Monoclonal antibodies in type 2 asthma : a systematic review and network meta-analysis

Since novel treatments to target eosinophilic inflammation in Type 2 asthma are emerging, we aimed to evaluate and meta-analyze the efficacy of monoclonal antibodies to reduce exacerbation rate. PubMed and Web of Science were searched for phase II and phase III randomized clinical trials with monoclonal antibodies targeting key mediators of type 2-associated asthma. Thirty trials were selected involving biologics that target the IL-5 pathway, IL-13, the common IL-4 and IL-13 receptor, IL-9, IL-2 and TSLP. As no head-to-head trials were retrieved from literature, we performed an arm-based network meta-analysis to compare effects on exacerbation rate between the different treatments. Mepolizumab, reslizumab and benralizumab significantly reduced the risk of exacerbations compared to placebo (by 47-52%, 50-60%, and 28-51% respectively). Reslizumab and benralizumab also improved lung function. Dupilumab and tezepelumab improved lung function in frequent exacerbators. Lebrikizumab had no significant effect on the number of exacerbations, symptom control or health-related quality of life. Tralokinumab improved lung function compared to placebo. Network meta-analysis of all treatment and placebo arms, showed no superiority of one biologic over the others. Large reductions in exacerbation rates were observed compared to placebo, though only benralizumab was sufficiently powered (n = 2051) to demonstrate significantly decreased exacerbation rates in the subgroup analysis of IL-5 acting agents compared to placebo. Monoclonal antibodies such as mepolizumab, reslizumab and benralizumab have proven their benefit to reduce exacerbation rates in severe persistent eosinophilic asthma in the published trials. However, no statistically significant superiority was observed of one biologic over the other in the network meta-analysis. More studies with direct head to head comparisons and better defined endotypes are required

Recent Advances in Methods Detecting the Dengue Virus

Dengue fever, caused by the Dengue virus (DENV), has emerged as a mild to lethal human infection. Globally, an estimated 400 million patients have been infected with DENV over the past 10 years, and this number is expected to increase in the coming years. The DENV, possessing a single positive- stranded RNA with five serotypes, is transmitted by mosquitos of the Flaviviridae family—particularly, the Flavivirus genus and Aedes species. The DENV genome encodes three structural and seven non- structural proteins. In the Kingdom of Saudi Arabia (KSA), serotype 2 of the dengue virus (DENV-2) emerged in 1994 and caused a major epidemic in Jeddah, KSA. Dengue outbreaks first appeared in Makkah in 2004, according to the characteristics studied in hospitalized patients. Major factors causing the wide and rapid distribution of the virus include increased urbanization, migration, global commerce, weather variation, inadequate mosquito control, the development of pesticide resistance in mosquitos, irregular use of insecticides, and shifting climatic circumstances. Detection methods currently used for DENV include the detection of viral antigens (Ag) (virus extraction and purification, immunofluorescence test, and NS1 detection assay), serological assays (plaque reduction neutralization titers (PRNT), IgM/IgG immunological assays), and RNA detection using RT-PCR. Low sensitivity, specificity, and accessibility of the detection protocols represent major challenges necessitating the advent of more amenable protocols. The Aedes mosquito is the primary vector for horizontal transmission of DENV. DENV-infected mosquitos infect people, and DENV passes from one human to another through this vector. Once acquired, the virus requires 5–7 days of incubation before the patient exhibits various symptoms of dengue fever; subsequently, uninfected mosquitoes that come in contact with infected patients feed on their blood and become infected. The DENV may also be spread through the mating of male and female Aedes mosquitoes. The reverse transcription loop-mediated isothermal application (RT-LAMP) has emerged as one of the most adaptable viral detection procedures. This method could prove to be an excellent pathogen detection tool because it is cheap, simple, sensitive, cost-effective, accessible, and fast. The method relies on the use of 4–6 primers to recognize eight different loci in the target sequence contained in the DENV clinical isolates with a 100% success rate and a sensitivity of about 93%. We strongly recommend the use of LAMP in detecting spots of virus spread, especially in urban regions where accessibility to detection methods is scarce

