Antiviral actions of natural compounds against dengue virus RNA dependent RNA polymerase: insights from molecular dynamics and Gibbs free energy landscape.

Dengue fever, a major global health challenge, affects nearly half the world's population and lacks effective treatments or vaccines. Addressing this, our study focused on natural compounds that potentially inhibit the dengue virus's RNA-dependent RNA polymerase (RdRp), a crucial target in the viral replication cycle. Utilizing the MTiOpenScreen webserver, we screened 1226 natural compounds from the NP-lib database. This screening identified four promising compounds ZINC000059779788, ZINC0000044404209, ZINC0000253504517 and ZINC0000253499146), each demonstrating high negative binding energies between -10.4 and -9.9 kcal/mol, indicative of strong potential as RdRp inhibitors. These compounds underwent rigorous validation through re-docking and a detailed 100 ns molecular dynamics (MD) simulation. This analysis affirmed the dynamic stability of the protein-ligand complexes, a critical factor in the effectiveness of potential drug candidates. Additionally, we conducted essential dynamics and free energy landscape calculations to understand the structural transitions in the RdRp protein upon ligand binding, providing valuable insights into the mechanism of inhibition. Our findings present these natural molecules as promising therapeutic agents against the dengue virus. By targeting the allosteric site of RdRp, these compounds offer a novel approach to hinder the viral replication process. This research significantly contributes to the search for effective anti-dengue treatments, positioning natural compounds as potential key players in dengue virus control strategies.Communicated by Ramaswamy H. Sarma.

The relationship between hand hygiene and rates of acute respiratory infections among Umrah pilgrims: A pilot randomised controlled trial.

BACKGROUND: There is a lack of randomised controlled trials (RCTs) investigating the role of hand hygiene in preventing and containing acute respiratory infections (ARIs) in mass gatherings. In this pilot RCT, we assessed the feasibility of establishing a large-scale trial to explore the relationship between practising hand hygiene and rates of ARI in Umrah pilgrimage amidst the COVID-19 pandemic. METHODS: A parallel RCT was conducted in hotels in Makkah, Saudi Arabia, between April and July 2021. Domestic adult pilgrims who consented to participate were randomised 1:1 to the intervention group who received alcohol-based hand rub (ABHR) and instructions, or to the control group who did not receive ABHR or instructions but were free to use their own supplies. Pilgrims in both groups were then followed up for seven days for ARI symptoms. The primary outcome was the difference in the proportions of syndromic ARIs among pilgrims between the randomised groups. RESULTS: A total of 507 (control: intervention = 267: 240) participants aged between 18 and 75 (median 34) years were randomised; 61 participants were lost to follow-up or withdrew leaving 446 participants (control: intervention = 237:209) for the primary outcome analysis; of whom 10 (2.2 %) had developed at least one respiratory symptom, three (0.7 %) had 'possible ILI' and two (0.4 %) had 'possible COVID-19'. The analysis of the primary outcome found no evidence of difference in the proportions of ARIs between the randomised groups (odds ratio 1.1 [0.3-4.0] for intervention relative to control). CONCLUSION: This pilot trial suggests that conducting a future definitive RCT to assess the role of hand hygiene in the prevention of ARIs is feasible in Umrah setting amidst such a pandemic; however, outcomes from this trial are inconclusive, and such a study would need to be very large given the low rates of outcomes observed here. TRIAL REGISTRATION: This trial was registered in the Australian New Zealand Clinical Trials Registry (ANZCTR) (ACTRN12622001287729), the full protocol can be accessed there.

Investigation of Zika virus methyl transferase inhibitors using steered molecular dynamics.

