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\"Going boldly forth as a pioneer in the fledgling field of space archaeology, Dr. Alice Gorman (aka Dr. Space Junk) turns the common perception of archaeology as an exploration of the ancient on its head. Her captivating inquiry into the most modern and daring of technologies spanning some 60 years--a mere speck in cosmic terms--takes the reader on a journey which captures the relics of space forays and uncovers the cultural value of detritus all too readily dismissed as junk\"-- Provided by publisher.

Background The enrichment of Gram-negative bacteria of oral origin in the esophageal microbiome has been associated with the development of metaplasia. However, to date, no study has comprehensively assessed the relationships between the esophageal microbiome and the host. Methods Here, we examine the esophageal microenvironment in gastro-esophageal reflux disease and metaplasia using multi-omics strategies targeting the microbiome and host transcriptome, followed by targeted culture, comparative genomics, and host-microbial interaction studies of bacterial signatures of interest. Results Profiling of the host transcriptome from esophageal mucosal biopsies revealed profound changes during metaplasia. Importantly, five biomarkers showed consistent longitudinal changes with disease progression from reflux disease to metaplasia. We showed for the first time that the esophageal microbiome is distinct from the salivary microbiome and the enrichment of Campylobacter species as a consistent signature in disease across two independent cohorts. Shape fitting and matrix correlation identified associations between the microbiome and host transcriptome profiles, with a novel co-exclusion relationship found between Campylobacter and napsin B aspartic peptidase. Targeted culture of Campylobacter species from the same cohort revealed a subset of isolates to have a higher capacity to survive within primary human macrophages. Comparative genomic analyses showed these isolates could be differentiated by specific genomic features, one of which was validated to be associated with intracellular fitness. Screening for these Campylobacter strain-specific signatures in shotgun metagenomics data from another cohort showed an increase in prevalence with disease progression. Comparative transcriptomic analyses of primary esophageal epithelial cells exposed to the Campylobacter isolates revealed expression changes within those infected with strains with high intracellular fitness that could explain the increased likelihood of disease progression. Conclusions We provide a comprehensive assessment of the esophageal microenvironment, identifying bacterial strain-specific signatures with high relevance to progression of metaplasia.

Background: Parents of children with higher weight are blamed and shamed for their children's weight. However, parents' experiences of this form of stigma, termed weight stigma by association, are poorly understood. The objective of this study was to investigate the sources, forms, and impacts of weight stigma by association among mothers of children with overweight or obesity. Methods: In this qualitative study, mothers who reported concern about their children's weight participated in semistructured interviews administered by the research team. A coding scheme was developed and reliably applied to interview transcripts. Mothers' self-reported sociodemographic information, and height and weight were measured. Results: Thirty-four mothers (Mage: 43.4 years; 26.5% non-Hispanic Black or African American, 70.6% with obesity) participated in the study. Mothers reported that family members were a common source of negative comments about their children's weight; these comments were often critical of mothers' parenting and in some cases contributed to negative affect among mothers. Many mothers also reported negative experiences during children's physicians' visits as a result of their children's weight. Almost all mothers expressed guilt and sadness for their perceived role in their children's weight status, expressing regret that they did not parent differently. Conclusions: Mothers of children with overweight and obesity are frequently the target of weight stigma by association and experience negative cognitions and emotions regarding their perceived role in their children's weight. Continued research is needed to elucidate the impacts of stigma by association due to child weight on parents' health, the parent/child relationship, and children's health.

Global society faces the pressing question of how to eliminate reliance on fossil fuels while meeting increasing energy demand. In comparison to solar and wind energy, nuclear power has been largely ignored in urban studies research. However, nuclear energy has recently regained attention through the emergence of Small Modular Reactors (SMRs), and as the stakes of decarbonization become increasingly essential. To evaluate situations in which SMRs bring value to urban energy mixes, this paper focuses on Nuclear Batteries (NBs), a specific class of SMRs, that can fit in standard shipping containers. First, we outline an evaluation framework for the use and application of NBs; second, we present use cases for NBs in real-world situations, from disaster relief to grid reinforcement; and third, we discuss the social challenges around this technology.