Epigenome-wide association study on diffusing capacity of the lung

Background: Epigenetics may play an important role in the pathogenesis of lung diseases. However, little is known about the epigenetic factors that influence impaired gas exchange at the lung. Aim: To identify the epigenetic signatures of the diffusing capacity of the lung measured by carbon monoxide uptake (the diffusing capacity of the lung for carbon monoxide (DLCO)). Methods: An epigenome-wide association study (EWAS) was performed on diffusing capacity, measured by carbon monoxide uptake (DLCO) and per alveolar volume (VA) (as DLCO/VA), using the single-breath technique in 2674 individuals from two population-based cohort studies. These were the Rotterdam Study (RS, the "discovery panel") and the Framingham Heart Study (FHS, the "replication panel"). We assessed the clinical relevance of our findings by investigating the identified sites in whole blood and by lung tissue specific gene expression. Results: We identified and replicated two CpG sites (cg05575921 and cg05951221) that were significantly associated with DLCO/VA and one (cg05575921) suggestively associated with DLCO. Furthermore, we found a positive association between aryl hydrocarbon receptor repressor (AHRR) gene (cg05575921) hypomethylation and gene expression of exocyst complex component 3 (EXOC3) in whole blood. We confirmed that the expression of EXOC3 in lung tissue is positively associated with DLCO/VA and DLCO. Conclusions: We report on epigenome-wide associations with diffusing capacity in the general population. Our results suggest EXOC3 to be an excellent candidate, through which smoking-induced hypomethylation of AHRR might affect pulmonary gas exchange

Molecular detection of Epstein-Barr virus among Sudanese patients diagnosed with Hashimoto’s thyroiditis

Objectives: Hashimoto’s thyroiditis (HT) is the most common cause of hypothyroidism. The exact mechanism initiating the development of HT is not yet clear. This study aimed to investigate the correlation between HT and the presence of Epstein-Barr virus (EBV) in a Sudanese population. Results: EBV-LMP1 was detected in 11.1% of HT cases, which is consistent with previous studies. Studies have reported a wide range of frequencies indicating the presence of EBV in HT, and patients with autoimmune thyroiditis have increased titers of anti-EBV antibodies in their sera compared to healthy subjects. Intrathyroidal EBV-infected B cells may be responsible for the increased risk of development of B-cell lymphoma in the thyroid gland in patients with autoimmune thyroiditis. Our study suggests that regular follow-up is necessary for patients diagnosed with HT and are positive for EBV, as antiviral therapy is not applicable due to the risk of thyroid dysfunction. The study suggests an association between EBV and HT, but causation cannot be determined. The study also highlights the need for further research to determine the viral role and correlate it with the severity and progression of HT.</p

Molecular detection of Epstein-Barr virus among Sudanese patients diagnosed with Hashimoto’s thyroiditis

Objectives: Hashimoto’s thyroiditis (HT) is the most common cause of hypothyroidism. The exact mechanism initiating the development of HT is not yet clear. This study aimed to investigate the correlation between HT and the presence of Epstein-Barr virus (EBV) in a Sudanese population. Results: EBV-LMP1 was detected in 11.1% of HT cases, which is consistent with previous studies. Studies have reported a wide range of frequencies indicating the presence of EBV in HT, and patients with autoimmune thyroiditis have increased titers of anti-EBV antibodies in their sera compared to healthy subjects. Intrathyroidal EBV-infected B cells may be responsible for the increased risk of development of B-cell lymphoma in the thyroid gland in patients with autoimmune thyroiditis. Our study suggests that regular follow-up is necessary for patients diagnosed with HT and are positive for EBV, as antiviral therapy is not applicable due to the risk of thyroid dysfunction. The study suggests an association between EBV and HT, but causation cannot be determined. The study also highlights the need for further research to determine the viral role and correlate it with the severity and progression of HT.</p