Zika virus (ZIKV) spread is considered a major public health threat by the World Health Organization (WHO). There are no vaccines or drugs available to control the infection of the Zika virus, therefore a highly effective medicinal molecule is urgently required. In this study, a computationally intensive investigation was performed to identify a potent natural compound that could inhibit the ZIKV NS5 methyltransferase. This research approach is based on target-based drug identification principles where the native inhibitor SAH (S-adenosylhomocysteine) of ZIKV NS5 methyltransferase was selected as a reference. High-throughput virtual screening and tanimoto similarity coefficient were applied to the natural compound library for ranking the potential candidates. The top five compounds were selected for interaction analysis, MD simulation, total binding free energy through MM/GBSA, and steered MD simulation. Among these compounds, Adenosine 5'-monophosphate monohydrate, Tubercidin, and 5-Iodotubercidin showed stable binding to the protein compared to the native compound, SAH. These three compounds also showed less fluctuations in RMSF in contrast to native compound. Additionally, the same interacting residues observed in SAH also made strong interactions with these three compounds. Adenosine 5'-monophosphate monohydrate and 5-Iodotubercidin had greater total binding free energies than the reference ligand. Moreover, the dissociation resistance of all three compounds was equivalent to that of the reference ligand. This study suggested binding properties of three-hit compounds that could be used to develop drugs against Zika virus infections.Communicated by Ramaswamy H. Sarma.

Measuring the effectiveness of an integrated intervention package to improve the level of infection prevention and control: a multi-centre study in Bangladesh.

BACKGROUND: Infection prevention and control (IPC) is a critical component of delivering safe, effective and high-quality healthcare services, and eliminating avoidable healthcare-associated infections (HAIs) in health facilities, predominantly in population-dense settings such as Bangladesh. AIM: Our study aimed to assess the effect of an integrated intervention package in improving the IPC level of the health facilities in Bangladesh. METHODS: We conducted a pre-post intervention study in six district hospitals (DHs) and 13 Upazila Health Complexes (UHCs) in the six districts of Bangladesh. Baseline and endline assessments were conducted between March and December 2021 using the adapted World Health Organization Infection Prevention and Control Assessment Framework (WHO-IPCAF) tool. The IPCAF score, ranging from 0-800, was calculated by adding the scores of eight components, and the IPC promotion and practice level was categorized as Inadequate (0-200), Basic (201-400), Intermediate (401-600) and Advanced (601-800). The integrated intervention package including IPC committee formation, healthcare provider training, logistics provision, necessary guidelines distribution, triage/flu corners establishment, and infrastructure development was implemented in all facilities. RESULTS: The average IPCAF score across all the facilities showed a significant increase from 16% (95% CI: 11.5-20.65%) to 54% (95% CI: 51.4-57.1%). Overall, the IPCAF score increased by 34 percentage points (P<0.001) in DHs and 40 percentage points (P<0.001) in UHCs. Following the intervention, 12 (three DHs, nine UHCs) of 19 facilities progressed from inadequate to intermediate, and another three DHs upgraded from basic to intermediate in terms of IPC level. CONCLUSION: The integrated intervention package improved IPCAF score in all facilities.

Immunoinformatic Execution and Design of an Anti-Epstein-Barr Virus Vaccine with Multiple Epitopes Triggering Innate and Adaptive Immune Responses.

One of the most important breakthroughs in healthcare is the development of vaccines. The life cycle and its gene expression in the numerous virus-associated disorders must be considered when choosing the target vaccine antigen for Epstein-Barr virus (EBV). The vaccine candidate used in the current study will also be effective against all other herpesvirus strains, based on the conservancy study, which verified that the protein is present in all herpesviruses. From the screening, two B-cell epitopes, four MHC-I, and five MHC-II restricted epitopes were chosen for further study. The refined epitopes indicated 70.59% coverage of the population in Malaysia and 93.98% worldwide. After removing the one toxin (PADRE) from the original vaccine design, it was projected that the new vaccine would not be similar to the human host and would instead be antigenic, immunogenic, non-allergenic, and non-toxic. The vaccine construct was stable, thermostable, soluble, and hydrophilic. The immunological simulation projected that the vaccine candidate would be subject to a long-lasting active adaptive response and a short-lived active innate response. With IgM concentrations of up to 450 cells per mm3 and active B-cell concentrations of up to 400 cells per mm3, the B-cells remain active for a considerable time. The construct also discovered other conformational epitopes, improving its ability to stimulate an immune response. This suggests that, upon injection, the epitope will target the B-cell surface receptors and elicit a potent immune response. Furthermore, the discotope analysis confirmed that our conformational B-cell epitope was not displaced during the design. Lastly, the docking complex was stable and exhibited little deformability under heat pressure. These computational results are very encouraging for future testing of our proposed vaccine, which may potentially help in the management and prevention of EBV infections worldwide.

