Multi-Donor longitudinal antibody repertoire sequencing reveals the existence of public antibody clonotypes in HIV-1 infection

Characterization of single antibody lineages within infected individuals has provided insights into the development of Env-specific antibodies. However, a systems-level understanding of the humoral response against HIV-1 is limited. Here, we interrogated the antibody repertoires of multiple HIV-infected donors from an infection-naive state through acute and chronic infection using next-generation sequencing. This analysis revealed the existence of “public” antibody clonotypes that were shared among multiple HIV-infected individuals. The HIV-1 reactivity for representative antibodies from an identified public clonotype shared by three donors was confirmed. Furthermore, a meta-analysis of publicly available antibody repertoire sequencing datasets revealed antibodies with high sequence identity to known HIV-reactive antibodies, even in repertoires that were reported to be HIV naive. The discovery of public antibody clonotypes in HIV-infected individuals represents an avenue of significant potential for better understanding antibody responses to HIV-1 infection, as well as for clonotype-specific vaccine development

Effects of site dilution on the magnetic properties of geometrically frustrated antiferromagnets

The effect of site dilution by non magnetic impurities on the susceptibility of geometrically frustrated antiferromagnets (kagome and pyrochlore lattices) is discussed in the framework of the Generalized Constant Coupling model, for both classical and quantum Heisenberg spins. For the classical diluted pyrochlore lattice, excellent agreement is found when compared with Monte Carlo data. Results for the quantum case are also presented and discussed.Comment: 5 pages, 3 figure

Disease-specific, neurosphere-derived cells as models for brain disorders

There is a pressing need for patient-derived cell models of brain diseases that are relevant and robust enough to produce the large quantities of cells required for molecular and functional analyses. We describe here a new cell model based on patient-derived cells from the human olfactory mucosa, the organ of smell, which regenerates throughout life from neural stem cells. Olfactory mucosa biopsies were obtained from healthy controls and patients with either schizophrenia, a neurodevelopmental psychiatric disorder, or Parkinson's disease, a neurodegenerative disease. Biopsies were dissociated and grown as neurospheres in defined medium. Neurosphere-derived cell lines were grown in serum-containing medium as adherent monolayers and stored frozen. By comparing 42 patient and control cell lines we demonstrated significant disease-specific alterations in gene expression, protein expression and cell function, including dysregulated neurodevelopmental pathways in schizophrenia and dysregulated mitochondrial function, oxidative stress and xenobiotic metabolism in Parkinson's disease. The study has identified new candidate genes and cell pathways for future investigation. Fibroblasts from schizophrenia patients did not show these differences. Olfactory neurosphere-derived cells have many advantages over embryonic stem cells and induced pluripotent stem cells as models for brain diseases. They do not require genetic reprogramming and they can be obtained from adults with complex genetic diseases. They will be useful for understanding disease aetiology, for diagnostics and for drug discovery

Cost-benefits and environmental impact of the no-biopsy approach for the diagnosis of coeliac disease in adults

Objective: Recent evidence suggests that adult patients with IgA tissue transglutaminase levels of ≥10× the upper limit of normal could be accurately diagnosed with coeliac disease without undergoing endoscopy and biopsy. We aimed to evaluate the cost-benefits and the environmental impact of implementing the no-biopsy approach for diagnosing coeliac disease in clinical practice. Design: We calculated the overall direct and indirect costs of the conventional serology-biopsy approach and the no-biopsy approach for the diagnosis of coeliac disease based on the national average unit costs and the Office of National Statistics data. We further estimated the environmental impact of avoiding endoscopy based on the estimated greenhouse gas emissions from endoscopy. Results: Approximately 3000 endoscopies for suspected coeliac disease could be avoided each year in the UK. Implementing the no-biopsy approach for the diagnosis of coeliac disease in adults could save the National Health Service over £2.5 million in direct and indirect costs per annum and reduce endoscopy carbon footprint by 87 tonnes of CO2 per year, equivalent to greenhouse gas emissions from driving 222 875 miles, carbon emissions from charging over 10 million smartphones and the carbon sequestrated by 1438 trees grown for 10 years. Conclusion: The implementation of this non-invasive green approach could be an essential first step in the ‘Reduce’ strategy advocated by the British Society of Gastroenterology and other international endoscopy societies for sustainable endoscopy practice

First UK data for CT angiography in persisting upper GI bleeding

Letters to the edito

Sedimentation record in the Konkan-Kerala Basin: implications for the evolution of the Western Ghats and the Western Indian passive margin

The Konkan and Kerala Basins constitute a major depocentre for sediment from the onshore hinterland of Western India and as such provide a valuable record of the timing and magnitude of Cenozoic denudation along the continental margin. This paper presents an analysis of sedimentation in the Konkan-Kerala Basin, coupledwith a mass balance study, and numerical modelling of flexural responses to onshore denudational unloading and o¡shore sediment loading in order to test competing conceptual models for the development of high-elevation passive margins. The Konkan-Kerala Basin contains an estimated 109,000 km<sup>3</sup>; of Cenozoic clastic sediment, a volume difficult to reconcile with the denudation of a downwarped rift flank onshore, and more consistent with denudation of an elevated rift flank. We infer from modelling of the isostatic response of the lithosphere to sediment loading offshore and denudation onshore that flexure is an important component in the development of the Western Indian Margin.There is evidence for two major pulses in sedimentation: an early phase in the Palaeocene, and a second beginning in the Pliocene. The Palaeocene increase in sedimentation can be interpreted in terms of a denudational response to the rifting between India and the Seychelles, whereas the mechanism responsible for the Pliocene pulse is more enigmatic