Background Rheumatologists increasingly perform ultrasound (US) imaging to aid diagnosis and management decisions. There is a need to determine the role of US in facilitating early diagnosis of inflammatory arthritis. This study describes the impact of US use by rheumatologists on diagnosis and management of inflammatory arthritis in routine UK clinical practice. Methods We conducted a prospective study in four secondary care rheumatology clinics, each with one consultant who routinely used US and one who did not. Consenting patients aged > 18, newly referred with suspected inflammatory arthritis were included. Data were collected both retrospectively from medical records and via a prospectively-completed physician questionnaire on US use. Analyses were stratified by US/non-US groups and by sub-population of rheumatoid arthritis (RA)-diagnosed patients. Results 258 patients were included; 134 US and 124 non-US. 42% (56/134) of US and 47% (58/124) of non-US were diagnosed with RA. Results described for US and non-US cohorts, respectively as follows. The proportion of patients diagnosed at their first clinic visit was 37% vs 19% overall ( p  = 0.004) and 41% vs 19% in RA-diagnosed patients ( p  = 0.01). The median time to diagnosis (months) was 0.85 vs 2.00 (overall, p  = 0.0046) and 0.23 vs 1.38 (RA-diagnosed, p  = 0.0016). Median time (months) to initiation on a DMARD (where initiated) was 0.62 vs 1.41 (overall, p  = 0.0048) and 0.46 vs 1.81 (RA-diagnosed, p  = 0.0007). Conclusion In patients with suspected inflammatory arthritis, routine US use in newly referred patients seems to be associated with significantly earlier diagnosis and DMARD initiation.

Individuals with serum antibodies to citrullinated protein antigens (ACPA), rheumatoid factor, and symptoms, such as inflammatory joint pain, are at high risk of developing rheumatoid arthritis. In the arthritis prevention in the pre-clinical phase of rheumatoid arthritis with abatacept (APIPPRA) trial, we aimed to evaluate the feasibility, efficacy, and acceptability of treating high risk individuals with the T-cell co-stimulation modulator abatacept. The APIPPRA study was a randomised, double-blind, multicentre, parallel, placebo-controlled, phase 2b clinical trial done in 28 hospital-based early arthritis clinics in the UK and three in the Netherlands. Participants (aged ≥18 years) at risk of rheumatoid arthritis positive for ACPA and rheumatoid factor with inflammatory joint pain were recruited. Exclusion criteria included previous episodes of clinical synovitis and previous use of corticosteroids or disease-modifying antirheumatic drugs. Participants were randomly assigned (1:1) using a computer-generated permuted block randomisation (block sizes of 2 and 4) stratified by sex, smoking, and country, to 125 mg abatacept subcutaneous injections weekly or placebo for 12 months, and then followed up for 12 months. Masking was achieved by providing four kits (identical in appearance and packaging) with pre-filled syringes with coded labels of abatacept or placebo every 3 months. The primary endpoint was the time to development of clinical synovitis in three or more joints or rheumatoid arthritis according to American College of Rheumatology and European Alliance of Associations for Rheumatology 2010 criteria, whichever was met first. Synovitis was confirmed by ultrasonography. Follow-up was completed on Jan 13, 2021. All participants meeting the intention-to-treat principle were included in the analysis. This trial was registered with EudraCT (2013–003413–18). Between Dec 22, 2014, and Jan 14, 2019, 280 individuals were evaluated for eligibility and, of 213 participants, 110 were randomly assigned to abatacept and 103 to placebo. During the treatment period, seven (6%) of 110 participants in the abatacept group and 30 (29%) of 103 participants in the placebo group met the primary endpoint. At 24 months, 27 (25%) of 110 participants in the abatacept group had progressed to rheumatoid arthritis, compared with 38 (37%) of 103 in the placebo group. The estimated proportion of participants remaining arthritis-free at 12 months was 92·8% (SE 2·6) in the abatacept group and 69·2% (4·7) in the placebo group. Kaplan–Meier arthritis-free survival plots over 24 months favoured abatacept (log-rank test p=0·044). The difference in restricted mean survival time between groups was 53 days (95% CI 28–78; p<0·0001) at 12 months and 99 days (95% CI 38–161; p=0·0016) at 24 months in favour of abatacept. During treatment, abatacept was associated with improvements in pain scores, functional wellbeing, and quality-of-life measurements, as well as low scores of subclinical synovitis by ultrasonography, compared with placebo. However, the effects were not sustained at 24 months. Seven serious adverse events occurred in the abatacept group and 11 in the placebo group, including one death in each group deemed unrelated to treatment. Therapeutic intervention during the at-risk phase of rheumatoid arthritis is feasible, with acceptable safety profiles. T-cell co-stimulation modulation with abatacept for 12 months reduces progression to rheumatoid arthritis, with evidence of sustained efficacy beyond the treatment period, and with no new safety signals. Bristol Myers Squibb.

