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Hepatitis B virus resistance to nucleos(t)ide analogue therapy: WHO consultation on questions, challenges, and a roadmap for the field.
In this Review, we summarise outputs from a multidisciplinary consultation convened by WHO between July 11 and 13, 2023, to discuss hepatitis B virus (HBV) drug resistance (HBVDR). Treatment of chronic HBV infection with highly effective nucleos(t)ide analogue agents, tenofovir and entecavir, is a crucial intervention that supports the global goal of elimination of HBV infection as a public health threat. The risk of HBVDR as a threat to treatment outcomes is currently considered low from a public health perspective; however, drug resistance can influence individual outcomes, particularly among those who are treatment-experienced. We highlight the need to develop appropriate prevention, monitoring, and surveillance approaches for HBVDR, to support investment in the global scale-up of HBV diagnosis and treatment. Recommendations for the HBVDR field will ultimately be incorporated into a WHO integrated Global Action Plan for drug-resistant HIV, viral hepatitis, and priority sexually transmitted infections.
Pleural fluid proteomics from patients with pleural infection shows signatures of diverse neutrophilic responses: The Oxford Pleural Infection Endotyping Study (TORPIDS-2).
BACKGROUND: Pleural infection is a complex disease with poor clinical outcomes and increasing incidence worldwide, yet its biological endotypes remain unknown. METHODS: We analysed 80 pleural fluid samples from the PILOT study, a prospective study on pleural infection, using unlabelled mass spectrometry. A total of 449 proteins were retained after filtering. Unsupervised hierarchical clustering and UMAP analyses were used to cluster samples and pathway analysis was performed to identify the biological processes. Protein signatures as identified by the pathway analysis were compared to microbiology as defined by 16S rRNA next generation sequencing. Spearman and exact Fischer's methods were used for correlation assessment. RESULTS: Higher neutrophil degranulation was correlated with increased glycolysis (OR=281, p<2.2E-16) and pentose phosphate activation (OR=371.45, p<2.2E-16). Samples dominated by Streptococcus pneumoniae exhibited higher neutrophil degranulation (OR=12.08, p=0.005), glycolysis (OR=11.4, p=0.006), and pentose phosphate activity (OR=12.82, p=0.004). On the other hand, samples dominated by anaerobes and Gram-negative bacteria exhibited lower neutrophil degranulation (OR=0.15, p=0.01, glycolysis (OR=0.14, p=0.01), and pentose phosphate activity (OR=0.07, p=0.001). Increased activity of the liver and retinoid X receptors (LXR-RXR) pathway was associated with lower risk of one-year mortality (OR=0.24, p=0.04). CONCLUSIONS: These findings suggest that pleural infection patients exhibit diverse responses of neutrophil mediated immunity, glycolysis, and pentose phosphate activation which are associated with microbiology. Therapeutic targeting of the LXR-RXR pathway with agonists is a possible treatment approach.
Kharon Is Crucial for Trypanosoma cruzi Morphology but Does Not Impair In Vitro Infection
Chagas disease, caused by Trypanosoma cruzi, is a neglected tropical disease with few options for treatment and no available vaccine. Deletion mutants for live attenuated vaccines, particularly deletions of proteins related to the cytoskeleton, have been widely tested in related parasites but candidates have not been tested in T. cruzi. Kharon is one such protein, identified as being associated with the cytoskeleton in Leishmania and essential for amastigote replication. Here we investigated the T. cruzi Kharon ortholog (TcKharon) to test if it has orthologous function and thus potential in generating a live attenuated vaccine. In silico analysis predicted TcKharon to be an intrinsically disordered protein, consistent with its ortholog feature, and GFP fusion protein revealed that TcKharon is associated with the cytoskeleton of epimastigotes. CRISPR-Cas9-mediated gene disruption impaired epimastigote proliferation and cytokinesis, resulting in altered nucleus-to-kinetoplast ratios and pronounced morphological defects, particularly in the posterior cell region. Despite these abnormalities, TcKharon−/− mutants retained the ability to differentiate into metacyclic trypomastigotes and exhibited in vitro infection rates comparable to wild-type parasites. Our data show that TcKharon is crucial for cell morphology. However, in contrast to close related parasites, TcKharon is not essential for in vitro infectivity.
