[Detection of SARS-CoV-2 RNA in the mucosa of the appendices of children with COVID-19]. / Vyyavlenie RNK SARS-CoV-2 v slizistoi obolochke cherveobraznogo otrostka u detei s COVID-19.

Background. The novel coronavirus infection (COVID-19) often manifests in children as diarrhea, vomiting, abdominal pain, and some children develop acute appendicitis. To elucidate the role of SARS-CoV-2 in the development of acute appendicitis, a more detailed study of the presence of its genetic material in the tissue of the appendix. OBJECTIVE: Determination of SARS-CoV-2 RNA in appendices of children with COVID-19 by fluorescence in situ hybridization (FISH). MATERIAL AND METHODS: A retrospective analysis of case histories and morphological analysis using FISH of appendices of pediatric patients with established clinical diagnosis of acute appendicitis and confirmed infection with SARS-CoV-2 was performed. The material was divided into 3 groups: 1st -appendices obtained during appendectomy in children with established clinical diagnosis of «coronavirus infection¼ (COVID-19, PCR+) (n=42; mean age 10.8 years); 2nd - appendices of children (n=55; mean age 9.7 years) with acute appendicitis obtained before the onset of the COVID-19 pandemic; 3rd (control) group (n=38; mean age 10.3 years) - autopsy material of the appendices (intact). RESULTS: In all samples of the appendices of the 1st group, a positive SARS-CoV-2 viral RNA signal was noted in the cytoplasm of most epithelial cells and single immunocompetent cells. The signal intensity remained the same in all slides, regardless of age. In all samples obtained from patients without COVID-19 (groups 2 and 3), confocal microscopy did not reveal a signal, which indicates successful adaptation of the FISH method in this study and excludes the false positive results. CONCLUSION: In the epithelium of the appendices of children of different age with COVID-19, the FISH method revealed SARS-CoV-2 RNA, which does not exclude the association between viral invasion and the development of acute appendicitis.

The nursing care for the medical device related pressure injury patient with a mucosal pressure injury due to an endotracheal tube: a case report.

BACKGROUND: Pressure injury (PI) due to medical devices is one of the most common PIs, especially in patients treated in intensive care. Medical device-related pressure injuries (MDRPIs), as part of their treatment, require extra care and prevention interventions than injuries caused by immobilization. Standardized nursing models are needed to care for PIs caused by medical devices on mucous membranes. PURPOSE: To provide information about the evaluation and care of the MDRPIs in the mucosal membrane due to the endotracheal tube (ET). CASE REPORT: A 35-year-old male with chronic obstructive pulmonary disease (COPD) and coronavirus disease has MDRPIs on the lower lip edge due to the ET on the fifteenth day after intubation. North American Nursing Diagnosis Association (NANDA) diagnoses were determined by systematically analyzing the data using the Gordon's Functional Health Patterns (GFHP) model in the patient. Nursing care was planned and applied in line with the determined NANDA diagnoses, Nursing Outcomes Classification (NOC) interventions, and using the recommendations of current PI guides for treatment of MDRPIs. CONCLUSION: This case report illustrates MDRPIs resulting from ET and provides information about the formation of MDRPIs and appropriate maintenance therapy. Future research is recommended to examine and evaluate the nursing care and outcome of MDRPIs in different mucosal membranes.

Gut distress and intervention via communications of SARS-CoV-2 with mucosal exposome.

Acute coronavirus disease 2019 (COVID-19) has been associated with prevalent gastrointestinal distress, characterized by fecal shedding of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) RNA or persistent antigen presence in the gut. Using a meta-analysis, the present review addressed gastrointestinal symptoms, such as nausea, vomiting, abdominal pain, and diarrhea. Despite limited data on the gut-lung axis, viral transmission to the gut and its influence on gut mucosa and microbial community were found to be associated by means of various biochemical mechanisms. Notably, the prolonged presence of viral antigens and disrupted mucosal immunity may increase gut microbial and inflammatory risks, leading to acute pathological outcomes or post-acute COVID-19 symptoms. Patients with COVID-19 exhibit lower bacterial diversity and a higher relative abundance of opportunistic pathogens in their gut microbiota than healthy controls. Considering the dysbiotic changes during infection, remodeling or supplementation with beneficial microbial communities may counteract adverse outcomes in the gut and other organs in patients with COVID-19. Moreover, nutritional status, such as vitamin D deficiency, has been associated with disease severity in patients with COVID-19 via the regulation of the gut microbial community and host immunity. The nutritional and microbiological interventions improve the gut exposome including the host immunity, gut microbiota, and nutritional status, contributing to defense against acute or post-acute COVID-19 in the gut-lung axis.