Cheminformatics and machine learning approaches for repurposing anti-viral compounds against monkeypox virus thymidylate kinase.

One of the emerging epidemic concerns is Monkeypox disease which is spreading globally. This disease is caused by the monkeypox virus (MPXV), with an increasing global incidence with an outbreak in 2022. One of the novel targets for monkeypox disease is thymidylate kinase, which is involved in pyrimidine metabolism. In this study, docking-based virtual screening and molecular dynamics techniques were employed in addition to the machine learning (ML) model to investigate the potential anti-viral natural small compounds to inhibit thymidylate kinase of MPXV. Several potential hits were identified through high-throughput virtual screening, and further top three candidates were selected, which ranked using the ML model. These three compounds were then examined under molecular dynamics simulation and MM/GBSA-binding free energy analysis. Among these, Chlorhexidine HCl showed high potential for binding to the thymidylate kinase with stable and consistent conformation with RMSD < 0.3 nm. The MM/GBSA analysis also showed the minimum binding free energy (ΔGTOTAL) of -62.41 kcal/mol for this compound. Overall, this study used structure-based drug design complemented by machine learning-guided ligand-based drug design to screen potential hit compounds from the anti-viral natural compound database.

Experimental drugs in randomized controlled trials for long-COVID: what's in the pipeline? A systematic and critical review.

INTRODUCTION: Over three years have passed since the emergence of coronavirus disease 2019 (COVID-19), and yet the treatment for long-COVID, a post-COVID-19 syndrome, remains long overdue. Currently, there is no standardized treatment available for long-COVID, primarily due to the lack of funding for post-acute infection syndromes (PAIS). Nevertheless, the past few years have seen a renewed interest in long-COVID research, with billions of dollars allocated for this purpose. As a result, multiple randomized controlled trials (RCTs) have been funded in the quest to find an effective treatment for long-COVID. AREAS COVERED: This systematic review identified and evaluated the potential of current drug treatments for long-COVID, examining both completed and ongoing RCTs. EXPERT OPINION: We identified four completed and 22 ongoing RCTs, investigating 22 unique drugs. However, most drugs were deemed to not have high potential for treating long-COVID, according to three pre-specified domains, a testament to the ordeal of treating long-COVID. Given that long-COVID is highly multifaceted with several proposed subtypes, treatments likely need to be tailored accordingly. Currently, rintatolimod appears to have modest to high potential for treating the myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) subtype, LTY-100 and Treamid for pulmonary fibrosis subtype, and metformin for general long-COVID prevention.

Hand hygiene knowledge and practices, and rates of respiratory tract infections between Hajj and Umrah pilgrims: a comparative study.

BACKGROUND: Hajj and Umrah mass gatherings (MGs) in the Kingdom of Saudi Arabia amplify the risk of viral respiratory tract infections (RTIs), but there is a lack of comparative data from these two MGs. This study aims to compare pilgrims' hand hygiene knowledge, practices, and rates of RTIs during the peak periods of Umrah and Hajj in 2021. MATERIALS AND METHODS: The datasets of this comparative study were obtained from two previously conducted studies that used similar study tools and identical syndromic definitions. The binary logistic regression was applied to compare the categorical variables and, a t-test was used to compare the continuous variables. RESULTS: A total of 510 Hajj pilgrims and 507 Umrah pilgrims were recruited. The majority of Hajj pilgrims (68%) were ≥ 40 years old, while most Umrah pilgrims (63%) were < 40 years old. The mean total knowledge scores of hand hygiene between the Hajj and Umrah pilgrims differed significantly (4.1 vs. 3.7, respectively, p < 0.001) so did their compliance with frequent use of alcohol-based hand rubs (53.0% vs. 36.3%, respectively, p < 0.001) and the rates of RTIs (4.7% vs. 2.2%, respectively, p = 0.05). CONCLUSIONS: These differences could be attributable to the distinctive characteristics of Hajj and Umrah pilgrimages, and the unique differences in risks posed by those MGs.