Genetically distinct within-host subpopulations of hepatitis C virus persist after Direct-Acting Antiviral treatment failure
Analysis of viral genetic data has previously revealed distinct within-host population structures in both untreated and interferon-treated chronic hepatitis C virus (HCV) infections. While multiple subpopulations persisted during the infection, each subpopulation was observed only intermittently. However, it was unknown whether similar patterns were also present after Direct-Acting Antiviral (DAA) treatment, where viral populations were often assumed to go through narrow bottlenecks. Here we tested for the maintenance of population structure after DAA treatment failure, and whether there were different evolutionary rates along distinct lineages where they were observed. We analysed whole-genome next-generation sequencing data generated from a randomised study using DAAs (the BOSON study). We focused on samples collected from patients (N=84) who did not achieve sustained virological response (i.e., treatment failure) and had sequenced virus from multiple timepoints. Given the short-read nature of the data, we used a number of methods to identify distinct within-host lineages including tracking concordance in intra-host nucleotide variant (iSNV) frequencies, applying sequenced-based and tree-based clustering algorithms to sliding windows along the genome, and haplotype reconstruction. Distinct viral subpopulations were maintained among a high proportion of individuals post DAA treatment failure. Using maximum likelihood modelling and model comparison, we found an overdispersion of viral evolutionary rates among individuals, and significant differences in evolutionary rates between lineages within individuals. These results suggest the virus is compartmentalised within individuals, with the varying evolutionary rates due to different viral replication rates and/or different selection pressures. We endorse lineage awareness in future analyses of HCV evolution and infections to avoid conflating patterns from distinct lineages, and to recognise the likely existence of unsampled subpopulations.
Animal models of intestinal inflammation: clues to the pathogenesis of inflammatory bowel disease
In the last decade a number of models of chronic intestinal inflammation have been described that resemble aspects of the pathology found in patients with inflammatory bowel disease. Several themes have emerged from these studies that are of relevance to the pathogenesis of inflammatory bowel disease. Firstly, intestinal inflammation is a consequence of an aberrant chronic immune response triggered by enteric bacteria. Both innate and adaptive immune mechanisms can cause colitis and in many models there is evidence of differential activation of T helper 1 (Th1)-type cells. Targeting the Th1 pathway prevents experimental colitis and there is also evidence that this may be useful in Crohn's disease. Secondly, specialized populations of regulatory T cells have been shown to prevent colitis and in some systems cure it, suggesting immune responses in the intestine are subject to dominant T cell-mediated control. Here we focus on new insights into the pathogenesis and regulation of intestinal inflammation as revealed by model systems and how these may be harnessed for the treatment of IBD.
Homing of intestinal immune cells
The homing of immune cells into the intestinal mucosa, the gut-associated lymphoid tissue or the mesenteric lymph nodes involves a complex process of molecular events that is dependent on cell type and cell maturation. Key factors that collectively determine the homing of leukocytes and their interaction with resident endothelial, epithelial, stromal and immune cells are interactions between integrins or selectins with their tissue adhesion molecules as well as chemokine receptors and their ligands. The organization of the small and large intestinal tissue and the mucosa associated lymphoid tissue as well as the presence or absence of inflammatory stimuli influence the homing of intestinal immune cells. The homing pattern of intestinal dendritic cells and CD4+ T cells and its role for the pathogenesis and regulation of inflammatory bowel disease are discussed.
Pilot feasibility study to determine the utility of direct access and quantitative magnetic resonance cholangiopancreatography (MRCP) in the assessment of suspected acute biliary or ductal gallstone presentations.
BackgroundPatients with suspected acute gallstone disease typically undergo abdominal ultrasound. MRCP is often used for patients with abnormal LFTs, potentially making ultrasound unnecessary for this group. Despite high inter-reader variability in MRCP interpretation, new AI technologies may automate and standardize detection and measurement.MethodPatients with suspected acute gallstone disease and abnormal liver function tests were randomized into two diagnostic pathways, direct MRCP and standard care. Admission data, healthcare resource use, and clinical outcomes were recorded. National Health Service national 20/21 tariffs were used to calculate and compare healthcare costs. MRCP scans were subsequently analysed using MRCP + software (Perspectum Ltd).Results27 participants were enrolled over 12 months, 15 to direct MRCP and 11 to standard care. One patient was excluded from analysis. Mean patient time to diagnostic report and mean per patient associated direct medical cost and mean cost to diagnosis for the direct MRCP and standard of care group was 2.53 days, £449.54, and £647 respectively for the direct MRCP group and 4.18 days costing £742.06 and £896 for standard care. MRCP + analysis of 11 scans showed significant differences between the groups in terms of gallbladder volume (80.2mm3 gallstone present versus 30.1mm3 without, p = 0.018 and cystic duct median width (4.6 mm gallstone present versus 2.7 mm without, p = 0.042).ConclusionsDirect MRCP may be a feasible and potentially cost-effective diagnostic strategy for patients with suspected acute gallstone disease and deranged LFTs. Automated measurement of MRCP parameters shows promise in detecting obstruction. Larger trials are warranted to assess this potential.Clinical trial numberThis study is registered with ClinicalTrials.gov (NCT03709030). Registration date: October 17, 2018.