Genetic, Immunological, and Clinical Features of 32 Patients with Autosomal Recessive STAT1 Deficiency.

Autosomal recessive (AR) STAT1 deficiency is a severe inborn error of immunity disrupting cellular responses to type I, II, and III IFNs, and IL-27, and conferring a predisposition to both viral and mycobacterial infections. We report the genetic, immunological, and clinical features of an international cohort of 32 patients from 20 kindreds: 24 patients with complete deficiency, and 8 patients with partial deficiency. Twenty-four patients suffered from mycobacterial disease (bacillus Calmette-Guérin = 13, environmental mycobacteria = 10, or both in 1 patient). Fifty-four severe viral episodes occurred in sixteen patients, mainly caused by Herpesviridae viruses. Attenuated live measles, mumps, and rubella and/or varicella zoster virus vaccines triggered severe reactions in the five patients with complete deficiency who were vaccinated. Seven patients developed features of hemophagocytic syndrome. Twenty-one patients died, and death was almost twice as likely in patients with complete STAT1 deficiency than in those with partial STAT1 deficiency. All but one of the eight survivors with AR complete deficiency underwent hematopoietic stem cell transplantation. Overall survival after hematopoietic stem cell transplantation was 64%. A diagnosis of AR STAT1 deficiency should be considered in children with mycobacterial and/or viral infectious diseases. It is important to distinguish between complete and partial forms of AR STAT1 deficiency, as their clinical outcome and management differ significantly.

Identification of natural potent inhibitors against Mycobacterium tuberculosis isocitrate lyase: an in silico study.

Tuberculosis (TB) is a global burden to humanity due to its adverse effects on health and society since time is not clearly defined. The existence of drug-resistant strains and the potential threat posed by latent tuberculosis act as strong impetuses for developing novel anti-tuberculosis drugs. In this study, various flavonoids were tested against the Mycobacterium tuberculosis (Mtb) Isocitrate Lyase (ICL), which has been identified as an authorised therapeutic target for treating Mtb infection. Using in silico drug discovery approach, a library of 241 flavonoid compounds was virtually screened against the binding pocket of the crystalline ligand, the VGX inhibitor, in the Mtb ICL protein. As a result, the top four flavonoids were selected based on binding score and were further considered for redocking and intermolecular contact profiling analysis. The global and local fluctuations in the protein and ligand structure were analysed using their root mean square deviation (RMSD) and root mean square fluctuation (RMSF) values obtained from the GROMACS generated 100 ns molecular dynamics (MD) simulation trajectories. The end-state binding free energy was also calculated using the MMPBSA approach for all the respective docked complexes. All four selected compounds exhibited considerable stability and affinity compared to control ligands, i.e. VGX inhibitor; however, Vaccarin showed the highest stability and affinity against the Mtb ICL protein active site, followed by the Genistin, Glabridin, and Corylin. Therefore, this study recommends selected flavonoids for in vitro and in vivo experimental studies to check their potency and efficacy against Mtb.

Clinical and laboratory characteristics of patients hospitalised with COVID-19: clinical outcomes in Abu Dhabi, United Arab Emirates.

