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Inflammasomes can prevent systemic dissemination of enteropathogenic bacteria. As adapted pathogens including Salmonella Typhimurium (S. Tm) have evolved evasion strategies, it has remained unclear when and where inflammasomes restrict their dissemination. Bacterial population dynamics establish that the NAIP/NLRC4 inflammasome specifically restricts S. Tm migration from the gut to draining lymph nodes. This is solely attributable to NAIP/NLRC4 within intestinal epithelial cells (IECs), while S. Tm evades restriction by phagocyte NAIP/NLRC4. NLRP3 and Caspase-11 also fail to restrict S. Tm mucosa traversal, migration to lymph nodes, and systemic pathogen growth. The ability of IECs (not phagocytes) to mount a NAIP/NLRC4 defense in vivo is explained by particularly high NAIP/NLRC4 expression in IECs and the necessity for epithelium-invading S. Tm to express the NAIP1-6 ligands-flagella and type-III-secretion-system-1. Imaging reveals both ligands to be promptly downregulated following IEC-traversal. These results highlight the importance of intestinal epithelial NAIP/NLRC4 in blocking bacterial dissemination in vivo, and explain why this constitutes a uniquely evasion-proof defense against the adapted enteropathogen S. Tm.

One‐dimensional (1D) cardiovascular models offer a non‐invasive method to answer medical questions, including predictions of wave‐reflection, shear stress, functional flow reserve, vascular resistance and compliance. This model type can predict patient‐specific outcomes by solving 1D fluid dynamics equations in geometric networks extracted from medical images. However, the inherent uncertainty in in vivo imaging introduces variability in network size and vessel dimensions, affecting haemodynamic predictions. Understanding the influence of variation in image‐derived properties is essential to assess the fidelity of model predictions. Numerous programs exist to render three‐dimensional surfaces and construct vessel centrelines. Still, there is no exact way to generate vascular trees from the centrelines while accounting for uncertainty in data. This study introduces an innovative framework employing statistical change point analysis to generate labelled trees that encode vessel dimensions and their associated uncertainty from medical images. To test this framework, we explore the impact of uncertainty in 1D haemodynamic predictions in a systemic and pulmonary arterial network. Simulations explore haemodynamic variations resulting from changes in vessel dimensions and segmentation; the latter is achieved by analysing multiple segmentations of the same images. Results demonstrate the importance of accurately defining vessel radii and lengths when generating high‐fidelity patient‐specific haemodynamics models. Key points: This study introduces novel algorithms for generating labelled directed trees from medical images, focusing on accurate junction node placement and radius extraction using change points to provide haemodynamic predictions with uncertainty within expected measurement error.Geometric features, such as vessel dimension (length and radius) and network size, significantly impact pressure and flow predictions in both pulmonary and aortic arterial networks.Standardizing networks to a consistent number of vessels is crucial for meaningful comparisons and decreases haemodynamic uncertainty.Change points are valuable to understanding structural transitions in vascular data, providing an automated and efficient way to detect shifts in vessel characteristics and ensure reliable extraction of representative vessel radii. [ABSTRACT FROM AUTHOR]

Background There are established risk factors for liver fibrosis (LF), but data on the impact of methotrexate on LF in patients with psoriasis are lacking. Objectives This cross-sectional study aimed to determine the prevalence of LF in patients with psoriasis and to evaluate the relationship between LF, cumulative methotrexate dose and other LF risk factors. Methods Adults with a history of moderate-to-severe chronic plaque psoriasis were recruited between June 2020 and March 2021. Patients underwent transient elastography to evaluate LF. Three values for liver stiffness measurement (LSM) were assessed, indicating mild or worse LF (≥ 7 kPa), moderate or worse LF (≥ 7.9 kPa) and advanced LF (≥ 9.5kPa). Cumulative methotrexate dose and other potential risk factors for LF were assessed. Results Overall, 240 patients were recruited and 204 participants with valid LSM values were included in the analysis [median age 48 years [interquartile range (IQR) 37–57]; 51% female sex; 56% body mass index (BMI) ≥ 30 (kg m−2) and a median Alcohol Use Disorders Identification Test (AUDIT) score of 4 (IQR 1–7, 23% score ≥ 8)]. In total, 91% had received methotrexate [median duration 36 months (IQR 14–78)]. Prevalence of LF was 36%, 25% and 17% using LSM ≥ 7 kPa, ≥ 7.9 kPa and ≥ 9.5 kPa, respectively. There was no association between cumulative methotrexate dose [median 2.16 (IQR 0.93–5.2)] and continuous LSM values [unstandardized coefficient 0.16, 95% confidence interval (CI) −0.49 to 0.82, P = 0.626] or using the categorical LSM cutoff values: ≥ 7 kPa [unadjusted odds ratio 1.06 (95% CI 0.97–1.15), P = 0.192], ≥ 7.9 kPa [unadjusted odds ratio 1.03 (95% CI 0.94–1.12), P = 0.577] and ≥ 9.5 kPa (unadjusted odds ratio 1.01, 95% CI 0.91–1.12; P = 0.843). The following risk factors were associated with higher LSM values: BMI (P ≤ 0.001), waist circumference (P ≤ 0.001), metabolic syndrome (P ≤ 0.001), AUDIT score (P = 0.020) and FIB-4 score (P = 0.03). BMI ≥ 28, diabetes and metabolic syndrome were shown to be better predictors of LF compared with FIB-4 score. Conclusions This study confirms a high prevalence of significant LF in patients with psoriasis. Cumulative methotrexate dose was not associated with LF. Patients with BMI ≥ 28, metabolic syndrome and diabetes are at higher risk for LF. These risk factors may help to identify when a more detailed liver health assessment is needed. [ABSTRACT FROM AUTHOR]