N-Terminomic Changes in Neurons During Excitotoxicity Reveal Proteolytic Events Associated With Synaptic Dysfunctions and Potential Targets for Neuroprotection.

Excitotoxicity, a neuronal death process in neurological disorders such as stroke, is initiated by the overstimulation of ionotropic glutamate receptors. Although dysregulation of proteolytic signaling networks is critical for excitotoxicity, the identity of affected proteins and mechanisms by which they induce neuronal cell death remain unclear. To address this, we used quantitative N-terminomics to identify proteins modified by proteolysis in neurons undergoing excitotoxic cell death. We found that most proteolytically processed proteins in excitotoxic neurons are likely substrates of calpains, including key synaptic regulatory proteins such as CRMP2, doublecortin-like kinase I, Src tyrosine kinase and calmodulin-dependent protein kinase IIß (CaMKIIß). Critically, calpain-catalyzed proteolytic processing of these proteins generates stable truncated fragments with altered activities that potentially contribute to neuronal death by perturbing synaptic organization and function. Blocking calpain-mediated proteolysis of one of these proteins, Src, protected against neuronal loss in a rat model of neurotoxicity. Extrapolation of our N-terminomic results led to the discovery that CaMKIIα, an isoform of CaMKIIß, undergoes differential processing in mouse brains under physiological conditions and during ischemic stroke. In summary, by identifying the neuronal proteins undergoing proteolysis during excitotoxicity, our findings offer new insights into excitotoxic neuronal death mechanisms and reveal potential neuroprotective targets for neurological disorders.

Regulatory T Cells (Tregs) and COVID-19: Unveiling the Mechanisms, and Therapeutic Potentialities with a Special Focus on Long COVID.

The COVID-19 pandemic has caused havoc all around the world. The causative agent of COVID-19 is the novel form of the coronavirus (CoV) named SARS-CoV-2, which results in immune system disruption, increased inflammation, and acute respiratory distress syndrome (ARDS). T cells have been important components of the immune system, which decide the fate of the COVID-19 disease. Recent studies have reported an important subset of T cells known as regulatory T cells (Tregs), which possess immunosuppressive and immunoregulatory properties and play a crucial role in the prognosis of COVID-19 disease. Recent studies have shown that COVID-19 patients have considerably fewer Tregs than the general population. Such a decrement may have an impact on COVID-19 patients in a number of ways, including diminishing the effect of inflammatory inhibition, creating an inequality in the Treg/Th17 percentage, and raising the chance of respiratory failure. Having fewer Tregs may enhance the likelihood of long COVID development in addition to contributing to the disease's poor prognosis. Additionally, tissue-resident Tregs provide tissue repair in addition to immunosuppressive and immunoregulatory activities, which may aid in the recovery of COVID-19 patients. The severity of the illness is also linked to abnormalities in the Tregs' phenotype, such as reduced expression of FoxP3 and other immunosuppressive cytokines, including IL-10 and TGF-beta. Hence, in this review, we summarize the immunosuppressive mechanisms and their possible roles in the prognosis of COVID-19 disease. Furthermore, the perturbations in Tregs have been associated with disease severity. The roles of Tregs are also explained in the long COVID. This review also discusses the potential therapeutic roles of Tregs in the management of patients with COVID-19.

Anti-tubercular activity evaluation of natural compounds by targeting Mycobacterium tuberculosis resuscitation promoting factor B inhibition: An in silico study.