BACKGROUND: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was first reported in December 2019. The severity of coronavirus disease 2019 (COVID-19) ranges from asymptomatic to severe and potentially fatal. We aimed to describe the clinical and laboratory features and outcomes of hospitalised patients with COVID-19 within the Abu Dhabi Healthcare Services Facilities (SEHA). METHODS: Our retrospective analysis of patient data collected from electronic health records (EHRs) available from the SEHA health information system included all patients admitted from 1 March to 31 May 2020 with a laboratory-confirmed PCR diagnosis of SARS-CoV-2 infection. Data of clinical features, co-morbidities, laboratory markers, length of hospital stay, treatment received and mortality were analysed according to severe versus non-severe disease. RESULTS: The study included 9390 patients. Patients were divided into severe and non-severe groups. Seven hundred twenty-one (7.68%) patients required intensive care, whereas the remaining patients (92.32%) had mild or moderate disease. The mean patient age of our cohort (41.8 years) was lower than the global average. Our population had male predominance, and it included various nationalities. The major co-morbidities were hypertension, diabetes mellitus and chronic kidney disease. Laboratory tests revealed significant differences in lactate dehydrogenase, ferritin, C-reactive protein, interleukin-6 and creatinine levels and the neutrophil count between the severe and non-severe groups. The most common anti-viral therapy was the combination of Hydroxychloroquine and Favipiravir. The overall in-hospital mortality rate was 1.63%, although the rate was 19.56% in the severe group. The mortality rate was higher in adults younger than 30 years than in those older than 60 years (2.3% vs. 0.95%). CONCLUSIONS: Our analysis suggested that Abu Dhabi had lower COVID-19 morbidity and mortalities rates were less than the reported rates then in China, Italy and the US. The affected population was relatively young, and it had an international representation. Globally, Abu Dhabi had one of the highest testing rates in relation to the population volume. We believe the early identification of patients and their younger age resulted in more favourable outcomes.

An analysis of antibody responses and clinical sequalae of the Sinopharm HB02 COVID19 vaccine in dialysis patients in the United Arab Emirates.

AIM: To establish the responses to the Sinopharm HB02 COVID-19 vaccination in the dialysis population, which are not well established. We examined the humoral responses to the Sinopharm COVID vaccine in haemodialysis patients. METHODS: Standard vaccinations (two doses at interval of ~21 days) were given to all consenting haemodialysis patients on dialysis (n = 1296). We measured the antibody responses at 14-21 days after the second vaccine to define the development of anti-spike antibodies >15 AU/ml after vaccination and observed the clinical effects of vaccination. RESULTS: Vaccination was very well tolerated with few side-effects. In those who consented to antibody measurements, (n = 446) baseline sampling showed 77 had positive antibodies, yet received full vaccination without any apparent adverse events. Positive anti-spike antibodies developed in 50% of the 270 baseline negative patients who had full sampling, compared with 78.1% in the general population. COVID infection continues to occur in both vaccinated and unvaccinated individuals, but in the whole group vaccination appears to have been associated with a reduction in the case fatality rate. CONCLUSION: The humoral immune responses to standard HB02 vaccination schedules are attenuated in a haemodialysis cohort, but likely the vaccine saves lives. We suggest that an enhanced HB02 vaccination course or antibody checking may be prudent to protect this vulnerable group of patients. We suggest a booster dose of this vaccine at 3 months should be given to all dialysis patients, on the grounds that it is well tolerated even in those with good antibody levels and there may be a survival advantage.

Effect of 2 Inactivated SARS-CoV-2 Vaccines on Symptomatic COVID-19 Infection in Adults: A Randomized Clinical Trial.

