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Time of day of vaccination does not influence antibody responses to pneumococcal and annual influenza vaccination in a cohort of healthy older adults.
No full textVaccines are less immunogenic in older adults, partly due to immunosenescence. Having previously shown that morning influenza vaccination may be more immunogenic in older adults (mean age 71), we assessed if this could be replicated in a younger cohort (mean age 57) and with a T-cell independent vaccine. This study examined whether diurnal timing of a single dose of Pneumovax® (PPV-23) and seasonal influenza vaccine influenced antibody responses in 140 healthy adults over the age of 50. Pneumococcal serotype-specific (PnPS) antibodies and Haemagglutination Inhibition Assays (HAI) were used to characterize antibody responses at Baseline, 1, 4, and 52 weeks post-vaccination. Protective thresholds were set at 0.35 μg/mL for two-thirds of PnPS tested (WHO≥8/12PnPS) and a titre of ≥40 HAI for H1N1, H3N2, and B/Victoria strains. Both AM and PM cohorts showed increased Pn-specific antibodies to one PPV-23 dose at weeks 1, 4, and 52; however, time of day did not significantly influence antibody responses. Baseline immunity for pneumococcus was high (57.1 % AM, 50.0 % PM had WHO≥8/12PnPS), and immunity was maintained with at least 7/12 serotypes elevated at 52 weeks. Time of day did not alter short- or long-term influenza antibody responses. H1N1 had the highest baseline immunity (67.6 % AM, 48.6 % PM had ≥40 HAI) and the most increased responses at week 4 post-vaccination (92.8 % AM, 94.1 % PM) that were maintained at 52 weeks post-vaccination (91.7 % AM, 89.3 % PM). The poorest serotype immunity was for the B/Victoria strain at all time points. Although time of day did not influence vaccine immunogenicity in AM and PM cohorts, sustained cohort-wide antibody responses were demonstrated in an older population. Identifying 18 % of the total cohort exhibited suboptimal responses to pneumococcal or influenza vaccines underscores the imperative for enhancing vaccine efficacy within this age group to reduce morbidity and mortality.</p
Evolving our understanding of cancer: an interview with Charles Swanton.
No full textNo description supplie
Expanding the clinical spectrum of CRB1-retinopathies: A novel genotype-phenotype correlation with macular dystrophy and elevated intraocular pressure.
No full textBiallelic pathogenic variants in the CRB1 gene are associated with severe retinal dystrophies, including early onset severe retinal dystrophy/Leber congenital amaurosis (EOSRD/LCA), retinitis pigmentosa (RP), cone-rod dystrophy (CORD), and macular dystrophy (MD). Despite growing research, scant genotype-phenotype correlations have been established. Here, we present two cases involving individuals that presented with cystoid macular oedema and high intraocular pressure, which were later diagnosed as CRB1-MD, demonstrating a mild and stable phenotype. Two unrelated patients of African heritage were included, a 7-year-old female (case 1) and a 25-year-old female (case 2), both presenting with ocular hypertension and cystoid macular oedema. Case 2 had a history of bilateral plateau iris, treated with laser iridotomy. Baseline visual acuity for case 1 was 0.66 logMAR in the right eye and 0.54 logMAR in the left eye. For case 2, visual acuity was recorded as 0.30 logMAR in both eyes. Genetic testing confirmed a homozygous c.2506C>A p.(Pro836Thr) variant in the CRB1 gene in both cases. Longitudinal follow-up over seven years revealed stable visual acuity, improvement of cystoid macular oedema, and effective intraocular pressure control with topical ocular hypotensive therapy. This study establishes a novel genotype-phenotype correlation between the c.2506C>A p.(Pro836Thr) variant and MD, suggesting a mild, stable disease course in homozygous cases. The findings also highlight a potential association of this variant with elevated IOP, expanding the clinical spectrum of CRB1-related ocular conditions. Early genetic diagnosis and regular ophthalmic monitoring are essential to optimise management and identify therapeutic opportunities in patients with mild CRB1-related phenotypes
Tracking nongenetic evolution from primary to metastatic ccRCC: TRACERx Renal.