Tuberculosis (TB), an infectious disease caused by the Mycobacterium tuberculosis (Mtb), has been responsible for the deaths of millions of individuals around the globe. A vital protein in viral pathogenesis known as resuscitation promoting factor (RpfB) has been identified as a potential therapeutic target of anti-tuberculosis drugs. This study offered an in silico process to examine possible RpfB inhibitors employing a computational drug design pipeline. In this study, a total of 1228 phytomolecules were virtually tested against the RpfB of Mtb. These phytomolecules were sourced from the NP-lib database of the MTi-OpenScreen server, and five top hits (ZINC000044404209, ZINC000059779788, ZINC000001562130, ZINC000014766825, and ZINC000043552589) were prioritized for compute intensive docking with dock score ≤ - 8.5 kcal/mole. Later, molecular dynamics (MD) simulation and principal component analysis (PCA) were used to validate these top five hits. In the list of these top five hits, the ligands ZINC000044404209, ZINC000059779788, and ZINC000043552589 showed hydrogen bond formation with the functional residue Glu292 of the RpfB protein suggesting biological significance of the binding. The RMSD study showed stable protein-ligand complexes and higher conformational consistency for the ligands ZINC000014766825, and ZINC000043552589 with RMSD 3-4 Å during 100 ns MD simulation. The overall analysis performed in the study suggested promising binding of these compounds with the RpfB protein of the Mtb at its functional site, further experimental investigation is needed to validate the computational finding.

Designing Novel Multi-Epitope Vaccine Construct against Prevotella intermedia-Interpain A: An Immunoinformatics Approach.

Background and Objectives: Periodontitis is a chronic multifactorial inflammatory infectious disease marked by continuous degradation of teeth and surrounding parts. One of the most important periodontal pathogens is P. intermedia, and with its interpain A proteinase, it leads to an increase in lethal infection. Materials and Methods: The current study was designed to create a multi-epitope vaccine using an immunoinformatics method that targets the interpain A of P. intermedia. For the development of vaccines, P. intermedia peptides InpA were found appropriate. To create a multi-epitope vaccination design, interpain A, B, and T-cell epitopes were found and assessed depending on the essential variables. The vaccine construct was evaluated based on its stability, antigenicity, and allergenicity. Results: The vaccine construct reached a more significant population and was able to bind to both the binding epitopes of major histocompatibility complex (MHC)-I and MHC-II. Through the C3 receptor complex route, P. intermedia InpA promotes an immunological subunit. Utilizing InpA-C3 and vaccination epitopes as the receptor and ligand, the molecular docking and dynamics were performed using the ClusPro 2.0 server. Conclusion: The developed vaccine had shown good antigenicity, solubility, and stability. Molecular docking indicated the vaccine's 3D structure interacts strongly with the complement C3. The current study describes the design for vaccine, and steady interaction with the C3 immunological receptor to induce a good memory and an adaptive immune response against Interpain A of P. intermedia.

Prediction of Putative Epitope Peptides against BaeR Associated with TCS Adaptation in Acinetobacter baumannii Using an In Silico Approach.

Background and Objectives: The BaeR protein is involved in the adaptation system of A. baumannii and is associated with virulence factors responsible for systemic infections in hospitalized patients. This study was conducted to characterize putative epitope peptides for the design of vaccines against BaeR protein, using an immune-informatic approach. Materials and Methods: FASTA sequences of BaeR from five different strains of A. baumannii were retrieved from the UNIPROT database and evaluated for their antigenicity, allergenicity and vaccine properties using BepiPred, Vaxijen, AlgPred, AntigenPro and SolPro. Their physio-chemical properties were assessed using the Expasy Protparam server. Immuno-dominant B-cell and T-cell epitope peptides were predicted using the IEDB database and MHC cluster server with a final assessment of their interactions with TLR-2. Results: A final selection of two peptide sequences (36aa and 22aa) was made from the 38 antigenic peptides. E1 was considered a soluble, non-allergenic antigen, and possessed negative GRAVY values, substantiating the hydrophilic nature of the proteins. Further analysis on the T-cell epitopes, class I immunogenicity and HLA allele frequencies yielded T-cell immuno-dominant peptides. The protein-peptide interactions of the TLR-2 receptor showed good similarity scores in terms of the high number of hydrogen bonds compared to other protein-peptide interactions. Conclusions: The two epitopes predicted from BaeR in the present investigation are promising vaccine candidates for targeting the TCS of A. baumannii in systemic and nosocomial infections. This study also demonstrates an alternative strategy to tackling and mitigating MDR strains of A. baumannii and provides a useful reference for the design and construction of novel vaccine candidates against this bacteria.