Intranasal administration of sodium nitroprusside augments antigen-specific mucosal and systemic antibody production in mice.

The coronavirus disease 2019, i.e., the COVID-19 pandemic, caused by a highly virulent and transmissible pathogen, has profoundly impacted global society. One approach to combat infectious diseases caused by pathogenic microbes is using mucosal vaccines, which can induce antigen-specific immune responses at both the mucosal and systemic sites. Despite its potential, the clinical implementation of mucosal vaccination is hampered by the lack of safe and effective mucosal adjuvants. Therefore, developing safe and effective mucosal adjuvants is essential for the fight against infectious diseases and the widespread clinical use of mucosal vaccines. In this study, we demonstrated the potent mucosal adjuvant effects of intranasal administration of sodium nitroprusside (SNP), a known nitric oxide (NO) donor, in mice. The results showed that intranasal administration of ovalbumin (OVA) in combination with SNP induced the production of OVA-specific immunoglobulin A in the mucosa and increased serum immunoglobulin G1 levels, indicating a T helper-2 (Th2)-type immune response. However, an analog of SNP, sodium ferrocyanide, which does not generate NO, failed to show any adjuvant effects, suggesting the critical role of NO generation in activating an immune response. In addition, SNPs facilitated the delivery of antigens to the lamina propria, where antigen-presenting cells are located, when co-administered with antigens, and also transiently elicited the expression of interleukin-6, interleukin-1ß, granulocyte colony-stimulating factor, C-X-C motif chemokine ligand 1, and C-X-C motif chemokine ligand 2 in nasal tissue. These result suggest that SNP is a dual-functional formulation with antigen delivery capabilities to the lamina propria and the capacity to activate innate immunity. In summary, these results demonstrate the ability of SNP to induce immune responses via an antigen-specific Th2-type response, making it a promising candidate for further development as a mucosal vaccine formulation against infectious diseases.

Mucosal vaccines for SARS-CoV-2: triumph of hope over experience.

Currently approved COVID-19 vaccines administered parenterally induce robust systemic humoral and cellular responses. While highly effective against severe disease, there is reduced effectiveness of these vaccines in preventing breakthrough infection and/or onward transmission, likely due to poor immunity elicited at the respiratory mucosa. As such, there has been considerable interest in developing novel mucosal vaccines that engenders more localised immune responses to provide better protection and recall responses at the site of virus entry, in contrast to traditional vaccine approaches that focus on systemic immunity. In this review, we explore the adaptive components of mucosal immunity, evaluate epidemiological studies to dissect if mucosal immunity conferred by parenteral vaccination or respiratory infection drives differential efficacy against virus acquisition or transmission, discuss mucosal vaccines undergoing clinical trials and assess key challenges and prospects for mucosal vaccine development.

Promises and challenges of mucosal COVID-19 vaccines.

Coronavirus disease-2019 (COVID-19) is an ongoing pandemic caused by the newly emerged virus severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Currently, COVID-19 vaccines are given intramuscularly and they have been shown to evoke systemic immune responses that are highly efficacious towards preventing severe disease and death. However, vaccine-induced immunity wanes within a short time, and booster doses are currently recommended. Furthermore, current vaccine formulations do not adequately restrict virus infection at the mucosal sites, such as in the nasopharyngeal tract and, therefore, have limited capacity to block virus transmission. With these challenges in mind, several mucosal vaccines are currently being developed with the aim of inducing long-lasting protective immune responses at the mucosal sites where SARS-COV-2 infection begins. Past successes in mucosal vaccinations underscore the potential of these developmental stage SARS-CoV-2 vaccines to reduce disease burden, if not eliminate it altogether. Here, we discuss immune responses that are triggered at the mucosal sites and recent advances in our understanding of mucosal responses induced by SARS-CoV-2 infection and current COVID-19 vaccines. We also highlight several mucosal SARS-COV-2 vaccine formulations that are currently being developed or tested for human use and discuss potential challenges to mucosal vaccination.

