Inderpal Singh

Introduction: Delirium is a common acute neuropsychiatric syndrome in older adults and is associated with poor outcomes. There is limited evidence on outcomes among older patients admitted to medical assessment units (MAUs) compared to those without delirium. Objective: To examine the association between delirium and mortality, hospital length of stay, and readmission rates in patients aged ≥65 years admitted to an MAU. Methods: A retrospective observational cohort study was conducted at Ysbyty Ystrad Fawr Hospital, Wales. Hospital records for patients aged ≥65 years admitted to the MAU during 2023 were reviewed. The primary outcomes were length of stay (LOS), inpatient mortality, 30-day mortality, 90-day mortality, and 30-day readmission. Patients were categorised into delirium and non-delirium groups based on documented 4AT screening results and clinical notes. Results: Of 200 patients included, 100 had delirium and 100 did not. The delirium group had a significantly longer LOS (26.3 vs 10.7 days, p=0.007) and higher inpatient mortality (18% vs 2%, p=0.002). Thirty-day mortality (23.0% vs 7.0%, p=0.0015) and 90-day mortality (35.0% vs 11.0%, p<0.0001) were also significantly higher in the delirium group. No significant difference was observed in 30-day readmissions (15.0% vs 20.0%, p=NS). Sub-analysis showed 32% patients were living with companion. It was observed those living with a companion had a lower rate of delirium (23%) as compared to those living alone (41%, p<0.0015). Conclusion: Delirium was associated with poorer clinical outcomes among older patients acutely admitted to the MAU. The observed association between companionship and lower rate of delirium warrants further investigation in larger, prospective studies.

Background: Nipah virus is a pathogenic virus of ruinous zoonotic potential with inflated rate of mortality in humans. Methods: Considering the emerging threat of this pandemic virus, the present investigation amid to design vaccine by using the bioinformatics tools such as host and virus codon usage analysis, CD8+ peptide prediction, immunogenicity/allergenicity/toxicity, MHC-I allele binding prediction and subsequent population coverage and MHC-I-peptide docking analysis. Results: In this study (conducted in 2022 at School of Biotechnology, Katra, India), a set of 11 peptides of the structural proteins of Nipah Virus were predicted and recognized by the set of MHC-I alleles that are expressed in 92% of the global human population. Conclusion: The strong interactions between these peptides and the MHC-I protein suggest them as strong peptide candidates for the development of vaccine against Nipah Virus.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a positive single-stranded RNA virus that causes a highly contagious Corona Virus Disease (COVID19). Entry of SARS-CoV-2 in human cells depends on binding of the viral spike (S) proteins to cellular receptor Angiotensin-converting enzyme 2 (ACE2) and on S-protein priming by host cell serine protease TMPRSS2. Recently, COVID19 has been declared pandemic by World Health Organization (WHO) yet high differences in disease outcomes across countries have been seen. We provide evidences to explain these population-level differences. One of the key factors of entry of the virus in host cells presumably is because of differential interaction of viral proteins with host cell proteins due to different genetic backgrounds. Based on our findings, we conclude that a higher expression of ACE2 is facilitated by natural variations, acting as Expression quantitative trait loci (eQTLs), with different frequencies in different populations. We suggest that high expression of ACE2 results in homo-dimerization, proving disadvantageous for TMPRSS2 mediated cleavage of ACE2; whereas, the monomeric ACE2 has higher preferential binding with SARS-CoV-2 S-Protein vis-a-vis its dimerized counterpart. Further, eQTLs in TMPRSS2 and natural structural variations in the gene may also result in differential outcomes towards priming of viral S-protein, a critical step for entry of the Virus in host cells. In addition, we suggest that several key host genes, like SLC6A19, ADAM17, RPS6, HNRNPA1, SUMO1, NACA, BTF3 and some other proteases as Cathepsins, might have a critical role. To conclude, understanding population specific differences in these genes may help in developing appropriate management strategies for COVID19 with better therapeutic interventions.

Screening of 20,000 clones of a fosmid gene bank, constructed from DNA extracted from North West Himalaya (NWH) glacier soil sample, using functional approach identified 10 esterase/lipase-producing clones. Of these, a clone designated pFG43 with an insert size of 45 kb which produced the highest concentration of enzyme (467.43 U/mg) was sequenced. Clone pFG43 contained 61 open reading frames (ORF) and of these an ORF of 1155 bp designated ME-003, was found to be closely related to a hydrolase from Acidobacteria sps (77% sequence identity and E value = 1e-164) and subsequently identified as a putative cocaine esterase. ORF ME-003 was amplified and sub-cloned using a TA vector system into E. coli (DH5α). The purified recombinant enzyme with a molecular weight of 43 kDa had optimal activity at 40 °C, pH 6 and the highest activity with shorter chain fatty acids than with higher chain length fatty acids. There is insignificant effect of inhibitors on the enzyme activity of ME-003, except PMSF which completely inhibited its activity. ME-003 activity was also inhibited in the presence of copper oxide but remained stable in presence of other metal ions. The enzyme activity was also inhibited in the presence of organic solvents; however, in the presence of 10% isopropanol, 12% of enzymatic activity was retained. Among various detergents, SDS completely inhibited enzymatic activity. The recombinant enzyme also shows enantio-specific activity against the racemic drug intermediates/precursors and exhibited 90% ee against racemic 1-phenyl ethanol and fluoxetine.

The prevailing multi-drug resistance in Mycobacterium tuberculosis continues to remain one of the main challenges to combat tuberculosis. Hence, it becomes imperative to focus on novel drug targets. Filamenting temperature-sensitive mutant Z (FtsZ) is an essential cell division protein, a eukaryotic tubulin homologue and a promising drug target. During cytokinesis, FtsZ polymerises in the presence of GTP to form Z-ring and recruits other proteins at this site that eventually lead to the formation of daughter cells. Benzimidazoles were experimentally shown to inhibit Mtb-FtsZ, with one of the benzimidazole derivatives, M1, being reported to have the minimum inhibitory concentration (MIC) value of 3.13µg/ml. In the present study, mechanism of destabilization of FtsZ in the presence of M1 was computationally investigated in the presence of its substrate GTP/GDP employing Molecular dynamics (MD) simulation analysis, principal component analysis (PCA), molecular mechanics combined with the generalized Born and surface area continuum salvation (MM-GBSA), and density functional theory (DFT). From the analyses it is proposed that binding of M1 in the inter-domain cleft induces structural changes in the GTP binding region that affect GTP binding, thus switching the preference of this protein towards depolymerised state and eventually inhibiting the cell division. Hence, this study provides mechanistic insights into the design of novel benzimidazole inhibitors against Mtb-FtsZ.