Pharmacogenetics of inhaled corticosteroids and exacerbation risk in adults with asthma

Background: Inhaled corticosteroids (ICS) are a cornerstone of asthma treatment. However, their efficacy is characterized by wide variability in individual responses. Objective: We investigated the association between genetic variants and risk of exacerbations in adults with asthma and how this association is affected by ICS treatment. Methods: We investigated the pharmacogenetic effect of 10 single nucleotide polymorphisms (SNPs) selected from the literature, including SNPs previously associated with response to ICS (assessed by change in lung function or exacerbations) and novel asthma risk alleles involved in inflammatory pathways, within all adults with asthma from the Dutch population-based Rotterdam study with replication in the American GERA cohort. The interaction effects of the SNPs with ICS on the incidence of asthma exacerbations were assessed using hurdle models adjusting for age, sex, BMI, smoking and treatment step according to the GINA guidelines. Haplotype analyses were also conducted for the SNPs located on the same chromosome. Results: rs242941 (CRHR1) homozygotes for the minor allele (A) showed a significant, replicated increased risk for frequent exacerbations (RR = 6.11, P < 0.005). In contrast, rs1134481T allele within TBXT (chromosome 6, member of a family associated with embryonic lung development) showed better response with ICS. rs37973 G allele (GLCCI1) showed a significantly poorer response on ICS within the discovery cohort, which was also significant but in the opposite direction in the replication cohort. Conclusion: rs242941 in CRHR1 was associated with poor ICS response. Conversely, TBXT variants were associated with improved ICS response. These associations may reveal specific endotypes, potentially allowing prediction of exacerbation risk and ICS response

Association of methionine synthase reductase (MTRR A66G) polymorphism with susceptibility to acute lymphoblastic leukemia

Background and Objectives. The enzyme methionine synthase reductase is involved in cellular methylation reactions, DNA synthesis, and epigenetic processes. It is encoded by the MTRR gene, which garnered a lot of attention in current medical genetics research. This study was conducted to study the association between MTRR (A66G) polymorphism and the risk of developing acute lymphoblastic leukemia among Sudanese patients. Materials and Methods. This is a case-control study in which 150 patients with acute lymphoblastic leukemia (ALL) and 150 healthy participants as a control group were enrolled. DNA was extracted and analyzed for the MTRR (A66G) polymorphism using the real-time polymerase chain reaction. Results. Based on flow cytometry results, B-ALL was more common (79%) than T-ALL (21%). The comparison of hematological parameters in acute lymphoblastic leukemia subtypes showed a statistically significant high mean total white blood count (P=0.000) and mean blast percentage (P=0.050) in patients with T-ALL. The molecular analysis showed that the incidence of the MTRR homozygous genotypes AA and GG were higher in the patients (44% and 9.3%, respectively) compared to the control group (40% and 6.7%, respectively). In comparison, the heterozygous genotype AG was lower in the patients (46.7%) than in the control group (53.3%). However, the association between the polymorphism and acute lymphoblastic leukemia risk was not statistically significant (OR: 1.179, 95% CI 0.7459-1.865, P=0.445). Conclusions. This study concluded that MTRR A66G polymorphism was not associated with the risk of acute lymphoblastic leukemia among the Sudanese population

Unlocking the potential of approved drugs for the allosteric inhibition of tropomyosin-receptor kinase A using molecular docking and molecular dynamics studies