Growth in chikungunya virus-related research in ASEAN and South Asian countries from 1967 to 2022 following disease emergence: a bibliometric and graphical analysis.

BACKGROUND: ASEAN (Association of Southeast Asian Nations) is composed of ten Southeast Asian countries bound by socio-cultural ties that promote regional peace and stability. South Asia, located in the southern subregion of Asia, includes nine countries sharing similarities in geographical and ethno-cultural factors. Chikungunya is one of the most significant problems in Southeast and South Asian countries. Much of the current chikungunya epidemic in Southeast Asia is caused by the emergence of a virus strain that originated in Africa and spread to Southeast Asia. Meanwhile, in South Asia, three confirmed lineages are in circulation. Given the positive correlation between research activity and the improvement of the clinical framework of biomedical research, this article aimed to examine the growth of chikungunya virus-related research in ASEAN and South Asian countries. METHODS: The Scopus database was used for this bibliometric analysis. The retrieved publications were subjected to a number of analyses, including those for the most prolific countries, journals, authors, institutions, and articles. Co-occurrence mapping of terms and keywords was used to determine the current state, emerging topics, and future prospects of chikungunya virus-related research. Bibliometrix and VOSviewer were used to analyze the data and visualize the collaboration network mapping. RESULTS: The Scopus search engine identified 1280 chikungunya-related documents published by ASEAN and South Asian countries between 1967 and 2022. According to our findings, India was the most productive country in South Asia, and Thailand was the most productive country in Southeast Asia. In the early stages of the study, researchers investigated the vectors and outbreaks of the chikungunya virus. In recent years, the development of antivirus agents has emerged as a prominent topic. CONCLUSIONS: Our study is the first to present the growth of chikungunya virus-related research in ASEAN and South Asian countries from 1967 to 2022. In this study, the evaluation of the comprehensive profile of research on chikungunya can serve as a guide for future studies. In addition, a bibliometric analysis may serve as a resource for healthcare policymakers.

Nephroprotective potential of Polyalthia longifolia roots against vancomycin-induced renal toxicity in experimental animals.

This study was done to investigate the possible nephroprotective effect of an ethanolic root extract of Polyalthia Longifolia (PL) on vancomycin-induced nephrotoxicity using curative and protective models. Vancomycin (150 mg/kg, intravenous) was given to healthy Wistar albino rats in the curative model before the start of treatment, whereas the protective group received vancomycin at the conclusion of the 10-day treatment procedure. Animals were divided into six groups for both models; group I served as the normal control, while groups II, III, IV, V, and VI were kept as toxic control, standard (selenium, 6 mg/kg), LDPL (low dose of PL 200 mg/kg), HDPL (high dose of PL 400 mg/kg), and HDPL + selenium (interactive) groups, respectively. Renal biomarkers [(uric acid, creatinine, blood urea nitrogen (BUN), serum proteins], and blood electrolyte levels were measured for all tested groups. When compared to the vancomycin group, the HDPL significantly (p < 0.01) showed greater effectiveness in lowering the BUN, potassium, and calcium levels. Additionally, in the curative model, there was a significant (p < 0.05) decrease in the blood levels of uric acid, creatinine, BUN, potassium, and calcium in the animals who received the combination of selenium and HDPL. Both LDPL and HDPL did not provide any distinguishable effect in the protective model, but groups that received HDPL with selenium did provide detectable protection by significantly lowering their levels of uric acid, BUN, serum potassium, and total serum protein in comparison to the vancomycin control group. These findings indicate that, whether administered before or after renal damage is induced, the Polyalthia longifolia root extract provided only modest protection to nephrons, which require selenium support to prevent vancomycin-induced kidney damage.

Updated Insights into the T Cell-Mediated Immune Response against SARS-CoV-2: A Step towards Efficient and Reliable Vaccines.