Mucoadhesive drug delivery systems: a promising noninvasive approach to bioavailability enhancement. Part II: formulation considerations.

INTRODUCTION: Mucoadhesive drug delivery systems (MDDS) are specifically designed to interact and bind to the mucosal layer of the epithelium for localized, prolonged, and/or targeted drug delivery. Over the past 4 decades, several dosage forms have been developed for localized as well as systemic drug delivery at different anatomical sites. AREAS COVERED: The objective of this review is to provide a detailed understanding of the different aspects of MDDS. Part II describes the origin and evolution of MDDS, followed by a discussion of the properties of mucoadhesive polymers. Finally, a synopsis of the different commercial aspects of MDDS, recent advances in the development of MDDS for biologics and COVID-19 as well as future perspectives are provided. EXPERT OPINION: A review of the past reports and recent advances reveal MDDS as highly versatile, biocompatible, and noninvasive drug delivery systems. The rise in the number of approved biologics, the introduction of newer highly efficient thiomers, as well as the recent advances in the field of nanotechnology have led to several excellent applications of MDDS, which are predicted to grow significantly in the future.

Multidisciplinary Treatment in Toxic Epidermal Necrolysis.

Toxic epidermal necrolysis, Leyll's syndrome (TEN), is a rare mucocutaneous blistering disease burdened with high mortality rates. The diagnosis of TEN is based on clinical symptoms and histopathological findings. In approximately 90% of cases, it is a severe adverse reaction to drugs. In TEN, not only is the skin affected, but also mucosa and organs' epithelium. There are no unequivocal recommendations in regard to systemic and topical treatment of the patients. The aim of this paper is to review available literature and propose unified protocols to be discussed. Early management and multidisciplinary treatment are necessary to improve patients' outcome. Treatment of patients with TEN suspicions should be initiated with early drug withdrawal. TEN patients, like patients with burns, require intensive care and multidisciplinary management. Each patient with TEN should be provided with adequate fluid resuscitation, respiratory support, nutritional treatment, pain control, infection prophylaxis, anticoagulant therapy, and gastric ulcer prophylaxis. The key to local treatment of patients with TEN is the use of nonadherent dressings that do not damage the epidermis during the change. The aim of the systemic treatment is purification of the blood stream from the causative agent. The most efficient way to clarify serum of TEN patients' is the combination of plasmapheresis and IVIG. Immunomodulatory therapy can reduce the mortality five times in comparison with the patients with immunosuppression or lack of full protocol.

Vaccines, adjuvants and key factors for mucosal immune response.

Vaccines are the most effective tool to control infectious diseases, which provoke significant morbidity and mortality rates. Most vaccines are administered through the parenteral route and can elicit a robust systemic humoral response, but they induce a weak T-cell-mediated immunity and are poor inducers of mucosal protection. Considering that most pathogens enter the body through mucosal surfaces, a vaccine that elicits protection in the first site of contact between the host and the pathogen is promising. However, despite the advantages of mucosal vaccines as good options to confer protection on the mucosal surface, only a few mucosal vaccines are currently approved. In this review, we discuss the impact of vaccine administration in different mucosal surfaces; how appropriate adjuvants enhance the induction of protective mucosal immunity and other factors that can influence the mucosal immune response to vaccines.

MORPHOLOGICAL AND FUNCTIONAL FEATURES OF THE MUCOUS MEMBRANE OF SMALL AND LARGE INTESTINE IN PATIENTS WITH COVID-19 AND IN POST-COVID-19 PERIOD.

