Typhoid toxin exhausts the RPA response to DNA replication stress driving senescence and Salmonella infection

Salmonella Typhi activates the host DNA damage response through the typhoid toxin, facilitating typhoid symptoms and chronic infections. Here we reveal a non-canonical DNA damage response, which we call RING (response induced by a genotoxin), characterized by accumulation of phosphorylated histone H2AX (γH2AX) at the nuclear periphery. RING is the result of persistent DNA damage mediated by toxin nuclease activity and is characterized by hyperphosphorylation of RPA, a sensor of single-stranded DNA (ssDNA) and DNA replication stress. The toxin overloads the RPA pathway with ssDNA substrate, causing RPA exhaustion and senescence. Senescence is also induced by canonical γΗ2ΑΧ foci revealing distinct mechanisms. Senescence is transmitted to non-intoxicated bystander cells by an unidentified senescence-associated secreted factor that enhances Salmonella infections. Thus, our work uncovers a mechanism by which genotoxic Salmonella exhausts the RPA response by inducing ssDNA formation, driving host cell senescence and facilitating infection

Editorial Statement About JCCAP’s 2023 Special Issue on Informant Discrepancies in Youth Mental Health Assessments: Observations, Guidelines, and Future Directions Grounded in 60 Years of Research

Issue 1 of the 2011 Volume of the Journal of Clinical Child and Adolescent Psychology (JCCAP) included a Special Section about the use of multi-informant approaches to measure child and adolescent (i.e., hereafter referred to collectively as “youth”) mental health (De Los Reyes, 2011). Researchers collect reports from multiple informants or sources (e.g., parent and peer, youth and teacher) to estimate a given youth’s mental health. The 2011 JCCAP Special Section focused on the most common outcome of these approaches, namely the significant discrepancies that arise when comparing estimates from any two informant’s reports (i.e., informant discrepancies). These discrepancies appear in assessments conducted across the lifespan (Achenbach, 2020). That said, JCCAP dedicated space to understanding informant discrepancies, because they have been a focus of scholarship in youth mental health for over 60 years (e.g., Achenbach et al., 1987; De Los Reyes & Kazdin, 2005; Glennon & Weisz, 1978; Kazdin et al., 1983; Kraemer et al., 2003; Lapouse & Monk, 1958; Quay et al., 1966; Richters, 1992; Rutter et al., 1970; van der Ende et al., 2012). Thus, we have a thorough understanding of the areas of research for which they reliably appear when clinically assessing youth. For instance, intervention researchers observe informant discrepancies in estimates of intervention effects within randomized controlled trials (e.g., Casey & Berman, 1985; Weisz et al., 2017). Service providers observe informant discrepancies when working with individual clients, most notably when making decisions about treatment planning (e.g., Hawley & Weisz, 2003; Hoffman & Chu, 2015). Scholars in developmental psychopathology observe these discrepancies when seeking to understand risk and protective factors linked to youth mental health concerns (e.g., Hawker & Boulton, 2000; Hou et al., 2020; Ivanova et al., 2022). Thus, the 2011 JCCAP Special Section posed a question: Might these informant discrepancies contain data relevant to understanding youth mental health? Suppose none of the work in youth mental health is immune from these discrepancies. In that case, the answer to this question strikes at the core of what we produce―from the interventions we develop and implement, to the developmental psychopathology research that informs intervention development

Socioeconomic deprivation is associated with reduced response and lower treatment persistence with TNF inhibitors in rheumatoid arthritis

Objective To investigate the association between socioeconomic deprivation and outcomes following TNF inhibitor (TNFi) treatment. Methods Individuals commencing their first TNFi in the British Society for Rheumatology Biologics Register for RA (BSRBR-RA) and Biologics in RA Genetics and Genomics Study Syndicate (BRAGGSS) cohort were included. Socioeconomic deprivation was proxied using the Index of Multiple Deprivation and categorized as 20% most deprived, middle 40% or 40% least deprived. DAS28-derived outcomes at 6 months (BSRBR-RA) and 3 months (BRAGGSS) were compared using regression models with the least deprived as referent. Risks of all-cause and cause-specific drug discontinuation were compared using Cox models in the BSRBR-RA. Additional analyses adjusted for lifestyle factors (e.g. smoking, BMI) as potential mediators. Results 16 085 individuals in the BSRBR-RA were included (mean age 56 years, 76% female), of whom 18%, 41% and 41% were in the most, middle and least deprived groups, respectively. Of 3459 included in BRAGGSS (mean age 57, 77% female), proportions were 22%, 36% and 41%, respectively. The most deprived group had 0.3-unit higher 6-month DAS28 (95% CI 0.22, 0.37) and were less likely to achieve low disease activity (odds ratio [OR] 0.76; 95% CI 0.68, 0.84) in unadjusted models. Results were similar for 3-month DAS28 (β = 0.23; 95% CI 0.11, 0.36) and low disease activity (OR 0.77; 95% CI 0.63, 0.94). The most deprived were more likely to discontinue treatment (hazard ratio 1.18; 95% CI 1.12, 1.25), driven by ineffectiveness rather than adverse events. Adjusted estimates were generally attenuated. Conclusion Socioeconomic deprivation is associated with reduced response to TNFi. Improvements in determinants of health other than lifestyle factors are needed to address socioeconomic inequities

Spatial and temporal attention deficits following brain injury : a neuroanatomical decomposition of the temporal order judgement task

We investigated spatial and temporal deficits following brain injury using the temporal order judgement (TOJ) task. Patients judged the order in which two letters appeared to the left and right of fixation. We measured the extent of any spatial bias and the temporal resolution of the decision. Temporal and spatial deficits on the TOJ task were significantly correlated. The spatial bias on the TOJ task was also correlated with the spatial bias on a neglect task and with unilateral deficits on an extinction task, but not with extinction itself. These spatial deficits were all associated with damage to contralateral temporoparietal cortex. In contrast, the temporal resolution of TOJs was linked specifically to deficits in processing multiple stimuli on the neglect and extinction tasks and to damage to the right parietal lobe and the cerebellum. These data suggest that spatial and temporal deficits on the TOJ task reflect different underlying processes

Anti-Carbamylated Antibody Positivity Is Associated With More Severe Radiological Progression In Patients With Recent Onset ACPA Negative Rheumatoid Arthritis: Results From The Norfolk Arthritis Register (NOAR)

Pathophysiology and treatment of rheumatic disease