Tropomyosin-receptor kinase A (TrkA) is the primary isoform among the tropomyosin-receptor kinases that have been associated with human cancer development, contributing to approximately 7.4% of all cancer cases. TrkA represents an attractive target for cancer treatment; however, currently available TrkA inhibitors face limitations in terms of resistance development and potential toxicity. Hence, the objective of this study was to identify new allosteric-approved inhibitors of TrkA that can overcome these challenges and be employed in cancer therapy. To achieve this goal, a screening of 9,923 drugs from the ChEMBL database was conducted to assess their repurposing potential using molecular docking. The top 49 drug candidates, exhibiting the highest docking scores (−11.569 to −7.962 kcal/mol), underwent MM-GBSA calculations to evaluate their binding energies. Delanzomib and tibalosin, the top two drugs with docking scores of −10.643 and −10.184 kcal/mol, respectively, along with MM-GBSA dG bind values of −67.96 and −50.54 kcal/mol, were subjected to 200 ns molecular dynamic simulations, confirming their stable interactions with TrkA. Based on these findings, we recommend further experimental evaluation of delanzomib and tibalosin to determine their potential as allosteric inhibitors of TrkA. These drugs have the potential to provide more effective and less toxic therapeutic alternatives. The approach employed in this study, which involves repurposing drugs through molecular docking and molecular dynamics, serves as a valuable tool for identifying novel drug candidates with distinct therapeutic uses. This methodology can contribute to reducing the attrition rate and expediting the process of drug discovery

Impact of COVID-19 Pandemic on TAVR Activity: A Worldwide Registry

Background: The COVID-19 pandemic had a considerable impact on the provision of structural heart intervention worldwide. Our objectives were: 1) to assess the impact of the COVID-19 pandemic on transcatheter aortic valve replacement (TAVR) activity globally; and 2) to determine the differences in the impact according to geographic region and the demographic, development, and economic status of diverse international health care systems. Methods: We developed a multinational registry of global TAVR activity and invited individual TAVR sites to submit TAVR implant data before and during the COVID-19 pandemic. Specifically, the number of TAVR procedures performed monthly from January 2019 to December 2021 was collected. The adaptive measures to maintain TAVR activity by each site were recorded, as was a variety of indices relating to type of health care system and national economic indices. The primary subject of interest was the impact on TAVR activity during each of the pandemic waves (2020 and 2021) compared with the same period pre–COVID-19 (2019). Results: Data were received from 130 centers from 61 countries, with 14 subcontinents and 5 continents participating in the study. Overall, TAVR activity increased by 16.7% (2,337 procedures) between 2018 and 2019 (ie, before the pandemic), but between 2019 and 2020 (ie, first year of the pandemic), there was no significant growth (–0.1%; –10 procedures). In contrast, activity again increased by 18.9% (3,085 procedures) between 2020 and 2021 (ie, second year of the pandemic). During the first pandemic wave, there was a reduction of 18.9% (945 procedures) in TAVR activity among participating sites, while during the second and third waves, there was an increase of 6.7% (489 procedures) and 15.9% (1,042 procedures), respectively. Further analysis and results of this study are ongoing and will be available at the time of the congress. Conclusion: The COVID-19 pandemic initially led to a reduction in the number of patients undergoing TAVR worldwide, although health care systems subsequently adapted, and the number of TAVR recipients continued to grow in subsequent COVID-19 pandemic waves. Categories: STRUCTURAL: Valvular Disease: Aorti

Mapping 123 million neonatal, infant and child deaths between 2000 and 2017

Since 2000, many countries have achieved considerable success in improving child survival, but localized progress remains unclear. To inform efforts towards United Nations Sustainable Development Goal 3.2—to end preventable child deaths by 2030—we need consistently estimated data at the subnational level regarding child mortality rates and trends. Here we quantified, for the period 2000–2017, the subnational variation in mortality rates and number of deaths of neonates, infants and children under 5 years of age within 99 low- and middle-income countries using a geostatistical survival model. We estimated that 32% of children under 5 in these countries lived in districts that had attained rates of 25 or fewer child deaths per 1,000 live births by 2017, and that 58% of child deaths between 2000 and 2017 in these countries could have been averted in the absence of geographical inequality. This study enables the identification of high-mortality clusters, patterns of progress and geographical inequalities to inform appropriate investments and implementations that will help to improve the health of all populations