OBJECTIVE: The aim: To reveal the morphological and functional features of the mucous membrane of small and large intestine in patients with COVID-19 and in post-COVID-19 period. PATIENTS AND METHODS: Materials and methods: In the present study, the authors used biopsy and autopsy material represented by the fragments of the mucous membrane of small and large intestine. All studied material was divided into 10 groups. Group 1 (comparison group) included autopsy material from the deceased who did not have COVID-19 during their lifetime. Groups 2-4 included autopsy material from the deceased who had COVID-19 of varying severity during their lifetime. Groups 5-7 included biopsy material from patients who had recovered from COVID-19 of varying severity, while the duration of the post-COVID period ranged from 1 to 50 days. Groups 8-10 included biopsy material from patients who had in anamnesis COVID-19 of varying severity (the duration of the post-COVID period lasted from 51 to 100 days). Histological, immunohistochemical, morphometric and statistical research methods were used. RESULTS: Results: The comparative analysis showed a more expressed deficiency of ACE2 in the mucous membrane of small and large intestine in patients with moderate and severe COVID-19 compared with patients in post-COVID-19 period of different duration. In patients who had moderate and severe COVID-19 in anamnesis, ACE2 deficiency decreases with increasing duration of post-COVID-19 period. In patients recovered from mild COVID-19, the ACE2 content increases with the duration of post-COVID-19 period from 1 to 50 days and corresponds to the norm with the duration of this period from 51 to 100 days. CONCLUSION: Conclusions: The comprehensive morphological study conducted by the authors made it possible, firstly, to clarify the morphological and functional features of the mucous membrane of small and large intestine in patients with COVID-19 of various degrees of severity; secondly, to obtain new data about the morpho-functional state of the mucous membrane of small and large intestine in patients, taking into account different duration of the post-COVID-19 period and the severity of the infection.

Morphological and Phenotypic Characteristics of the Bovine Nasopharyngeal Mucosa and Associated Lymphoid Tissue.

The mammalian nasopharynx is an anatomically complex region of the upper respiratory tract that directly communicates with the nasal cavity, laryngopharynx, oesophagus and trachea. The nasopharyngeal mucosa contains moderate quantities of mucosa-associated lymphoid tissue (MALT) that is appropriately located for immunological sampling but also creates vulnerability to pathogens. In recent years, the nasopharynx has been inculpated in the pathogenesis of important diseases of cattle (foot-and-mouth disease) and humans (COVID-19), yet the tissue has never been described in detail in any species. In order to characterize the morphology and cellular composition of the bovine nasopharynx, samples of mucosa were collected from the nasopharynx of five 8-13-month-old steers and examined using light microscopy, immunohistochemistry and multichannel immunofluorescence. Morphologically, the nasopharyngeal epithelium was highly heterogeneous, with a continuum ranging from stratified squamous epithelium to highly attenuated, follicle-associated epithelium (FAE). Distribution of MALT was similarly regionally variable ranging from absent to clusters of multiple lymphoid follicles. Phenotypic characterization demonstrated dense distributions of dendritic cells and T lymphocytes surrounding lymphoid follicles, which comprised mostly B lymphocytes. The FAE overlaying the lymphoid follicles also contained higher numbers of dendritic cells and lymphocytes compared with the adjacent non-lymphoid epithelium, although cytotoxic T cells were notably scarce in the FAE. The bovine nasopharyngeal lymphoid tissue had comparable elements to other MALTs with specific differences that may help to elucidate the pathogenesis of infectious agents that have specific tropism for this tissue.

Experimental investigations of the human oesophagus: anisotropic properties of the embalmed mucosa-submucosa layer under large deformation.

Mechanical characterisation of the layer-specific, viscoelastic properties of the human oesophagus is crucial in furthering the development of devices emerging in the field, such as robotic endoscopic biopsy devices, as well as in enhancing the realism, and therefore effectiveness, of surgical simulations. In this study, the viscoelastic and stress-softening behaviour of the passive human oesophagus was investigated through ex vivo cyclic mechanical tests. Due to restrictions placed on the laboratory as a result of COVID-19, only oesophagi from cadavers fixed in formalin were allowed for testing. Three oesophagi in total were separated into their two main layers and the mucosa-submucosa layer was investigated. A series of uniaxial tensile tests were conducted in the form of increasing stretch level cyclic tests at two different strain rates: 1% s[Formula: see text] and 10% s[Formula: see text]. Rectangular samples in both the longitudinal and circumferential directions were tested to observe any anisotropy. Histological analysis was also performed through a variety of staining methods. Overall, the longitudinal direction was found to be much stiffer than the circumferential direction. Stress-softening was observed in both directions, as well as permanent set and hysteresis. Strain rate-dependent behaviour was also apparent in the two directions, with an increase in strain rate resulting in an increase in stiffness. This strain rate dependency was more pronounced in the longitudinal direction than the circumferential direction. Finally, the results were discussed in regard to the histological content of the layer, and the behaviour was modelled and validated using a visco-hyperelastic matrix-fibre model.