Importance: Although effective vaccines against COVID-19 have been developed, additional vaccines are still needed. Objective: To evaluate the efficacy and adverse events of 2 inactivated COVID-19 vaccines. Design, Setting, and Participants: Prespecified interim analysis of an ongoing randomized, double-blind, phase 3 trial in the United Arab Emirates and Bahrain among adults 18 years and older without known history of COVID-19. Study enrollment began on July 16, 2020. Data sets used for the interim analysis of efficacy and adverse events were locked on December 20, 2020, and December 31, 2020, respectively. Interventions: Participants were randomized to receive 1 of 2 inactivated vaccines developed from SARS-CoV-2 WIV04 (5 µg/dose; n = 13 459) and HB02 (4 µg/dose; n = 13 465) strains or an aluminum hydroxide (alum)-only control (n = 13 458); they received 2 intramuscular injections 21 days apart. Main Outcomes and Measures: The primary outcome was efficacy against laboratory-confirmed symptomatic COVID-19 14 days following a second vaccine dose among participants who had no virologic evidence of SARS-CoV-2 infection at randomization. The secondary outcome was efficacy against severe COVID-19. Incidence of adverse events and reactions was collected among participants who received at least 1 dose. Results: Among 40 382 participants randomized to receive at least 1 dose of the 2 vaccines or alum-only control (mean age, 36.1 years; 32 261 [84.4%] men), 38 206 (94.6%) who received 2 doses, contributed at least 1 follow-up measure after day 14 following the second dose, and had negative reverse transcriptase-polymerase chain reaction test results at enrollment were included in the primary efficacy analysis. During a median (range) follow-up duration of 77 (1-121) days, symptomatic COVID-19 was identified in 26 participants in the WIV04 group (12.1 [95% CI, 8.3-17.8] per 1000 person-years), 21 in the HB02 group (9.8 [95% CI, 6.4-15.0] per 1000 person-years), and 95 in the alum-only group (44.7 [95% CI, 36.6-54.6] per 1000 person-years), resulting in a vaccine efficacy, compared with alum-only, of 72.8% (95% CI, 58.1%-82.4%) for WIV04 and 78.1% (95% CI, 64.8%-86.3%) for HB02 (P < .001 for both). Two severe cases of COVID-19 occurred in the alum-only group and none occurred in the vaccine groups. Adverse reactions 7 days after each injection occurred in 41.7% to 46.5% of participants in the 3 groups; serious adverse events were rare and similar in the 3 groups (WIV04: 64 [0.5%]; HB02: 59 [0.4%]; alum-only: 78 [0.6%]). Conclusions and Relevance: In this prespecified interim analysis of a randomized clinical trial, treatment of adults with either of 2 inactivated SARS-CoV-2 vaccines significantly reduced the risk of symptomatic COVID-19, and serious adverse events were rare. Data collection for final analysis is pending. Trial Registration: ClinicalTrials.gov Identifier: NCT04510207; Chinese Clinical Trial Registry: ChiCTR2000034780.

Transmission of Middle East Respiratory Syndrome Coronavirus Infections in Healthcare Settings, Abu Dhabi.

Middle East respiratory syndrome coronavirus (MERS-CoV) infections sharply increased in the Arabian Peninsula during spring 2014. In Abu Dhabi, United Arab Emirates, these infections occurred primarily among healthcare workers and patients. To identify and describe epidemiologic and clinical characteristics of persons with healthcare-associated infection, we reviewed laboratory-confirmed MERS-CoV cases reported to the Health Authority of Abu Dhabi during January 1, 2013-May 9, 2014. Of 65 case-patients identified with MERS-CoV infection, 27 (42%) had healthcare-associated cases. Epidemiologic and genetic sequencing findings suggest that 3 healthcare clusters of MERS-CoV infection occurred, including 1 that resulted in 20 infected persons in 1 hospital. MERS-CoV in healthcare settings spread predominantly before MERS-CoV infection was diagnosed, underscoring the importance of increasing awareness and infection control measures at first points of entry to healthcare facilities.

Prevalence of hepatitis B and C infections among HIV-positive men who have sex with men: A systematic review and meta-analysis.

