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The Global Protection Force refused to share any details with Jack about his brother's whereabouts, but on two previous missions, Jack had collected clues that pointed to Max being in Egypt. Now Jack has reason to believe that King Tut's diadem--a crown thought to have magical powers--is the cause of Max's disappearance. Can Jack prevent an ancient and terrible curse of the pharaohs from wreaking havoc and finally save Max?

Biofilm-dwelling microorganisms coat the surfaces of stones in rivers and streams, forming diverse communities that are fundamental to biogeochemical processes and ecosystem functioning. Flowing water (lotic) ecosystems face mounting pressures from changes in land use, chemical pollution, and climate change. Despite their ecological importance, the taxonomic and functional diversity of river biofilms and their responses to environmental change are poorly understood at large spatial scales. We conducted a national-scale assessment of bacterial diversity and function using metagenomic sequencing from rivers and streams across England. We recovered 1,014 metagenome-assembled genomes (MAGs) from 450 biofilms collected across England’s extensive river network. Substantial taxonomic novelty was identified, with ~20% of the MAGs representing novel genera. Here we show that biofilm communities, dominated by generalist bacteria, exhibit remarkable functional diversity and metabolic versatility, and likely play a significant role in nutrient cycling with the potential for contaminant transformation. Measured environmental drivers collectively explained an average of 71% of variation in the relative abundance of bacterial MAGs, with geology and land cover contributing most strongly. These findings highlight the importance of river biofilms and establish a foundation for future research on the roles of biofilms in ecosystem health and resilience to environmental change. Here, the authors conduct a metagenomic-based study of England’s rivers to show that biofilm bacteria are taxonomically and functionally diverse and are key to biogeochemical cycling, highlighting the importance of river biofilm bacteria in understanding and monitoring freshwater ecosystem health.

Genealogies, knowledge, and purity all can provide separate identities with the means for competing self-definition. This article assumes a social location near Ephesus with Samaritan Israelites and Judeans in a Jesus-believing network. Rather than providing an analysis in which divisions are transcended, this reading suggests that a negotiation in John 4:4–45 of these three characteristics navigates divisions to create a complex, merged superordinate identity.

ObjectivesAn increased prevalence of periodontitis and perturbation of the oral microbiome has been identified in patients with rheumatoid arthritis (RA). The periodontal pathogen Porphyromonas gingivalis may cause local citrullination of proteins, potentially triggering anti-citrullinated protein antibody production. However, it is not known if oral dysbiosis precedes the onset of clinical arthritis. This study comprehensively characterised the oral microbiome in anti-cyclic citrullinated peptide (anti-CCP) positive at-risk individuals without clinical synovitis (CCP+at risk).MethodsSubgingival plaque was collected from periodontally healthy and diseased sites in 48 CCP+at risk, 26 early RA and 32 asymptomatic healthy control (HC) individuals. DNA libraries were sequenced on the Illumina HiSeq 3000 platform. Taxonomic profile and functional capability of the subgingival microbiome were compared between groups.ResultsAt periodontally healthy sites, CCP+at risk individuals had significantly lower microbial richness compared with HC and early RA groups (p=0.004 and 0.021). Microbial community alterations were found at phylum, genus and species levels. A large proportion of the community differed significantly in membership (523 species; 35.6%) and structure (575 species; 39.1%) comparing CCP+at risk and HC groups. Certain core species, including P. gingivalis, had higher relative abundance in the CCP+at risk group. Seventeen clusters of orthologous gene functional units were significantly over-represented in the CCP+at risk group compared with HC (adjusted p value <0.05).ConclusionAnti-CCP positive at-risk individuals have dysbiotic subgingival microbiomes and increased abundance of P. gingivalis compared with controls. This supports the hypothesis that the oral microbiome and specifically P. gingivalis are important in RA initiation.

