Rheumatoid arthritis (RA) consists of two syndromes, one autoantibody-positive and one autoantibody-negative. Existing data on the relation between age of onset and prevalence of autoantibodies were ...conflicting. Therefore this multicohort study assessed the age of onset in relation to the presence of autoantibodies. The association with characteristics of the anti-citrullinated protein antibodies (ACPA) response was also explored.
The 1987 criteria-positive RA patients included in the Leiden EAC, BARFOT, ESPOIR, Umeå and Lund cohorts (n = 3321) were studied at presentation for age of onset and the presence of ACPA, rheumatoid factor (RF) and anti-carbamylated protein (anti-CarP) antibodies. Logistic regression analyses were performed; effect sizes were summarized in inverse-weighted meta-analyses. Within ACPA-positive RA, ACPA level was studied in all cohorts; ACPA isotypes, ACPA fine specificity and ACPA avidity index and clinical characteristics were studied in the Leiden EAC.
From the age of 50 onward, the proportion of ACPA-negative RA patients increased with age in the five cohorts. Similar observations were made for RF and anti-CarP. The composition of the ACPA response did not change with increasing age of onset with respect to titer, isotype distribution, fine specificity and avidity index. With increasing age of onset, RA patients smoked less often, had higher acute phase reactants and more often had a sub(acute) symptom onset.
Data of five cohorts revealed that with older age of onset ACPA-negative RA is more frequent than ACPA-positive RA, while characteristics of ACPA-positive RA as judged by the composition of the ACPA response appeared not age dependent. Further biologic studies are needed to characterize the pathogenesis of ACPA-negative polyarthritis at older age and to promote personalized treatment decisions in ACPA-negative patients in daily practice.
The contribution of smoking to rheumatoid arthritis (RA) is hypothesized to be mediated through formation of anti-citrullinated protein antibodies (ACPA). In RA, however, autoantibodies such as ACPA, ...rheumatoid factor (RF), and anti-carbamylated protein antibodies (anti-CarP) often occur together, and it is thus unclear whether smoking is specifically associated with some autoantibodies rather than others. We therefore investigated whether smoking is only associated with ACPA or with the presence of multiple RA-related autoantibodies.
A population-based Japanese cohort (n = 9575) was used to investigate the association of smoking with RF and anti-cyclic citrullinated peptide antibodies (anti-CCP2) in individuals without RA. Furthermore, RA patients fulfilling the 1987 criteria from three early arthritis cohorts from the Netherlands (n = 678), the United Kingdom (n = 761), and Sweden (n = 795) were used. Data on smoking, RF, anti-CCP2, and anti-CarP were available. A total score of autoantibodies was calculated, and odds ratios (ORs) and 95% confidence intervals (95% CIs) were calculated by logistic regression.
In the population-based non-RA cohort, no association was found between smoking and one autoantibody (RF or anti-CCP2), but smoking was associated with double-autoantibody positivity (OR 2.95, 95% CI 1.32-6.58). In RA patients, there was no association between smoking and the presence of one autoantibody (OR 0.99, 95% CI 0.78-1.26), but smoking was associated with double-autoantibody positivity (OR 1.32, 95% CI 1.04-1.68) and triple-autoantibody positivity (OR 2.05, 95% CI 1.53-2.73).
Smoking is associated with the concurrent presence of multiple RA-associated autoantibodies rather than just ACPA. This indicates that smoking is a risk factor for breaking tolerance to multiple autoantigens in RA.
Background
The military has used topical hemostatic agents to successfully treat life‐threatening external bleeding for years. In contrast to the military environment, the general population are ...increasingly prescribed anticoagulants. There are only few comparative evaluations of topical hemostatic agents with anticoagulated human blood. It is important to understand the impact of these agents on those who take anticoagulants.
Study design and Methods
Citrated blood of patients treated with enoxaparin, heparin, and acetylsalicylic acid, apixaban or phenprocoumon was incubated with different hemostatic agents (QuikClot Gauze, Celox Granules, Celox Gauze, Chito SAM 100, WoundClot Trauma Gauze, QuikClot Gauze Moulage Trainer and Kerlix) and rotational thromboelastometry was performed with non‐activated thromboelastometry (NATEM reagent).
Results
All tested agents improved the onset of coagulation in all anticoagulants, mostly to a significant degree. Most significant improvements were produced by QuikClot Gauze and QuikClot Gauze Moulage Trainer, followed by the tested chitosans (Celox Granules, Celox Gauze, Chito SAM 100). Of the anticoagulant groups, the most significant improvements were seen in enoxaparin. This was followed in order by apixaban, heparin, and acetylsalicylic acid, and phenprocoumon.