Background: Human immunodeficiency virus (HIV) infection is highly prevalent and often coexists with other infectious diseases, especially Hepatitis B virus (HBV) and Hepatitis C virus (HCV). Men who have sex with men (MSM) represent a vulnerable population in terms of HIV infection. We aimed to determine the prevalence of HCV, HBV among HIV-infected MSM. Methods: This systematic review and meta-analysis searched PubMed, Cochrane, Scopus, Web of Science, and ProQuest up-to 2023/04/22. All studies reporting the prevalence of HBV or HCV infection in MSM PLHIV were included. Meta-analysis used random effect model for synthesis and I 2 along with prediction interval for heterogeneity. Subgroup analysis based on continent and meta-regression for study size, average age and year of publication were used to explore heterogeneity. Modified Newcastle-Ottawa Scale was used to evaluate the quality of studies according to the protocol (PROSPERO: CRD42023428764). Results: Fifty-six of 5948 studies are included. In 53 studies with 3,07,589 participants, a pooled prevalence of 7% (95% confidence interval [CI]: 5-10) was found for HCV among MSM PLHIV, while a 9% (95% CI: 4-18) prevalence was found for HBV infection from five studies which included 5641 MSM PLHIV. Asia reported the lowest pooled prevalence at 5.84% (95% CI: 2.98-11.13) for HCV while Europe reported the highest pooled prevalence at 7.76% (95% CI: 4.35-13.45). Baujat plot and influence diagnostic identified contributors to influence and between-study heterogeneity. Sensitivity analyses omitting these studies result in considerably more precise estimates. Another sensitivity analysis as leave-one-out meta-analysis did not change any pooled estimate significantly. Conclusion: There is a significant burden of HCV and HBV among MSM PLHIV worldwide, with varying prevalence rates. Future studies should focus on these multimorbidity clusters and investigate factors influencing disease burden, long-term outcomes, optimal testing strategies, and tailored interventions.

Antifungal drug discovery for targeting Candida albicans morphogenesis through structural dynamics study.

In response to the escalating threat of drug-resistant fungi to human health, there is an urgent need for innovative strategies. Our focus is on addressing this challenge by exploring a previously untapped target, yeast casein kinase (Yck2), as a potential space for antifungal development. To identify promising antifungal candidates, we conducted a thorough screening of the diverse-lib drug-like molecule library, comprising 99,288 molecules. Five notable drug-like compounds with diverse-lib IDs 24334243, 24342416, 17516746, 17407455, and 24360740 were selected based on their binding energy scores surpassing 11 Kcal/mol. Our investigation delved into the interaction studies and dynamic stability of these compounds. Remarkably, all selected molecules demonstrated acceptable RMSD values during the 200 ns simulation, indicating their stable nature. Further analysis through Principal Component Analysis (PCA)-based Free Energy Landscape (FEL) revealed minimal energy transitions for most compounds, signifying dynamic stability. Notably, the two compounds exhibited slightly different behaviour in terms of energy transitions. These findings mark a significant breakthrough in the realm of antifungal drugs against C. albicans by targeting the Yck2 protein. However, it is crucial to note that additional experimental validation is imperative to assess the efficacy of these molecules as potential antifungal candidates. This study serves as a promising starting point for further exploration and development in the quest for effective antifungal solutions.Communicated by Ramaswamy H. Sarma.

Bioprospecting of Meliaceae family phytomolecules for the treatment of monkeypox virus infection: a QSAR modeling and MD simulation approach.

Recent monkeypox virus (MPXV) infections show the risk of MPXV transmission that persists today and the significance of surveillance and quick response methods to stop the virus's spread. Currently, the monkeypox virus infection is not specifically treated. In this study, QSAR models were designed using known inhibitors of cysteine proteinase from the vaccinia virus, where the Random Forest model and Ridge model had showed the best correlation between predicted and observed EC50. These models were used to screen Maliaceae family phytochemicals against MPXV cysteine proteinase. The compound, IMPHY010637 was detected in top 5 from both the QSAR screening models and showed best docked score (-8.6 kcal/mol) and thus selected for further investigation. Further, the IMPHY010637 showed interaction with the catalytic residue His241 of the protein as reported in earlier studies. The ADMET analysis of the compound showed the acceptable drug-like properties of IMPHY010637. However, these properties could be improved after experimental validation of protein-ligand binding. Both docked complex and poses created in 100 ns MD simulation of the protein-ligand complex showed the presence of multiple hydrogen bonds. RMSD and conformation analysis showed stable binding of IMPHY010637 with the cysteine proteinase of MPXV at its active site. Compared to the known inhibitor, IMPHY010637 showed better binding with the protein as observed by the PCA and MM/GBSA analysis. This study concluded IMPHY010637 as a potential inhibitor for the cysteine proteinase of MPXV using computational methods that could be tested in in-vitro experiments.Communicated by Ramaswamy H. Sarma.