No full textWhile the key aspects of genetic evolution and their clinical implications in clear cell renal-cell carcinoma (ccRCC) are well-documented, how genetic features co-evolve with the phenotype and tumor microenvironment (TME) remains elusive. Here, through joint genomic-transcriptomic analysis of 243 samples from 79 patients recruited to the TRACERx Renal study, we identify pervasive non-genetic intratumor heterogeneity, with over 40% not attributable to genetic alterations. By integrating tumor transcriptomes and phylogenetic structures, we observe convergent evolution to specific phenotypic traits, including cell proliferation, metabolic reprogramming and overexpression of putative cGAS-STING repressors amid high aneuploidy. We also uncover a co-evolution between the tumor and the T cell repertoire, as well as a longitudinal shift in the TME from an anti-tumor to an immunosuppressive state, linked to the acquisition of recurrently late ccRCC drivers 9p loss and SETD2 mutations. Our study reveals clinically-relevant and hitherto underappreciated non-genetic evolution patterns in ccRCC
Unravelling the transcriptome of the human tuberculosis lesion and its clinical implications.
No full textThe tuberculosis (TB) lesion is a complex structure, contributing to the overall spectrum of TB. We characterise, using RNA sequencing, 44 fresh human pulmonary TB lesion samples from 13 TB individuals (drug-sensitive and multidrug-resistant TB) undergoing therapeutic surgery. We confirm clear separation between the TB lesion and adjacent non-lesional tissue, with the lesion samples consistently displaying increased inflammatory profile despite heterogeneity. Using weighted correlation network analysis, we identify 17 transcriptional modules associated with TB lesion and demonstrate a gradient of immune-related transcript abundance according to spatial organization of the lesion. Furthermore, we associate the modular transcriptional signature of the TB lesion with clinical surrogates of treatment efficacy and TB severity. We show that patients with worse disease present an overabundance of immune/inflammation-related modules and downregulated tissue repair and metabolism modules. Our findings provide evidence of a relationship between clinical parameters, treatment response and immune signatures at the infection site
In situ structure of a bacterial flagellar motor at subnanometre resolution reveals adaptations for increased torque.
No full textThe bacterial flagellar motor, which spins a helical propeller for propulsion, has undergone evolutionary diversification across bacterial species, often involving the addition of structures associated with increasing torque for motility in viscous environments. Understanding how such structures function and have evolved is hampered by challenges in visualizing motors in situ. Here we developed a Campylobacter jejuni minicell system for in situ cryogenic electron microscopy imaging and single-particle analysis of its motor, one of the most complex flagellar motors known, to subnanometre resolution. Focusing on the large periplasmic structures which are essential for increasing torque, our structural data, interpreted with molecular models, show that the basal disk comprises concentric rings of FlgP. The medial disk is a lattice of PflC with PflD, while the proximal disk is a rim of PflB attached to spokes of PflA. PflAB dimerization is essential for proximal disk assembly, recruiting FliL to scaffold more stator complexes at a wider radius which increases torque. We also acquired insights into universal principles of flagellar torque generation. This in situ approach is broadly applicable to other membrane-residing bacterial molecular machines
NeuralProg_DiffCom12March
No full textDifferentiations from 12th March. Constant Sonic Hedgehog Agonist at different concentrations. </p
Diagnostic accuracy of chest X-ray computer-aided detection software for detection of prevalent and incident tuberculosis in household contacts.
