New insight into strategies used to develop long-acting G-CSF biologics for neutropenia therapy

Over the last 20 years, granulocyte colony-stimulating factors (G-CSFs) have become the major therapeutic option for the treatment of patients with neutropenia. Most of the current G-CSFs require daily injections, which are inconvenient and expensive for patients. Increased understanding of G-CSFs’ structure, expression, and mechanism of clearance has been very instrumental in the development of new generations of long-acting G-CSFs with improved efficacy. Several approaches to reducing G-CSF clearance via conjugation techniques have been investigated. PEGylation, glycosylation, polysialylation, or conjugation with immunoglobulins or albumins have successfully increased G-CSFs’ half-lives. Pegfilgrastim (Neulasta) has been successfully approved and marketed for the treatment of patients with neutropenia. The rapidly expanding market for G-CSFs has increased demand for G-CSF biosimilars. Therefore, the importance of this review is to highlight the principle, elimination’s route, half-life, clearance, safety, benefits, and limitations of different strategies and techniques used to increase the half-life of biotherapeutic G-CSFs. Understanding these strategies will allow for a new treatment with more competitive manufacturing and lower unit costs compared with that of Neulasta

Association between different behavioral factors and dental caries among children attending the dental clinics in a sample from Saudi Arabia

Abstract Background This study aimed to assess the association between different behavioral factors and the prevalence of dental caries among children attending the dental clinic in a sample from the Hail and Tabuk regions, Saudi Arabia. Method A cross-sectional study design was employed to determine the burden of dental caries in teeth and key associated factors among 6-12-year-old children who attended different dental clinics. The data was recruited from Hail and Tabuk districts, Saudi Arabia. The study included only Saudi nationals, whose parents could fill out the self-administered questionnaire and provide informed consent for their child’s dental examination at clinics. Children underwent a simple dental examination based on the World Health Organization diagnostic criteria for oral health surveys. The Decayed, Missed, Filled Tooth (DMFT) index developed by the World Health Organization (WHO) was utilized to assess dental caries. Descriptive statistics were performed to describe categorical variables. The mean DMFT was compared between girls’ and boys’ and the children from Hail and Tabuk regions using the Mann-Whitney U-test. The chi-square test was used to examine the association between different behavioral factors and the prevalence of dental caries. Results Of the total 399 children examined, 203 (50.9%) were boys, whilst 196 (49.1%) were girls. The prevalence of dental caries was correlated with the cleaning tool, parental educational level, dental visits, and sugar consumption (p  0.05). The total mean DMFT for the studied sample was 7.81 (SD ± 1.9). Caries’ experience was made up mainly of decayed teeth. Decayed teeth made up an average of 3.30 (SD ± 1.07). The total mean of missing and filling teeth was 2.51 (SD ± 0.99) and 1.99 (SD ± 1.26) respectively. There was no statistically significant difference in the mean DMFT and gender or between Hail and Tabuk (p < 0.05). Conclusion Saudi Arabia continues to have a high prevalence of dental caries compared to the global norm

The risk of venous thromboembolism and blood hyperlactatemia is associated with increased mortality among critically ill patients with Covid‐19

Abstract Introduction Coronavirus disease 2019 (Covid‐19) following venous thromboembolism (VTE) and blood hyperlactatemia are associated with higher mortality. However, reliable biomarkers for this association remain to be elucidated. This study investigated the associations of VTE risk and blood hyperlactatemia with mortality among critically ill Covid‐19 patients admitted to the intensive care unit (ICU). Methods In this single‐centre retrospective study, we included 171 patients aged ≥18 years with confirmed Covid‐19 admitted to the ICU at a tertiary healthcare clinic in the Eastern region of Saudi Arabia between 1 March 2020 and 31 January 2021. Patients were divided into two groups: survivor and non‐survivor. The survivors have been identified as the patients discharged from the ICU alive. The VTE risk was defined using a Padua prediction score (PPS) >4. The blood lactate concentration (BLC) cut‐off value >2 mmol/L was used to determine the blood hyperlactatemia. Results Multi‐factor Cox analysis showed that PPS >4 and BLC >2 mmol/L were more likely to be significantly associated with higher odds of ICU mortality in critically ill Covid‐19 patients (hazard ratio [HR] = 2.80, 95% confidence interval [CI] = 1.00–8.08, p = 0.050; HR = 3.87, 95% CI = 1.12–13.45, p = 0.033, respectively). The Area under the Curve for VTE and blood hyperlactatemia were 0.62 and 0.85, respectively. Conclusion VTE risk and blood hyperlactatemia have been associated with a higher mortality risk in critically ill Covid‐19 patients who are hospitalized in the ICU in Saudi Arabia. According to our findings, these people needed more effective VTE prevention strategies based on a personalized assessment of their risk of bleeding. Moreover, persons without diabetes and other groups with a high risk of dying from COVID‐19 may be recognized by measuring glucose as having elevated glucose and lactate jointly