Application of temperature-dependent and steered molecular dynamics simulation to screen anti-dengue compounds against Marburg virus.

Marburg virus infections are extremely fatal with a fatality range of 23% to 90%, therefore there is an urgent requirement to design and develop efficient therapeutic molecules. Here, a comprehensive temperature-dependent molecular dynamics (MD) simulation method was implemented to identify the potential molecule from the anti-dengue compound library that can inhibit the function of the VP24 protein of Marburg. Virtual high throughput screening identified five effective binders of VP24 after screening 484 anti-dengue compounds. These compounds were treated in MD simulation at four different temperatures: 300, 340, 380, and 420 K. Higher temperatures showed dissociation of hit compounds from the protein. Further, triplicates of 100 ns MD simulation were conducted which showed that compounds ID = 118717693, and ID = 5361 showed strong stability with the protein molecule. These compounds were further validated using ΔG binding free energies and they showed: -30.38 kcal/mol, and -67.83 kcal/mol binding free energies, respectively. Later, these two compounds were used in steered MD simulation to detect its dissociation. Compound ID = 5361 showed the maximum pulling force of 199.02 kcal/mol/nm to dissociate the protein-ligand complex while ID = 118717693 had a pulling force of 101.11 kcal/mol/nm, respectively. This ligand highest number of hydrogen bonds with varying occupancies at 89.93%, 69.80%, 57.93%, 52.33%, and 50.63%. This study showed that ID = 5361 can bind with the VP24 strongly and has the potential to inhibit its function which can be validated in the in-vitro experiment.Communicated by Ramaswamy H. Sarma.

Influence of COVID-19 pandemic on pregnancy and fertility preferences among the residents of the United Arab Emirates (UAE).

Background: The coronavirus disease 2019 (COVID-19) significantly impacted the lifestyles of millions of people, with new challenges arising as the pandemic progresses. However, little attention has been given to issues like fertility intentions and pregnancy planning during COVID-19. Consequently, we aimed to investigate the influence of the pandemic on pregnancy and fertility decisions among the residents of the United Arab Emirates (UAE). Methods: We surveyed UAE residents of reproductive age between November 2021 to June 2022 via the Google Forms platform and collected data on demographics, associated health conditions, COVID-19 infections, as well as plans for pregnancy and fertility intentions. We presented data through descriptive statistics (frequencies and percentages) and used Pearson's χ2 test to compare the characteristics of participants who reported that the COVID-19 pandemic has influenced their fertility preferences with those who reported that it had not. Results: Overall, 564 participants completed the survey, of whom 115 (20.4%) stated that the COVID-19 pandemic had influenced their fertility preferences. Meanwhile, 234 (41.5%) reported previous history of COVID-19 infection; regarding post-COVID-19 infection symptoms, 53 (22.6%) reported decreased libido and 40 (17%) reported trouble in conceiving a baby. Participants who were ≤30 years of age were less likely to be influenced by the COVID-19 pandemic on their decision on fertility compared to those >30 years of age. Factors like education, income, chronic health conditions, and previous history of COVID-19 infection or vaccination did not have any significant effect on the COVID-19 pandemic influence on fertility preferences. Conclusions: The COVID-19 pandemic has brought in new challenges which could affect fertility and this needs to be studied further for planning effective measures.

The emergence and implications of SARS-CoV-2 omicron subvariant BA.2.86 on global health.

The SARS-CoV-2 subvariant BA.2.86 'Pirola', first identified in Denmark in August 2023, has manifested with a significantly mutated spike protein profile, suggesting a heightened ability to evade vaccine-induced and infection-induced antibodies. This article outlines the epidemiological spread, immune response implications, and global responses to BA.2.86. Preliminary observations indicate community transmissions of the subvariant, even among those previously infected or vaccinated. Notably, the BA.2.86 infection has shown a potential to amplify antibody responses. The variant's emergence has evoked memories of the Omicron variant's rise in late 2021, though global immunity levels might modulate the impact of BA.2.86 impact differently. Continuous genomic surveillance, coupled with integrated diagnostic and epidemiological strategies, proves crucial in early detection and management. The emergence of BA.2.86 reaffirms the unpredictable nature of the COVID-19 pandemic, emphasizing the need for ongoing research, adaptability, and global collaboration.

