduced in some countries, and substantially in the U.K. The objective of this scheme is to offer non-medical care mainly to primary care patients. Although the idea of this scheme is not new, its formalization is. Using a narrative synthesis of peer-reviewed and gray literature, this article discusses the social prescribing scheme, some of its compelling aspects and challenges in offering non-medical care, particularly regarding referrals being made from primary care settings. The social prescribing scheme has several impelling forces that include its potential to turn primary care to primary healthcare, tackle social determinants of health and social needs, improve wellbeing and physical health, offer person-centered care, strengthen preventive care, and bridge healthcare organizations with the third sector. This scheme also faces several challenges including service standards and boundaries, sustainability, availability of appropriate services, low engagement of clients and insufficient evidence. While this scheme lacks validated evidence, it is theoretically compelling. Given that the demand for non-medical care is growing in most societies and that the usefulness of non-medical care is gaining prominence, social prescribing is likely to continue to proliferate.

Neutralizing antibodies targeting the receptor binding domain (RBD) of the SARS-CoV-2 Spike (S) are among the most promising approaches against coronavirus disease 2019 (COVID-19)1,2. We developed a bispecific, IgG1-like molecule based on two antibodies derived from COVID-19 convalescent donors, C121 and C1353. CoV-X2 simultaneously binds two independent sites on the RBD and, unlike its parental antibodies, completely prevents S binding to Angiotensin-Converting Enzyme 2 (ACE2), the virus cellular receptor. Furthermore, CoV-X2 recognizes a broad panel of RBD variants and neutralizes SARS-CoV-2 and the escape mutants generated by the single monoclonals at sub-nanomolar concentrations. In a novel model of SARS-CoV-2 infection with lung inflammation, CoV-X2 protects mice from disease and suppresses viral escape. Thus, simultaneous targeting of non-overlapping RBD epitopes by IgG-like bispecific antibodies is feasible and effective, combining into a single molecule the advantages of antibody cocktails.

The campuses and classrooms of the University of Bangui do not have connectivity due to insufficient network infrastructure. However, there are Dynamic Spectrum Access technologies in the unused VHF and UHF analog TV band called TV White Space that can be used to provide high-speed Wi-Fi access over wide coverage and at lower cost. Since March 2020, courses have been suspended at the University of Bangui to effectively limit and combat the COVID-19 pandemic. After a three-month period of containment, academic activities have resumed. The increase in the number of cases of COVID-19 contamination raises concerns about this resumption. Given the rules of social distancing that limit the number of students in classrooms, the risks of travelling by public transport and the lack of motivation of some students following years of war, the University of Bangui can organize distance learning as a transitional measure. This paper is the subject of a feasibility study on the interconnection of surrounding neighborhoods and villages by TV White Space at the University of Bangui that can accommodate students and teachers for distance learning courses in the context of COVID-19. The methodological approach consists in studying the deployment of a White Space TV network to interconnect the peripheral areas at the University of Bangui, then using the Moodle distance learning platform on which we integrate the virtual classroom plugin, deployed locally and running without Internet connectivity. The bandwidth of the White Space TV will be important to practice the educational activities without spending money to pay the Internet credits of the operators' networks. Students can connect locally via Wi-Fi in the areas covered by the platform and follow the different academic activities according to their geographical location, while others closer to the university can go to the classroom to attend classes with the professor in the rules enacted for protection against COVID-19. Our solution initially helps to break the digital divide and then to promote e-learning at the University of Bangui in the context of COVID-19.