Sputnik-V reactogenicity and immunogenicity in the blood and mucosa: a prospective cohort study.

Sputnik-V (Gam-COVID-Vac) is a heterologous, recombinant adenoviral (rAdv) vector-based, COVID-19 vaccine now used in > 70 countries. Yet there is a shortage of data on this vaccine's performance in diverse populations. Here, we performed a prospective cohort study to assess the reactogenicity and immunologic outcomes of Sputnik-V vaccination in Kazakhstan. COVID-19-free participants (n = 82 at baseline) were followed at day 21 after Sputnik-V dose 1 (rAd5) and dose 2 (rAd26). Self-reported local and systemic adverse events were captured using questionnaires. Blood and nasopharyngeal swabs were collected to perform SARS-CoV-2 diagnostic and immunologic assays. We observed that most of the reported adverse events were mild-to-moderate injection site or systemic reactions, no severe or potentially life-threatening conditions were reported, and dose 1 appeared to be more reactogenic than dose 2. The seroconversion rate was 97% post-dose 1, remaining the same post-dose 2. The proportion of participants with detectable virus neutralization was 83% post-dose 1, increasing to 98% post-dose 2, with the largest relative increase observed in participants without prior COVID-19 exposure. Dose 1 boosted nasal S-IgG and S-IgA, while the boosting effect of dose 2 on mucosal S-IgG, but not S-IgA, was only observed in subjects without prior COVID-19. Systemically, vaccination reduced serum levels of growth regulated oncogene (GRO), which correlated with an elevation in blood platelet count. Overall, Sputnik-V dose 1 elicited both blood and mucosal SARS-CoV-2 immunity, while the immune boosting effect of dose 2 was minimal. Thus, adjustments to the current vaccine dosing regimen are necessary to optimize immunization efficacy and cost-effectiveness. While Sputnik-V reactogenicity is similar to that of other COVID-19 vaccines, the induced alterations to the GRO/platelet axis warrant investigation of the vaccine's effects on systemic immunology.

Know your enemy or find your friend?-Induction of IgA at mucosal surfaces.

Most antibodies produced in the body are of the IgA class. The dominant cell population producing them are plasma cells within the lamina propria of the gastrointestinal tract, but many IgA-producing cells are also found in the airways, within mammary tissues, the urogenital tract and inside the bone marrow. Most IgA antibodies are transported into the lumen by epithelial cells as part of the mucosal secretions, but they are also present in serum and other body fluids. A large part of the commensal microbiota in the gut is covered with IgA antibodies, and it has been demonstrated that this plays a role in maintaining a healthy balance between the host and the bacteria. However, IgA antibodies also play important roles in neutralizing pathogens in the gastrointestinal tract and the upper airways. The distinction between the two roles of IgA - protective and balance-maintaining - not only has implications on function but also on how the production is regulated. Here, we discuss these issues with a special focus on gut and airways.

An intranasal lentiviral booster reinforces the waning mRNA vaccine-induced SARS-CoV-2 immunity that it targets to lung mucosa.

As the coronavirus disease 2019 (COVID-19) pandemic continues and new severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants of concern emerge, the adaptive immunity initially induced by the first-generation COVID-19 vaccines starts waning and needs to be strengthened and broadened in specificity. Vaccination by the nasal route induces mucosal, humoral, and cellular immunity at the entry point of SARS-CoV-2 into the host organism and has been shown to be the most effective for reducing viral transmission. The lentiviral vaccination vector (LV) is particularly suitable for this route of immunization owing to its non-cytopathic, non-replicative, and scarcely inflammatory properties. Here, to set up an optimized cross-protective intranasal booster against COVID-19, we generated an LV encoding stabilized spike of SARS-CoV-2 Beta variant (LV::SBeta-2P). mRNA vaccine-primed and -boosted mice, with waning primary humoral immunity at 4 months after vaccination, were boosted intranasally with LV::SBeta-2P. A strong boost effect was detected on cross-sero-neutralizing activity and systemic T cell immunity. In addition, mucosal anti-spike IgG and IgA, lung-resident B cells, and effector memory and resident T cells were efficiently induced, correlating with complete pulmonary protection against the SARS-CoV-2 Delta variant, demonstrating the suitability of the LV::SBeta-2P vaccine candidate as an intranasal booster against COVID-19. LV::SBeta-2P vaccination was also fully protective against Omicron infection of the lungs and central nervous system, in the highly susceptible B6.K18-hACE2IP-THV transgenic mice.