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.

Safety and immunogenicity of the NVX-CoV2373 vaccine as a booster in adults previously vaccinated with the BBIBP-CorV vaccine.

This phase 3 observer-blind, randomized, controlled study was conducted in adults ≥18 years of age to assess the safety and immunogenicity of NVX-CoV2373 as a heterologous booster compared to BBIBP-CorV when utilized as a homologous booster. Approximately 1000 participants were randomly assigned in a 1:1 ratio to receive a single dose of NVX-CoV2373 or BBIBP-CorV after prior vaccination with 2 or 3 doses of BBIBP-CorV. Solicited adverse events (AEs) were collected for 7 days after vaccination. Unsolicited AEs were collected for 28 days following the booster dose and serious adverse and adverse events of special interest (AESI) were collected throughout the study. Anti-spike IgG and neutralizing antibodies against SARS-CoV-2 were measured at baseline, day 14, day 28, and day 180. The study achieved its primary non-inferiority endpoint and also demonstrated statistically higher neutralization responses when NVX-CoV2373 was utilized as a heterologous booster compared with BBIBP-CorV as a homologous booster. Both vaccines had an acceptably low reactogenicity profile, and no new safety concerns were found. Heterologous boosting with NVX-CoV2373 was a highly immunogenic and safe vaccine regimen in those previously vaccinated with BBIBP-CorV.

Incidence and Association of Uveitis with COVID-19 Vaccination: A Systematic Review and Meta-Analysis.

PURPOSE: In the wake of the COVID-19 pandemic, vaccines have been pivotal in curbing disease spread and severity. However, concerns over post-vaccination adverse events, including uveitis, an inflammatory ocular condition, have been noted. This systematic review and meta-analysis aimed to evaluate the incidence and association of uveitis following COVID-19 vaccination. METHODS: A literature search was performed across several databases on October 21, 2023. Human studies examining the incidence of uveitis post-COVID-19 vaccination were included. The Newcastle-Ottawa Scale was used for quality appraisal of the included studies. Meta-analysis was performed to assess the overall incidence of uveitis and the relative risk of developing the condition post-vaccination. All statistical analyses were performed using R software version 4.3. RESULTS: Six studies involving over 2 billion vaccine doses were included. The overall incidence of uveitis was 0.016% (95% CI: 0.010 to 0.026). No significant association was found between vaccination and the onset of uveitis (Relative Risk: 1.45 (95% CI: 0.82 to 2.57, p = 0.12) from four studies. The evidence quality was rated very low due to the limited number of studies and imprecision. CONCLUSION: This analysis indicates a low incidence of uveitis following COVID-19 vaccination and no significant association with the vaccine. The findings are constrained by the small number of studies and low certainty of evidence, underscoring the need for further research. Comprehensive and longitudinal studies are necessary to confirm these findings and reinforce public confidence in COVID-19 vaccination programs.

Status of vancomycin-resistant Enterococcus in species of wild birds: A systematic review and meta-analysis.