The emergence of novel variants of SARS-CoV-2 and their abilities to evade the immune response elicited through presently available vaccination makes it essential to recognize the mechanisms through which SARS-CoV-2 interacts with the human immune response. It is essential not only to comprehend the infection mechanism of SARS-CoV-2 but also for the generation of effective and reliable vaccines against COVID-19. The effectiveness of the vaccine is supported by the adaptive immune response, which mainly consists of B and T cells, which play a critical role in deciding the prognosis of the COVID-19 disease. T cells are essential for reducing the viral load and containing the infection. A plethora of viral proteins can be recognized by T cells and provide a broad range of protection, especially amid the emergence of novel variants of SARS-CoV-2. However, the hyperactivation of the effector T cells and reduced number of lymphocytes have been found to be the key characteristics of the severe disease. Notably, excessive T cell activation may cause acute respiratory distress syndrome (ARDS) by producing unwarranted and excessive amounts of cytokines and chemokines. Nevertheless, it is still unknown how T-cell-mediated immune responses function in determining the prognosis of SARS-CoV-2 infection. Additionally, it is unknown how the functional perturbations in the T cells lead to the severe form of the disease and to reduced protection not only against SARS-CoV-2 but many other viral infections. Hence, an updated review has been developed to understand the involvement of T cells in the infection mechanism, which in turn determines the prognosis of the disease. Importantly, we have also focused on the T cells' exhaustion under certain conditions and how these functional perturbations can be modulated for an effective immune response against SARS-CoV-2. Additionally, a range of therapeutic strategies has been discussed that can elevate the T cell-mediated immune response either directly or indirectly.

Cost-effectiveness of Staple Line Reinforcement in Laparoscopic Sleeve Gastrectomy.

OBJECTIVE: To perform a cost-effectiveness analysis of staple-line reinforcement in laparoscopic sleeve gastrectomy. SUMMARY OF BACKGROUND DATA: Exponential increases in surgical costs have underscored the critical need for evidence-based methods to determine the relative value of surgical devices. One such device is staple-line reinforcement, thought to decrease bleeding rates in laparoscopic sleeve gastrectomy. METHODS: Two intervention arms were modeled, staple-line reinforcement and standard nonreinforced stapling. Bleed and leak rates and 30-day treatment costs were obtained from national and state registries. Quality-adjusted life-year (QALY) values were drawn from previous literature. Device prices were drawn from institutional data. A final incremental cost-effectiveness ratio was calculated, and one-way and probabilistic sensitivity analyses were performed. RESULTS: A total of 346,530 patient records from 2012 to 2018 were included. Complication rates for the reinforced and standard cohorts were 0.05% for major bleed in both cohorts ( P = 0.8841); 0.45% compared with 0.59% for minor bleed ( P < 0.0001); and 0.24% compared with 0.26% for leak ( P = 0.4812). Median cost for a major bleed was $5552 ($3287, $16,817) and $2406 ($1861, $3484) for a minor bleed. Median leak cost was $9897 ($4589, $21,619) and median cost for patients who did not experience a bleed, leak, or other serious complication was $1908 ($1712, $2739). Mean incremental cost of reinforced stapling compared with standard was $819.60/surgery. Net QALY gain with reinforced stapling compared with standard was 0.00002. The resultant incremental cost-effectiveness ratio was $40,553,000/QALY. One-way and probabilistic sensitivity analyses failed to produce a value below $150,000/QALY. CONCLUSIONS: Compared with standard stapling, reinforced stapling reduces minor postoperative bleeding but not major bleeding or leaks and is not cost-effective if routinely used in laparoscopic sleeve gastrectomy.

Genetic Variants and Protective Immunity against SARS-CoV-2.

The novel coronavirus-19 (SARS-CoV-2), has infected numerous individuals worldwide, resulting in millions of fatalities. The pandemic spread with high mortality rates in multiple waves, leaving others with moderate to severe symptoms. Co-morbidity variables, including hypertension, diabetes, and immunosuppression, have exacerbated the severity of COVID-19. In addition, numerous efforts have been made to comprehend the pathogenic and host variables that contribute to COVID-19 susceptibility and pathogenesis. One of these endeavours is understanding the host genetic factors predisposing an individual to COVID-19. Genome-Wide Association Studies (GWAS) have demonstrated the host predisposition factors in different populations. These factors are involved in the appropriate immune response, their imbalance influences susceptibility or resistance to viral infection. This review investigated the host genetic components implicated at the various stages of viral pathogenesis, including viral entry, pathophysiological alterations, and immunological responses. In addition, the recent and most updated genetic variations associated with multiple host factors affecting COVID-19 pathogenesis are described in the study.