Strategies to Develop a Mucosa-Targeting Vaccine against Emerging Infectious Diseases.

Numerous pathogenic microbes, including viruses, bacteria, and fungi, usually infect the host through the mucosal surfaces of the respiratory tract, gastrointestinal tract, and reproductive tract. The mucosa is well known to provide the first line of host defense against pathogen entry by physical, chemical, biological, and immunological barriers, and therefore, mucosa-targeting vaccination is emerging as a promising strategy for conferring superior protection. However, there are still many challenges to be solved to develop an effective mucosal vaccine, such as poor adhesion to the mucosal surface, insufficient uptake to break through the mucus, and the difficulty in avoiding strong degradation through the gastrointestinal tract. Recently, increasing efforts to overcome these issues have been made, and we herein summarize the latest findings on these strategies to develop mucosa-targeting vaccines, including a novel needle-free mucosa-targeting route, the development of mucosa-targeting vectors, the administration of mucosal adjuvants, encapsulating vaccines into nanoparticle formulations, and antigen design to conjugate with mucosa-targeting ligands. Our work will highlight the importance of further developing mucosal vaccine technology to combat the frequent outbreaks of infectious diseases.

A systematic review on mucocutaneous presentations after COVID-19 vaccination and expert recommendations about vaccination of important immune-mediated dermatologic disorders.

With dermatologic side effects being fairly prevalent following vaccination against COVID-19, and the multitude of studies aiming to report and analyze these adverse events, the need for an extensive investigation on previous studies seemed urgent, in order to provide a thorough body of information about these post-COVID-19 immunization mucocutaneous reactions. To achieve this goal, a comprehensive electronic search was performed through the international databases including Medline (PubMed), Scopus, Cochrane, Web of science, and Google scholar on July 12, 2021, and all articles regarding mucocutaneous manifestations and considerations after COVID-19 vaccine administration were retrieved using the following keywords: COVID-19 vaccine, dermatology considerations and mucocutaneous manifestations. A total of 917 records were retrieved and a final number of 180 articles were included in data extraction. Mild, moderate, severe and potentially life-threatening adverse events have been reported following immunization with COVID vaccines, through case reports, case series, observational studies, randomized clinical trials, and further recommendations and consensus position papers regarding vaccination. In this systematic review, we categorized these results in detail into five elaborate tables, making what we believe to be an extensively informative, unprecedented set of data on this topic. Based on our findings, in the viewpoint of the pros and cons of vaccination, mucocutaneous adverse events were mostly non-significant, self-limiting reactions, and for the more uncommon moderate to severe reactions, guidelines and consensus position papers could be of great importance to provide those at higher risks and those with specific worries of flare-ups or inefficient immunization, with sufficient recommendations to safely schedule their vaccine doses, or avoid vaccination if they have the discussed contra-indications.

Ulcers on the bilateral palate mucosa following mRNA-based vaccination for coronavirus disease 2019 (COVID-19): A case report.

Severe acute respiratory syndrome coronavirus 2 has spread globally. Vaccination for coronavirus disease 2019 (COVID-19) is anticipated to reduce morbidity and mortality. However, the safety of vaccines against COVID-19 is a cause for concern and uncertainty, which leads to vaccine hesitancy. There have been some self-reported questionnaire studies regarding adverse effects after COVID-19 vaccination; however, adverse effects on the oral region are rare. In this report, we present one case of ulcers arising on the bilateral palate mucosa following COVID-19 vaccination, which was suspected to be an adverse effect of vaccination.