A recent study published in the journal Science has found that a gut bacterium called To-masiella immunophila can cause low levels of immunoglobulin A (IgA) in the intestines of mice. The bacterium releases vesicles with immunoglobulin protease activity that degrade IgA, which is an important component of the immune system. This manipulation of host immunity by a gut commensal highlights the need to study the functions of gut microbes in association with their hosts. The study also raises questions about the presence of similar immunoglobulin-degrading bacteria in human gut microbiomes and their potential impact on human health. [Extracted from the article]

The emergence of antibiotic-resistant bacteria through mutations or the acquisition of genetic material such as resistance plasmids represents a major public health issue.sup.1,2. Persisters are subpopulations of bacteria that survive antibiotics by reversibly adapting their physiology.sup.3-10, and can promote the emergence of antibiotic-resistant mutants.sup.11. We investigated whether persisters can also promote the spread of resistance plasmids. In contrast to mutations, the transfer of resistance plasmids requires the co-occurrence of both a donor and a recipient bacterial strain. For our experiments, we chose the facultative intracellular entero-pathogen Salmonella enterica serovar Typhimurium (S. Typhimurium) and Escherichia coli, a common member of the microbiota.sup.12. S. Typhimurium forms persisters that survive antibiotic therapy in several host tissues. Here we show that tissue-associated S. Typhimurium persisters represent long-lived reservoirs of plasmid donors or recipients. The formation of reservoirs of S. Typhimurium persisters requires Salmonella pathogenicity island (SPI)-1 and/or SPI-2 in gut-associated tissues, or SPI-2 at systemic sites. The re-seeding of these persister bacteria into the gut lumen enables the co-occurrence of donors with gut-resident recipients, and thereby favours plasmid transfer between various strains of Enterobacteriaceae. We observe up to 99% transconjugants within two to three days of re-seeding. Mathematical modelling shows that rare re-seeding events may suffice for a high frequency of conjugation. Vaccination reduces the formation of reservoirs of persisters after oral infection with S. Typhimurium, as well as subsequent plasmid transfer. We conclude that--even without selection for plasmid-encoded resistance genes--small reservoirs of pathogen persisters can foster the spread of promiscuous resistance plasmids in the gut. The re-seeding of antibiotic-resistant persister subpopulations of Salmonella enterica into the gut lumen favours the transfer of resistance plasmids to gut-resident enterobacteria, showing that even small reservoirs of persister bacteria facilitate the spread of antibiotic resistance., Author(s): Erik Bakkeren [sup.1] , Jana S. Huisman [sup.2] [sup.3] , Stefan A. Fattinger [sup.1] [sup.4] , Annika Hausmann [sup.1] , Markus Furter [sup.1] , Adrian Egli [sup.5] [sup.6] , [...]

Live attenuated vaccines are of great value for preventing infectious diseases. They represent a delicate compromise between sufficient colonization-mediated adaptive immunity and minimizing the risk for infection by the vaccine strain itself. Immune defects can predispose to vaccine strain infections. It has remained unclear whether vaccine safety could be improved via mutations attenuating a vaccine in immune-deficient individuals without compromising the vaccine's performance in the normal host. We have addressed this hypothesis using a mouse model for Salmonella diarrhea and a live attenuated Salmonella Typhimurium strain (ssaV). Vaccination with this strain elicited protective immunity in wild type mice, but a fatal systemic infection in immune-deficient cybb(-/-)nos2(-/-) animals lacking NADPH oxidase and inducible NO synthase. In cybb(-/-)nos2(-/-) mice, we analyzed the attenuation of 35 ssaV strains carrying one additional mutation each. One strain, Z234 (ssaV SL1344_3093), was >1000-fold attenuated in cybb(-/-)nos2(-/-) mice and ≈100 fold attenuated in tnfr1(-/-) animals. However, in wt mice, Z234 was as efficient as ssaV with respect to host colonization and the elicitation of a protective, O-antigen specific mucosal secretory IgA (sIgA) response. These data suggest that it is possible to engineer live attenuated vaccines which are specifically attenuated in immuno-compromised hosts. This might help to improve vaccine safety.

Purpose: Hearing loss is most prevalent among older adults, yet underestimated by patients, clinicians, and research communities. This study aimed to assess the accuracy of self-reported hearing difficulties among a group of adults aged 61--63 years, against audiometric measures. Method: The analysis used a sample (N = 346) of the Newcastle Thousand Families Study birth cohort. Data from audiological examinations and selfreported hearing difficulties were used to compare subjective and objective hearing. Hearing aid use was also assessed. Results: Over 40% of the participants had some level of hearing loss (n = 155, 44.8%), and 31% (n = 133) of these reported having hearing problems during subjective assessment. Only 18 (10%) of those with objectively measured hearing loss reported using hearing aids. Conclusions: There was an inconsistency between measured and selfperceived hearing loss among adults aged 61--63 years in this cohort. The small number of hearing aid users in the cohort is a concern, in that people in this age group appear not to be getting the help they need. The data also add to the research evidence that people at this age underestimate their hearing loss. [ABSTRACT FROM AUTHOR]