Wild birds could be a reservoir of medically relevant microorganisms, particularly multidrug-resistant Enterococcus spp. Resistant bacteria's epidemiology and transmission between animals and humans has grown, and their zoonotic potential cannot be ignored. This is the first study to evaluate the status of vancomycin resistant enterococci (VRE) in various wild bird species using meta-analysis and a systematic review. In this study, the pooled prevalence was obtained by analyzing data from published articles on the occurrence of VRE in wild bird species. It's unclear how the antibiotic resistance gene transfer cycle affects wild birds. Google Scholar and PubMed were used to conduct the research. The data and study methodology was assessed and extracted by two reviewers independently, with a third reviewing the results. Heterogeneity between study and publication bias were analyzed using the random effect model. Thirty-eight studies were included in the meta-analysis. 382 out of the 4144 isolates tested, were VRE. The pooled prevalence of VRE among wild birds was estimated at 11.0% (95% CI; 6.9 -17.2%; I2 = 93.204%; P < 0.001). There was high variability between study (t2 = 2.156; heterogeneity I2 = 93.204% with chi-square (Q) = 544.413, degrees of freedom (df) = 37, and P < 0.001). Egger's test verified the funnel plot's bias, while result from the leave-one-out forest plot had no effect on the pooled prevalence.

GENETIC VARIANTS AND SERUM PROFILES OF CYTOKINES IN COVID-19 SEVERITY.

ABSTRACT: Background: Patients with severe coronavirus disease 2019 (COVID-19) are at an increased risk of acute respiratory distress syndrome and mortality. This is due to the increased levels of pro-inflammatory cytokines that amplify downstream pathways that are controlled by immune regulators. Objective: This study aimed to investigate the association between cytokine genetic variants, cytokine serum levels/profiles, and disease severity in critically and noncritically ill COVID-19 patients. Methods: This cross-sectional study recruited 646 participants who tested positive for severe acute respiratory syndrome coronavirus 2 from six collection sites across the United Arab Emirates. Medical files were accessed to retrieve clinical data. Blood samples were collected from all participants. Patients were divided into two clinical groups, noncritical (n = 453) and critical (n = 193), according to World Health Organization classification guidelines for COVID-19 patients. Cytokine analyses were conducted on serum of a subset of the cohort, specifically on 426 participants (noncritical, 264; critical, 162). Candidate gene analyses of 33 cytokine-related genes (2,836 variants) were extracted from a genome-wide association study to identify genetic variants with pleiotropic effects on a specific cytokine and the severity of COVID-19 disease. Results: Age, body mass index (BMI), and pre-existing medical conditions were found to be significant risk factors that contribute to COVID-19 disease severity. After correcting for age, sex, and BMI, IP-10 ( P < 0.001), IFN ( P = 0.001), IL-6 ( P < 0.001), and CXCL-16 ( P < 0.001) serum levels were significantly higher among critical COVID-19 cases, when compared with noncritically ill patients. To investigate if the genetic variants involved in the serum cytokine levels are associated with COVID-19 severity, we studied several genes. Single nucleotide polymorphisms in IL6 (rs1554606; odd ratio (OR) G = 0.67 [0.66, 0.68]; P = 0.017), IFNG (rs2069718; OR G = 0.63 [0.62, 0.64]; P = 0.001), MIP (rs799187; OR A = 1.69 [1.66, 1.72]; P = 0.034), and CXCL16 (rs8071286; OR A = 1.42 [1.41, 1.44]; P = 0.018) were found to be associated with critically ill patients. Polymorphisms in the CXCL10 , CCL2 , IL1 , CCL7 , and TNF genes were not associated with the COVID-19 critical phenotype. The genotypes of IL-6 (gene, IL6 [7p15.3]) and CXCL-16 (gene, CXCL16 [17p13.2]) were significantly associated with the serum levels of the respective cytokine in critical cases of COVID-19. Conclusion: Data obtained from measuring cytokine levels and genetic variant analyses suggest that IL-6 and CXCL-16 could potentially be used as potential biomarkers for monitoring disease progression of COVID-19 patients. The findings in this study suggest that specific cytokine gene variants correlate with serum levels of the specific cytokine. These genetic variants could be of assistance in the early identification of high-risk patients on admission to the clinic to improve the management of COVID-19 patients and other infectious diseases.

Efficacy and Safety of a Booster Vaccination with Two Inactivated SARS-CoV-2 Vaccines on Symptomatic COVID-19 Infection in Adults: Results of a Double-Blind, Randomized, Placebo-Controlled, Phase 3 Trial in Abu Dhabi.