Designing an Epitope-Based Peptide Vaccine Derived from RNA-Dependent RNA Polymerase (RdRp) against Dengue Virus Serotype 2.

Dengue fever (DF) continues to be one of the tropical and subtropical health concerns. Its prevalence tends to increase in some places in these regions. This disease is caused by the dengue virus (DENV), which is transmitted through the mosquitoes Aedes aegypti and A. albopictus. The treatment of DF to date is only supportive and there is no definitive vaccine to prevent this disease. The non-structural DENV protein, RNA-dependent RNA Polymerase (RdRp), is involved in viral replication. The RdRp-derived peptides can be used in the construction of a universal dengue vaccine. These peptides can be utilized as epitopes to induce immunity. This study was an in silico evaluation of the affinity of the potential epitope for the universal dengue vaccine to dendritic cells and the bonds between the epitope and the dendritic cell receptor. The peptide sequence MGKREKKLGEFGKAKG generated from dengue virus subtype 2 (DENV-2) RdRp was antigenic, did not produce allergies, was non-toxic, and had no homology with the human genome. The potential epitope-based vaccine MGKREKKLGEFGKAKG binds stably to dendritic cell receptors with a binding free energy of -474,4 kcal/mol. This epitope is anticipated to induce an immunological response and has the potential to serve as a universal dengue virus vaccine candidate.

Immune and Oxidative Response against Sonicated Antigen of Mycoplasma capricolum subspecies capripneumonia-A Causative Agent of Contagious Caprine Pleuropneumonia.

Vaccines are vital for prevention and control of mycoplasma diseases. The exploration of a vaccine candidate for the development of a vaccine is imperative. The present study envisages the evaluation of immune and oxidative response against an adjuvanted, sonicated antigen of Mycoplasma capricolum subsp. capripneumonia in male Angora rabbits (1 year old, 2 kg) divided in four groups, each having six animals. Group 1 was the healthy control and received 1 mL PBS via subcutaneous route. Group 2 was administered 1 mL of saponin-adjuvanted and -sonicated antigen, Group 3 was given 1 mL of montanide ISA 50-adjuvanted and-sonicated antigen, and Group 4 was given 1 mL of standard vaccine via subcutaneous route. Animals were evaluated for cellular and humoral immune response and oxidative parameters at 0, 7, 14, 21, and 28 days of the study. Total leukocytic, neutrophilic, and basophilic counts showed a significant (p < 0.05) increase in vaccinated groups compared to the healthy group on most of the intervals. TNF-α levels were significantly (p < 0.05) higher in the Group 2 than the Group 1 at all the time intervals and more comparable to Group 4 than Group 3. IL-10 levels were significantly (p < 0.05) higher in vaccinated groups compared to the healthy group on days 14, 21, and 28, but were lower in Group 3 than in Group 2 and Group 4. More hypersensitivity as inflammation and histopathological cellular infiltration in the ear was produced in Group 2 and Group 4 than in Group 3. IgG levels were significantly (p < 0.05) higher in Group 2 and Group 4 than in Group 3 on days 14 and 21. Antibody titers were comparatively higher in Group 4, followed by Group 2 and 3, than Group 1. Significantly (p < 0.05) higher oxidant and lower antioxidant values were noted in Group 2 and 4 compared to Group 3 and Group 1 on most of the intervals. The TLC and antibody titer showed increasing trend throughout the trial, whereas TNF-α, IgG, L, M and E started decreasing from day 14, and IL-10, N and B started decreasing from day 21. This study concludes that the saponin-adjuvanted and-sonicated antigen induces comparatively higher immune response than montanide but is associated with oxidative and inflammatory reactions.