Conserved regions of Plasmodium vivax potential vaccine candidate antigens in Sri Lanka:Conscious in silico analysis of prospective conformational epitope regions

Objective:To do mapping and modeling of conformational B cell epitope regions of highly conserved and protective regions of three merozoitecandidate vaccine proteins of Plasmodium vivax(P.vivax),ie.merozoite purface protein-1(PvMSP-1),apical membrane antigen-1 domainⅡ(PvAMA1-DⅡ)and regionⅡof the Duffy binding protein(PvDBPⅡ).and to analyze the immunogenie properties of these predicted epitopes.Methods:3-D structures of amino acid haplotypes from Sri Lanka(available in GeneBank)of PvMSP-1_(19)(n=27),PvAMA1-DⅡ(n=21)and PvDBPⅡ(n=33)were modeled.SEPPA,selected as the best online server was used for conformational epitope predictions,while prediction and moodeling of protein structuve and properties related to immunogenicity was carried out with Geno3D server.SCRATCH Protein Server,NetSurfP Server and standaloneroftware,Genious 5.4.4.Results:SEPPA revealed that regions of predicted conformational epitopes formed 4 clusters in PvMSP-I_(19),and 3 clusters each in PvAMA1-DⅡand PvDBPⅡ,all of which displayed a high degree of hydrophilicity,contained solveut exposed residues,displayed high probability of antigenicity and showed positive antigenic propensity values,that indicated high degree of immunogenicity.Conclusions:Findings of this study revealed and confirmed that different parts of the sequences of each of the conserved regions of the three selected potential vaccine candidate antigens of P.vivax are important with regard to conformational epitope prediction that warrants further laboratory experimental invertigations in in vivo animal models.     

Aggressive Angiomyxoma of Inguinoscrotal Region Mimicking Inguinal Hernia: a Case Report

Aggressive angiomyxoma (AAM) is a rare mesenchymal tumour of pelvis and perineum, almost exclusively occurring in females. We are reporting a case of a 53-year-old gentleman who presented with a long standing inguinoscrotal swelling misdiagnosed as inguinal hernia, for which he underwent incomplete excision at local hospital and then was referred to our centre for completion surgery.     

Convalescent plasma therapy for severe Covid-19 in patients with hematological malignancies

BackgroundData on convalescent plasma therapy (CPT) in patients of hematological malignancies with severe Covid-19 is scarce.ObjectiveTo study 14-day mortality in patients who received CPT.Patients & methodsRetrospective multicentre observational study conducted in 4 centres treating haematological malignancies across Delhi-national capital region. Total 33 haematological malignancies patients with severe Covid-19 who received CPT were analysed.ResultsThe median age of the study cohort was 62 years (18–80 years). Twenty one percent patients had 1 comorbidity, 18 % had 2 comorbidities and 6% patients had 3 and 5 comorbidities each. Twenty four patients were on active therapy. Sixty nine percent of patients required ICU stay. Twenty five patients received plasma therapy within 7 days (early) of diagnosis of Covid-19 infection. Median day of plasma infusion from date of diagnosis of Covid-19 infection was 4 days (range: 2–25 days). Patient who had early initiation of plasma therapy had shorter duration of hospitalisation (12.7 vs 24.3 days, p = 0.000). Overall mortality in the cohort was 45.5%. There was no effect of disease status, active therapy, presence of comorbidity on mortality. There was no difference in the mortality in patients receiving early vs late initiation of plasma therapy or in patients receiving one versus two plasma therapy.ConclusionsWe provide a large series of patients with hematological malignancies and role of CPT in this group.     

In Vitro Activity and Resistance Profile of Dasabuvir,a Nonnucleoside Hepatitis C Virus Polymerase Inhibitor

Dasabuvir (ABT-333) is a nonnucleoside inhibitor of the RNA-dependent RNA polymerase encoded by the hepatitis C virus (HCV) NS5B gene. Dasabuvir inhibited recombinant NS5B polymerases derived from HCV genotype 1a and 1b clinical isolates, with 50% inhibitory concentration (IC₅₀) values between 2.2 and 10.7 nM, and was at least 7,000-fold selective for the inhibition of HCV genotype 1 polymerases over human/mammalian polymerases. In the HCV subgenomic replicon system, dasabuvir inhibited genotype 1a (strain H77) and 1b (strain Con1) replicons with 50% effective concentration (EC₅₀) values of 7.7 and 1.8 nM, respectively, with a 13-fold decrease in inhibitory activity in the presence of 40% human plasma. This level of activity was retained against a panel of chimeric subgenomic replicons that contained HCV NS5B genes from 22 genotype 1 clinical isolates from treatment-naive patients, with EC₅₀s ranging between 0.15 and 8.57 nM. Maintenance of replicon-containing cells in medium containing dasabuvir at concentrations 10-fold or 100-fold greater than the EC₅₀ resulted in selection of resistant replicon clones. Sequencing of the NS5B coding regions from these clones revealed the presence of variants, including C316Y, M414T, Y448C, Y448H, and S556G, that are consistent with binding to the palm I site of HCV polymerase. Consequently, dasabuvir retained full activity against replicons known to confer resistance to other polymerase inhibitors, including the S282T variant in the nucleoside binding site and the M423T, P495A, P495S, and V499A single variants in the thumb domain. The use of dasabuvir in combination with inhibitors targeting HCV NS3/NS4A protease (ABT-450 with ritonavir) and NS5A (ombitasvir) is in development for the treatment of HCV genotype 1 infections.     

Hepatitis C Virus Genotype 4 Resistance and Subtype Demographic Characterization of Patients Treated with Ombitasvir plus Paritaprevir/Ritonavir

Hepatitis C virus (HCV) genotype 4 (GT4) is genetically diverse, with 17 confirmed subtypes, and comprises approximately 13% of infections worldwide. In this study, we identified GT4 subtypes by phylogenetic analysis, assessed differences in patient demographics across GT4 subtypes, examined baseline sequence variability among subtypes and the potential impact on treatment outcome, and analyzed the development of viral resistance in patients who received a regimen of ombitasvir (nonstructural protein 5A [NS5A] inhibitor) plus ritonavir-boosted paritaprevir (NS3/4A inhibitor) with or without ribavirin (RBV) for the treatment of HCV GT4 infection. Phylogenetic analysis of HCV NS3/4A, NS5A, and NS5B nucleotide sequences identified 7 subtypes (4a, 4b, 4c, 4d, 4f, 4g/4k, and 4o) among 132 patient samples. Subtype prevalence varied by country, and the distributions of patient birth cohort and race were significantly different across GT4 subtypes 4a, 4d, and non-4a/4d. Baseline amino acid variability was detected in NS5A across GT4 subtypes but had no impact on treatment outcome. Three patients experienced virologic failure and were infected with subtype 4d, and the predominant resistance-associated variants at the time of failure were D168V in NS3 and L28V in NS5A. Overall, high response rates were observed among patients infected with 7 HCV GT4 subtypes, with no impact of baseline variants on treatment outcome. GT4 subtype distribution in this study differed based on patient demographics and geography.