IMPORTANCE: The protective efficacy of COVID-19 vaccinations has declined over time such that booster doses are required. OBJECTIVE: To evaluate the efficacy and adverse events of booster doses of two inactivated COVID-19 vaccines. DESIGN: This is a double-blind, randomized, placebo-controlled phase 3 trial aiming to evaluate the protective efficacy, safety, and immunogenicity of inactivated SARS-CoV-2 vaccine (Vero cells) after inoculation with booster doses of inactivated COVID-19 vaccine. SETTING: Healthy volunteers were recruited in an earlier phase 3 trial of two doses of inactivated vaccine. The participants in Abu Dhabi maintained the blind state of the trial and received a booster dose of vaccine or placebo at least six months after the primary immunization. PARTICIPANTS: Adults aged 18 and older with no history of SARS-CoV, SARS-CoV-2, or Middle East respiratory syndrome infection (via onsite inquiry) were screened for eligibility. INTERVENTIONS: A total of 9370 volunteers were screened and randomly allocated, of which 61 voluntarily withdrew from the screening stage without booster inoculation; 9309 received the booster vaccination, with 3083 in the WIV04 group, 3150 in the HB02 group, and 3076 in the alum-only group. Further, 5µg and 4µg of inactivated SARS-CoV-2 virion was adsorbed into aluminum hydroxide in a 0.5 mL aqueous suspension for WIV04 and HB02 vaccines. MAIN OUTCOMES AND MEASURES: The primary efficacy outcome was the prevention of PCR-confirmed symptomatic COVID-19 from 14 days after the booster vaccine in the per-protocol population. A safety analysis was performed in the intention-to-treat population. RESULTS: Symptomatic COVID-19 was identified in 36 participants in the WIV04 group (9.9 [95% CI, 7.2-13.8] per 1000 person-years), 28 in the HB02 group (7.6 [95% CI, 5.2-11.0] per 1000 person-years), and 193 in the alum-only group (55.2 [95% CI, 47.9-63.5] per 1000 person-years), resulting in a vaccine efficacy of 82.0% (95% CI, 74.2-87.8%) for WIV04 and 86.3% (95% CI, 79.6-91.1%) for HB02. One severe case of COVID-19 occurred in the alum-only group, and none occurred in the vaccine groups. Adverse reactions within seven days after vaccination occurred in 29.4% to 34.3% of participants in the three groups. Serious adverse events were rare and not related to vaccines (WIV04: 17 [0.5%]; HB02: 11 [0.4%]; alum only: 40 [1.3%]). CONCLUSIONS AND RELEVANCE: This study evaluated the safety of the booster dose, which was well tolerated by participants. Booster doses given over six months after the completion of primary immunization can help to provide more-effective protection against COVID-19 in healthy people 18 years of age or older. At the same time, the anti-SARS-CoV-2 antibodies produced by the two groups of experimental vaccines exhibited extensive cross-neutralization against representative SARS-CoV-2 variants. TRIAL REGISTRATION: This study is registered on ClinicalTrials.gov (NCT04510207).

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.

Antibodies to Combat Fungal Infections: Development Strategies and Progress.

The finding that some mAbs are antifungal suggests that antibody immunity may play a key role in the defense of the host against mycotic infections. The discovery of antibodies that guard against fungi is a significant advancement because it gives rise to the possibility of developing vaccinations that trigger protective antibody immunity. These vaccines might work by inducing antibody opsonins that improve the function of non-specific (such as neutrophils, macrophages, and NK cells) and specific (such as lymphocyte) cell-mediated immunity and stop or aid in eradicating fungus infections. The ability of antibodies to defend against fungi has been demonstrated by using monoclonal antibody technology to reconsider the function of antibody immunity. The next step is to develop vaccines that induce protective antibody immunity and to comprehend the mechanisms through which antibodies mediate protective effects against fungus.