Accuracy of the no-biopsy approach for the diagnosis of coeliac disease in adults: a systematic review and meta-analysis

BACKGROUND & AIMS: Current international guidelines recommend duodenal biopsies to confirm the diagnosis of coeliac disease in adult patients. However, growing evidence suggests that IgA anti-tissue transglutaminase (tTg) antibody levels ≥10 times the upper limit of normal (ULN) can accurately predict coeliac disease, eliminating the need for biopsy. We performed a systematic review and meta-analysis to evaluate the accuracy of the no-biopsy approach to confirm the diagnosis of coeliac disease in adults. METHODS: We systematically searched MEDLINE, EMBASE, Cochrane Library and Web of Science from January 1998 to October 2023 for studies reporting the sensitivity and specificity of IgA-tTG ≥10×ULN against duodenal biopsies (Marsh grade ≥2) in adults with suspected coeliac disease. We used a bivariate random-effects model to calculate the summary estimates of sensitivity, specificity, positive and negative likelihood ratios. The positive and negative likelihood ratios were used to calculate the positive predictive value (PPV) of the no-biopsy approach across different pre-test probabilities of coeliac disease. The methodological quality of the included studies was evaluated using the QUADAS-2 tool. This study was registered with PROSPERO, number CRD42023398812. RESULTS: A total of 18 studies comprising 12,103 participants from 15 countries were included. The pooled prevalence of biopsy-proven coeliac disease in the included studies was 62% (95% CI, 40% - 83%). The proportion of patients with IgA-tTG ≥10×ULN was 32% (95% CI, 24% - 40%). The summary sensitivity of IgA-tTG ≥10×ULN was 51% (95% CI, 42% - 60%), and the summary specificity was 100% (95% CI, 98% - 100%). The area under the summary receiver operating characteristic curve was 0.83 (95% CI, 0.77 - 0.89). The PPV of the no-biopsy approach to identify patients with coeliac disease was 65%, 88%, 95%, and 99% if coeliac disease prevalence was 1%, 4%, 10% and 40%, respectively. Between-study heterogeneity was moderate (I2 =30.3%), and additional sensitivity analyses did not significantly alter our findings. Only one study had a low risk of bias across all domains. CONCLUSION: The results of this meta-analysis suggest that selected adult patients with IgA-tTG ≥10×ULN and a moderate to high pre-test probability of coeliac disease could be diagnosed without undergoing invasive endoscopy and duodenal biopsy

Does a gluten-free diet improve quality of life and sleep in patients with non-coeliac gluten/wheat sensitivity?

Introduction: The role of a gluten-free diet (GFD) in Non-Coeliac Gluten/Wheat Sensitivity (NCGWS) is unclear. We present the largest study comparing adherence to a GFD in patients with Coeliac Disease (CD) and NCGWS and assess its impact on quality of life (QoL) and sleep in patients with NCGWS. Methods: Patients with NCGWS at a tertiary centre completed the Coeliac Disease Adherence Test (CDAT), Coeliac Symptom Index (CSI) and Sleep Condition Indicator (SCI). Higher CDAT scores indicate worse adherence, higher CSI scores indicate poorer QoL, and higher SCI scores indicate better sleep. CDAT scores were correlated with CSI and SCI scores. A second group of patients with CD completed the CDAT questionnaire only. Results were compared with the CDAT responses from the NCGWS group. Results: For the NCGWS cohort (n = 125), the median CDAT score was 17/35, indicating poor adherence. The median CSI score was 44/80, with 40% of scores associated with a poor QoL. The median SCI score was 14/32, and DSM-V criteria for insomnia was met by 42% of patients. There was a positive correlation between CSI and CDAT scores (r = 0.59, p < 0.0001) and a negative correlation between SCI and CDAT scores (r = −0.37, p = 0.0002). In the CD cohort (n = 170), the median CDAT score was 13/35. Patients with NCGWS had poorer adherence compared to CD (CDAT: 17.0 vs. 13.0, respectively, p = 0.0001). Conclusion: Patients with NCGWS adhere to a GFD less than those with CD. Poorer adherence to a GFD in patients with NCGWS correlates with a worse QoL and sleep performance

Does reverse mentoring work in the NHS: a feasibility study of clinicians in practice

Objective To assess the risks and benefits of reverse mentoring of consultants by junior doctors. Design A feasibility study divided into two phases: first a semistructured interview where performance of participating consultants was assessed by junior doctors and then a second phase allowing for feedback to be given on a one-to-one basis. Data collected through questionnaires with free text questions and Likert scores. Setting Tertiary teaching hospital in the UK. Participants Six junior doctors (66.6% male, age range 31–40 years) and five consultants (80% male, age range 35–65 years and consultants for 5–20 years). Intervention Reverse mentoring session. Main outcome measure The concerns and/or benefits of the process of reverse mentoring. Confidence was assessed in 7 domains: clinical practice, approach to juniors, approachability, use of technology, time management, strengths and areas for improvement using Likert scales giving a total out of 35. Results The most common concerns cited were overcoming the hierarchical difference and a selection bias in both mentors and mentees. However, no participant experienced this hierarchical difference through the reverse mentoring process and no relationships were negatively affected. Mentors became more confident in feeding back to seniors (23 vs 29 out of 35, p=0.04) most evident in clinical practice and areas to improve (3 vs 4 out of 5, p=0.041 and 3 vs 5 out of 5, p=0.041, respectively). Conclusion We present the first study of reverse mentoring in an NHS clinical setting. Initial concerns with regard to damaged relationships and hierarchical gradients were not experienced and all participants perceived that they benefited from the process. Reverse mentoring can play a role in engaging and training future leaders at junior stages and provide a means for consultants to receive valuable feedback from junior colleagues