Metabolic Syndrome and Coronary Artery Disease Risk: A Meta-Analysis of Observational Studies

Although numerous studies have described the link between metabolic syndrome (MetS) and Coronary Artery Disease (CAD), no meta-analysis has been carried out on this relationship. Thus, the present study intended to address this limitation. A systematic search was carried out using electronic databases, such as PubMed, CINAHL Plus, Medline, and Web of Science. A sum of 10 studies (n = 9327) was incorporated in the meta-analysis. Compared with non-MetS, MetS was significantly associated with high CAD risk (OR = 4.03, 95% CI = 3.56–4.56). The MetS components were also significantly correlated with high CAD risk (OR = 3.72, 95% CI = 3.22–4.40). The presence of two (OR = 3.93, 95% CI = 2.81–5.49), three (OR = 4.09, 95% CI = 2.85–5.86), four (OR = 4.04, 95% CI = 2.83–5.78), or all five MetS components (OR = 3.92, 95% CI = 3.11–4.93), were significantly associated with a high risk of CAD. MetS and its individual or combined elements were linked with high CAD risk based on contemporary evidence. Thus, the assessment of MetS and its components might help identify people at a higher risk of advancing CAD in the future

Designing of a Novel Multi-Antigenic Epitope-Based Vaccine against E. hormaechei: An Intergraded Reverse Vaccinology and Immunoinformatics Approach

Enterobacter hormaechei is involved in multiple hospital-associated infections and is resistant to beta-lactam and tetracycline antibiotics. Due to emerging antibiotics resistance in E. hormaechei and lack of licensed vaccine availability, efforts are required to overcome the antibiotics crisis. In the current research study, a multi-epitope-based vaccine against E. hormaechei was designed using reverse vaccinology and immunoinformatic approaches. A total number of 50 strains were analyzed from which the core proteome was extracted. One extracellular (curlin minor subunit CsgB) and two periplasmic membrane proteins (flagellar basal-body rod protein (FlgF) and flagellar basal body P-ring protein (FlgI) were prioritized for B and T-cell epitope prediction. Only three filtered TPGKMDYTS, GADMTPGKM and RLSAESQAT epitopes were used when designing the vaccine construct. The epitopes were linked via GPGPG linkers and EAAAK linker-linked cholera toxin B-subunit adjuvant was used to enhance the immune stimulation efficacy of the vaccine. Docking studies of the vaccine construct with immune cell receptors revealed better interactions, vital for generating proper immune reactions. Docked complexes of vaccine with MHC-I, MHC-II and Tool-like receptor 4 (TLR-4) reported the lowest binding energy of &minus;594.1 kcal/mol, &minus;706.7 kcal/mol, &minus;787.2 kcal/mol, respectively, and were further subjected to molecular dynamic simulations. Net binding free energy calculations also confirmed that the designed vaccine has a strong binding affinity for immune receptors and thus could be a good vaccine candidate for future experimental investigations

Design of a Multi-Epitope Vaccine against Tropheryma whipplei Using Immunoinformatics and Molecular Dynamics Simulation Techniques

Whipple&rsquo;s disease is caused by T. whipplei, a Gram-positive pathogenic bacterium. It is considered a persistent infection affecting various organs, more likely to infect males. There is currently no licensed vaccination available for Whipple&rsquo;s disease; thus, the development of a chimeric peptide-based vaccine against T. whipplei has the potential to be tremendously beneficial in preventing Whipple&rsquo;s disease in the future. The present study aimed to apply modern computational approaches to generate a multi-epitope-based vaccine that expresses antigenic determinants prioritized from the core proteome of two T. whipplei whole proteomes. Using an integrated computational approach, four immunodominant epitopes were found from two extracellular proteins. Combined, these epitopes covered 89.03% of the global population. The shortlisted epitopes exhibited a strong binding affinity for the B- and T-cell reference set of alleles, high antigenicity score, nonallergenic nature, high solubility, nontoxicity, and excellent binders of DRB1*0101. Through the use of appropriate linkers and adjuvation with a suitable adjuvant molecule, the epitopes were designed into a chimeric vaccine. An adjuvant was linked to the connected epitopes to boost immunogenicity and efficiently engage both innate and adaptive immunity. The physiochemical properties of the vaccine were observed favorable, leading toward the 3D modeling of the construct. Furthermore, the vaccine&rsquo;s binding confirmation to the TLR-4 critical innate immune receptor was also determined using molecular docking and molecular dynamics (MD) simulations, which shows that the vaccine has a strong binding affinity for TLR4 (&minus;29.4452 kcal/mol in MM-GBSA and &minus;42.3229 kcal/mol in MM-PBSA). Overall, the vaccine described here has a promising potential for eliciting protective and targeted immunogenicity, subject to further experimental testing