ObjectivesTo determine whether ultrasound can identify anti-cyclic citrullinated peptide (anti-CCP) antibody-positive patients without clinical synovitis (CS) who progress to inflammatory arthritis (IA).MethodsIn a prospective study, anti-CCP-positive patients without CS underwent ultrasound imaging of 32 joints (wrists, metacarpophalangeal joints, proximal interphalangeal joints and metatarsophalangeal joints (MTPs)) and were monitored for the development of IA. Associations between baseline ultrasound findings (grey scale (GS), power Doppler (PD) and erosions) and (1) progression to IA and (2) development of CS within an individual joint were measured.ResultsConsecutive anti-CCP-positive patients (n=136; mean age 51 years, 100 women) were followed up for median of 18.3 months (range 0.1–79.6). At baseline 96% had GS, 30% had PD and 21% had one or more erosions. IA developed in 57 patients (42%) after median of 8.6 months (range 0.1–52.4). Ultrasound abnormalities (GS ≥2, PD ≥1 or erosion ≥1) were found in 86% at baseline compared with 67% of non-progressors (χ2=6.3, p=0.012). Progression to IA was significantly higher in those with ultrasound findings in any joint (excluding MTPs for GS) (GS ≥2: 55% vs 24%, HR (95% CI) 2.3 (1.0 to 4.9), p=0.038; PD ≥2: 75% vs 32%, 3.7 (2.0 to 6.9), p<0.001 and erosion ≥1: 71% vs 34%, 2.9 (1.7 to 5.1), p<0.001). Furthermore, progression occurred earlier with PD ≥2 (median 7.1 vs 52.4 months) and erosion ≥1 (15.4 vs 46.5). At the individual joint level, the trend for progression to CS was more significant for GS and PD (GS ≥2: 26% vs 3%, 9.4 (5.1 to 17.5), p<0.001; PD ≥2: 55% vs 4%, 31.3 (15.6 to 62.9), p<0.001).ConclusionUltrasound features of joint inflammation may be detected in anti-CCP-positive patients without CS. Ultrasound findings predict progression (and rate of progression) to IA, with the risk of progression highest in those with PD signal.Trial registration numberNCT02012764; Results.

Key Points Disease prevention is a novel concept in rheumatoid arthritis (RA) but has been explored in other chronic diseases, with intervention at different stages of disease yielding varied results Defining the stages of RA prior to overt disease and characterizing 'at-risk' populations is essential in order to develop targeted and appropriate therapies, and prevention strategies At-risk individuals can be defined by their genetic, environmental, autoimmune and symptom profiles, and can possess one or several risk factors in combination Intervention in the early stages of inflammatory arthritis has shown high remission rates and, furthermore, progression to RA has in some cases been delayed but not necessarily prevented Population studies in autoimmune disease have demonstrated environmental and dietary risk factors for RA that might be targeted in interventional studies, similar to studies conducted in type 1 diabetes mellitus Relatives of individuals who have RA, and individuals with disease-associated autoantibodies, are ideal patient cohorts for studies to gain understanding of disease pathogenesis and to explore disease-prevention strategies Prevention of rheumatoid arthritis (RA) by intervening before the development of overt symptoms requires knowing which individuals are at risk of developing the disease. In this Review, Hunt and Emery consider several distinct at-risk cohorts, with a focus on those with systemic autoimmunity, and discuss the prospects for RA prevention in these cohorts drawing on lessons from disease prevention in other autoimmune conditions and early trials in RA. Preventing disease is a public health priority. In recent years, this focus has evolved to include noncommunicable chronic diseases such as cardiovascular disease and diabetes mellitus but is novel in rheumatic diseases such as rheumatoid arthritis (RA). In order to prevent RA, the 'at-risk' populations need to be defined. To date, a number of studies have attempted to clarify our understanding of these cohorts and how they could be identified. Suggested terminology has now been published to define individuals who might go on to develop RA. This Review considers categories of these 'at-risk' individuals, with a focus on those with systemic autoimmunity. Trials in very early RA demonstrate that disease outcomes can be reduced with early intervention. These principles are widely accepted in other diseases such as type 1 diabetes mellitus, in which steps have been taken to prevent disease in genetically predisposed individuals. Large population-based studies provide insights into potential interventions for RA prevention. By quantifying risk in different populations, the prospect of preventing this disease is feasible.

To investigate whether posttraumatic stress disorder (PTSD) from past trauma, alexithymia and suppression would impact on the experience of Posttraumatic Stress symptoms (PTSS) and psychological well-being following romantic relationship dissolution. One hundred and eighty-nine participants completed questionnaires measuring PTSD, alexithymia, suppression, PTSS and psychological well-being. The results showed that following relationship dissolution, higher levels of intrusion and avoidance (PTSS) and lower levels of psychological well-being were associated with PTSD from past trauma. Difficulty describing feelings was associated negatively with intrusion; difficulty identifying feelings was associated positively with psychological well-being. Suppression was associated negatively with avoidance. To conclude, PTSD from past traumas was related to PTSS symptoms and poor psychological well-being. Alexithymia and suppression were also related to the above outcomes but in a symptom-specific manner.