Approximately 40% of patients with rheumatoid arthritis do not respond to individual biologic therapies, while biomarkers predictive of treatment response are lacking. Here we analyse RNA-sequencing (RNA-Seq) of pre-treatment synovial tissue from the biopsy-based, precision-medicine STRAP trial ( n  = 208), to identify gene response signatures to the randomised therapies: etanercept (TNF-inhibitor), tocilizumab (interleukin-6 receptor inhibitor) and rituximab (anti-CD20 B-cell depleting antibody). Machine learning models applied to RNA-Seq predict clinical response to etanercept, tocilizumab and rituximab at the 16-week primary endpoint with area under receiver operating characteristic curve (AUC) values of 0.763, 0.748 and 0.754 respectively ( n  = 67-72) as determined by repeated nested cross-validation. Prediction models for tocilizumab and rituximab are validated in an independent cohort (R4RA): AUC 0.713 and 0.786 respectively ( n  = 65-68). Predictive signatures are converted for use with a custom synovium-specific 524-gene nCounter panel and retested on synovial biopsy RNA from STRAP patients, demonstrating accurate prediction of treatment response (AUC 0.82-0.87). The converted models are combined into a unified clinical decision algorithm that has the potential to transform future clinical practice by assisting the selection of biologic therapies. The heterogenous nature of rheumatoid arthritis renders the prediction of responsiveness to biological treatments difficult. Here the authors analyze bulk RNA-seq data from the STRAP trial ( n  = 208) to build a machine-learning model for predicting responses to etanercept, tocilizumab and rituximab with AUCs around 0.75 to potentially assist in therapy planning.

An integrated genomic and functional analysis to elucidate DNA damage signaling factors promoting self-renewal of glioma stem cells (GSCs) identified proliferating cell nuclear antigen (PCNA)-associated factor (PAF) up-regulation in glioblastoma. PAF is preferentially overexpressed in GSCs. Its depletion impairs maintenance of self-renewal without promoting differentiation and reduces tumor-initiating cell frequency. Combined transcriptomic and metabolomic analyses revealed that PAF supports GSC maintenance, in part, by influencing DNA replication and pyrimidine metabolism pathways. PAF interacts with PCNA and regulates PCNA-associated DNA translesion synthesis (TLS); consequently, PAF depletion in combination with radiation generated fewer tumorspheres compared with radiation alone. Correspondingly, pharmacological impairment of DNA replication and TLS phenocopied the effect of PAF depletion in compromising GSC self-renewal and radioresistance, providing preclinical proof of principle that combined TLS inhibition and radiation therapy may be a viable therapeutic option in the treatment of glioblastoma multiforme (GBM).

Primary Sjögren’s syndrome (pSS) is a chronic autoimmune rheumatic disease with symptoms including dryness, fatigue, and pain. The previous work by our group has suggested that certain proinflammatory cytokines are inversely related to patient-reported levels of fatigue. To date, these findings have not been validated. This study aims to validate this observation. Blood levels of seven cytokines were measured in 120 patients with pSS from the United Kingdom Primary Sjögren’s Syndrome Registry and 30 age-matched healthy non-fatigued controls. Patient-reported scores for fatigue were classified according to severity and compared to cytokine levels using analysis of variance. The differences between cytokines in cases and controls were evaluated using Wilcoxon test. A logistic regression model was used to determine the most important identifiers of fatigue. Five cytokines, interferon-γ-induced protein-10 (IP-10), tumour necrosis factor-α (TNFα), interferon-α (IFNα), interferon-γ (IFN-γ), and lymphotoxin-α (LT-α) were significantly higher in patients with pSS (n = 120) compared to non-fatigued controls (n = 30). Levels of two proinflammatory cytokines, TNF-α (p = 0.021) and LT-α (p = 0.043), were inversely related to patient-reported levels of fatigue. Cytokine levels, disease-specific and clinical parameters as well as pain, anxiety, and depression were used as predictors in our validation model. The model correctly identifies fatigue levels with 85% accuracy. Consistent with the original study, pain, depression, and proinflammatory cytokines appear to be the most powerful predictors of fatigue in pSS. TNF-α and LT-α have an inverse relationship with fatigue severity in pSS challenging the notion that proinflammatory cytokines directly mediate fatigue in chronic immunological conditions.