No full textBACKGROUND: World Health Organization (WHO) tuberculosis (TB) screening guidelines recommend computer-aided detection (CAD) software for chest radiograph (CXR) interpretation. However, studies evaluating their diagnostic and prognostic accuracy are limited. METHODS: We conducted a prospective cohort study of household contacts of rifampicin-resistant TB in South Africa. Participants underwent baseline CXR and sputum investigation (routine [single spontaneous] and enhanced [additionally 2-3 induced]) for prevalent TB and follow-up for incident TB. Three CXR-CAD software products (CAD4TBv7.0, qXRv3.0.0, and Lunit INSIGHT v3.1.4.111) were compared. We evaluated their performance to detect routine and enhanced prevalent and incident TB, comparing performance with blood tests (Xpert MTB host-response, erythrocyte sedimentation rate, C-reactive protein, QuantiFERON) in a subgroup. RESULTS: 483 participants were followed up for 4.6 years (median). There were 23 prevalent (7 routinely diagnosed) and 38 incident TB cases. The AUC ROCs (95% CIs) to identify prevalent TB for CAD4TBv7.0, qXRv3.0.0, and Lunit INSIGHT v3.1.4.111 were .87 (.77-.96), .88 (.79-.97), and .91 (.83-.99), respectively. More than 30% with scores above recommended CAD thresholds who were bacteriologically negative on routine baseline sputum were subsequently diagnosed by enhanced sputum investigation or during follow-up. The AUC performance of baseline CAD to identify incident cases ranged between .60 and .65. Diagnostic performance of CAD for prevalent TB was superior to blood testing. CONCLUSIONS: Our findings suggest that the potential of CAD-CXR screening for TB is not maximized as a high proportion of those above current thresholds, but with a negative routine confirmatory sputum, have true TB disease that may benefit intervention
Matrix mechano-sensing at the invasive front induces a cytoskeletal and transcriptional memory supporting metastasis.
No full textThe extracellular matrix (ECM) controls tumour dissemination. We characterise ECM organization in human and mouse tumours, identifying three regions: tumour body, proximal invasive front and distal invasive front. Invasive areas show increased matrix density, fibre thickness, length, and alignment, with unique radial fibre orientation at the distal invasive front correlating with amoeboid invasive features. Using patient samples and murine models, we find that metastases recapitulate ECM features of the primary tumour. Ex vivo culture of murine cancer cells isolated from the different tumour regions reveals a spatial cytoskeletal and transcriptional memory. Several in vitro models recapitulate the in vivo ECM organisation showing that increased matrix induces 3D confinement supporting Rho-ROCK-Myosin II activity, while radial orientation enhances directional invasion. Spatial transcriptomics identifies a mechano-inflammatory program associated with worse prognosis across multiple tumour types. These findings provide mechanistic insights into how ECM organization shapes local invasion and distant metastasis.</p
The association of class II HLA alleles with tuberculosis-associated immune reconstitution inflammatory syndrome.
No full textGenetic associations within the human leukocyte antigen (HLA) gene complex and linked genes in TB-IRIS outcomes remains population specific and not well understood. Here, we conducted a study including well characterised HIV-TB coinfected patients with (n = 86) and without (n = 124) TB-IRIS from the randomized, double-blind, prophylactic prednisone trial (PredART study) with HLA, ERAP and KIR genotyping data. We confirmed the association of TB-IRIS with lower CD4 counts pre-ART initiation. We identified nine classical class I and II HLA alleles protective against TB-IRIS, while four alleles were linked to increased risk. Associations ranged from strongly protective (HLA-DQB1*05:01, OR: 0.07, 95%CI: 0.02-0.28, Pc < 0.001) to strongly risk associated (notably DRB1*01:02, OR: 5.92, 95%CI: 1.36-26.7, Pc = 0.028), with conflicting signals at the HLA-DRB1 locus. Conditional regression analysis revealed that residue E71 at the polymorphic position 71 within the HLA-DRB1 peptide-binding groove was critical, and grouping of HLA-DRB1 alleles by the residue at position 71 corresponded with differential TB-IRIS association. In conclusion, this study identifies population-specific genetic factors influencing TB-IRIS susceptibility and highlights a potential mechanistic role for specific HLA-DRB1 residues in modulating immune responses during ART