The prevalence of periodontitis is increased in patients with rheumatoid arthritis (RA) and periodontopathic bacteria can citrullinate proteins. Periodontitis may, therefore, be an initiator of RA and a target for prevention. Periodontal disease and periodontal bacteria have not been investigated in at-risk individuals with RA autoimmunity but no arthritis. To examine periodontal disease and periodontopathic bacteria in anti-cyclic citrullinated protein (anti-CCP) antibody-positive at-risk individuals without arthritis. This cross-sectional study took place at a teaching hospital from April 27, 2015, to May 8, 2017. Forty-eight anti-CCP-positive individuals without arthritis (CCP+ at-risk) were recruited nationally. Twenty-six patients with early RA (ERA) and 32 healthy control individuals were recruited locally. Data were analyzed between June 1, 2017, and December 1, 2017. Periodontal assessment and examination of joints using ultrasonography. Prevalence of diseased periodontal sites, clinical periodontitis, and periodontal inflamed surface area in CCP+ at-risk individuals compared with patients with ERA and healthy individuals matched for age and smoking. Paired-end sequencing of DNA from subgingival plaque from diseased and healthy periodontal sites was performed and DNA was profiled and analyzed. A total of 48 CCP+ at-risk individuals (mean [SD] age, 51.9 [11.4] years; 31 [65%] female), 26 patients with ERA (mean [SD] age, 54.4 [16.7] years; 14 [54%] female), and 32 healthy individuals (mean [SD] age, 49.4 [15.3] years; 19 [59%] female) were recruited. Of 48 CCP+ at-risk individuals, 46 had no joint inflammation on ultrasonography. Thirty-five CCP+ at-risk individuals (73%), 12 healthy individuals (38%), and 14 patients with ERA (54%) had clinical periodontitis. The median (interquartile range) percentage of periodontal sites with disease was greater in CCP+ at-risk individuals compared with healthy individuals (3.3% [0%-11.3%] vs 0% [0%-0.7%]) and similar to patients with ERA (1.1% [0%-13.1%]). Median (interquartile range) periodontal inflamed surface area was higher in CCP+ at-risk individuals compared with healthy individuals (221 mm2 [81-504 mm2] vs 40 mm2 [12-205 mm2]). Patients with CCP+ at-risk had increased relative abundance of Porphyromonas gingivalis (but not Aggregatibacter actinomycetemcomitans) at healthy periodontal sites compared with healthy individuals (effect size, 3.00; 95% CI, 1.71-4.29) and patients with ERA (effect size, 2.14; 95% CI, 0.77-3.52). This study found increased prevalence of periodontitis and P gingivalis in CCP+ at-risk individuals. This suggests periodontitis and P gingivalis are associated with disease initiation and could be targets for preventive interventions in RA.

Interosseous tendon inflammation (ITI) has been described in rheumatoid arthritis (RA). Whether ITI occurs in at-risk individuals before the onset of clinical synovitis is unknown.ObjectivesTo investigate, by MRI, ITI in anti-cyclic citrullinated peptide (CCP)-positive at-risk individuals (CCP +at risk) and to describe the anatomy, prevalence and clinical associations across the RA continuum.MethodsHand MRI was performed in 93 CCP + at risk, 47 early RA (ERA), 28 established ‘late’ RA (LRA) and 20 healthy controls (HC) and scored for ITI, flexor tenosynovitis (TSV) and RA MRI scoring at the metacarpophalangeal joints (MCPJs). Cadaveric and histological studies were performed to explore the anatomical basis for MRI ITI.ResultsThe proportion of subjects with ITI and the number of inflamed interosseous tendons (ITs) increased along the disease continuum (p<0.001): 19% of CCP +at risk, 49% of ERA and 57% of LRA had ≥1 IT inflamed . ITI was not found in any HC. ITI was more frequently identified in tender MCPJs compared with nontender MCPJs (28% vs 12%, respectively). No IT tenosynovial sheath was identified in cadavers on dissection or histological studies suggesting MRI findings represent peritendonitis. Dye studies indicated no communication between the IT and the joint.ConclusionsITI occurs in CCP + at-risk individuals and can precede the onset of clinical synovitis. The ITs may be important nonsynovial extracapsular targets in the development and progression of RA.

Autoantibodies have been associated with human pathologies for a long time, particularly with autoimmune diseases (AIDs). Rheumatoid factor (RF) is known since the late 1930s to be associated with rheumatoid arthritis (RA). The discovery of anticitrullinated protein antibodies in the last century has changed this and other posttranslational modifications (PTM) relevant to RA have since been described. Such PTM introduce neoepitopes in proteins that can generate novel autoantibody specificities. The recent recognition of these novel specificities in RA provides a unique opportunity to understand human B-cell development in vivo. In this paper, we will review the three of the main classes of PTMs already associated with RA: citrullination, carbamylation, and oxidation. With the advancement of research methodologies it should be expected that other autoantibodies against PTM proteins could be discovered in patients with autoimmune diseases. Many of such autoantibodies may provide significant biomarker potential.