Discussion
All the hemostatic agents tested were able to activate the clotting cascade earlier and initiate faster clot formation in anticoagulated blood. A definitive head‐to‐head comparison is not feasible, because of the limitations of an in‐vitro analysis. However, the sometimes‐presented hypothesis that kaolin‐based hemostatic agents are ineffective in anticoagulated blood is inaccurate according to our data. Hemostasis with hemostatic agents appears most challenging with phenprocoumon.
Patients with rheumatoid arthritis (RA)-related autoantibodies have an increased mortality rate. Different autoantibodies are frequently co-occurring and it is unclear which autoantibodies associate ...with increased mortality. In addition, association with different causes of death is thus far unexplored. Both questions were addressed in three early RA populations.
2331 patients with early RA included in Better Anti-Rheumatic Farmaco-Therapy cohort (BARFOT) (n=805), Norfolk Arthritis Register (NOAR) (n=678) and Leiden Early Arthritis Clinic cohort (EAC) (n=848) were studied. The presence of anticitrullinated protein antibodies (ACPA), rheumatoid factor (RF) and anticarbamylated protein (anti-CarP) antibodies was studied in relation to all-cause and cause-specific mortality, obtained from national death registers. Cox proportional hazards regression models (adjusted for age, sex, smoking and inclusion year) were constructed per cohort; data were combined in inverse-weighted meta-analyses.
During 26 300 person-years of observation, 29% of BARFOT patients, 30% of NOAR and 18% of EAC patients died, corresponding to mortality rates of 24.9, 21.0 and 20.8 per 1000 person-years. The HR for all-cause mortality (95% CI) was 1.48 (1.22 to 1.79) for ACPA, 1.47 (1.22 to 1.78) for RF and 1.33 (1.11 to 1.60) for anti-CarP. When including all three antibodies in one model, RF was associated with all-cause mortality independent of other autoantibodies, HR 1.30 (1.04 to 1.63). When subsequently stratifying for death cause, ACPA positivity associated with increased cardiovascular death, HR 1.52 (1.04 to 2.21), and RF with increased neoplasm-related death, HR 1.64 (1.02 to 2.62), and respiratory disease-related death, HR 1.71 (1.01 to 2.88).
The presence of RF in patients with RA associates with an increased overall mortality rate. Cause-specific mortality rates differed between autoantibodies: ACPA associates with increased cardiovascular death and RF with death related to neoplasm and respiratory disease.
Abstract
A plethora of modified nucleotides extends the chemical and conformational space for natural occurring RNAs. tRNAs constitute the class of RNAs with the highest modification rate. The ...extensive modification modulates their overall stability, the fidelity and efficiency of translation. However, the impact of nucleotide modifications on the local structural dynamics is not well characterized. Here we show that the incorporation of the modified nucleotides in tRNAfMet from Escherichia coli leads to an increase in the local conformational dynamics, ultimately resulting in the stabilization of the overall tertiary structure. Through analysis of the local dynamics by NMR spectroscopic methods we find that, although the overall thermal stability of the tRNA is higher for the modified molecule, the conformational fluctuations on the local level are increased in comparison to an unmodified tRNA. In consequence, the melting of individual base pairs in the unmodified tRNA is determined by high entropic penalties compared to the modified. Further, we find that the modifications lead to a stabilization of long-range interactions harmonizing the stability of the tRNA’s secondary and tertiary structure. Our results demonstrate that the increase in chemical space through introduction of modifications enables the population of otherwise inaccessible conformational substates.
Resuscitation by laypersons is important in bridging the time between the occurrence of an out-of-hospital cardiac arrest (OHCA) and the arrival of emergency rescue service personnel. Depending on ...the reason for the cardiac arrest, however, the effectiveness of chest compressions is uncertain. The aim of this study was to explore the impact of lay resuscitation on survival following OHCA of different causes.
The data set for analysis comprised all cases of cardiac arrest before the arrival of emergency rescue service personnel that were fully documented in the German Resuscitation Registry in the period 2007-2019. The following endpoints related to resuscitation by bystanders were evaluated-separately for each cause-descriptively and by means of multivariate logistic regression analysis: return of spontaneous circulation (ROSC), 30 days' survival/discharged alive from the hospital, and good neurological function at discharge.
Altogether, 40 604 cases of cardiac arrest were included. Resuscitation by laypersons was carried out in 35.1% of these cases. The rate of ROSC was statistically significantly higher after lay resuscitation for OHCA caused by cardiac events, drowning, intoxication, or central nervous system disorders (overall 48.1% versus 41.0%). For all causes-with the exception of trauma/bleeding to death and sepsis- the endpoint 30 days' survival/discharged alive was better with lay resuscitation (overall 17.0% versus 9.5%). In multivariate regression analysis, lay resuscitation was associated with improvement of the endpoint 30 days' survival/discharged alive only for OHCA caused by cardiac events (odds ratio OR 1.16) or intoxication (OR 1.81). For all other causes-except hypoxia-lay resuscitation tended to yield better results. Neurological function at discharge was also significantly better (overall 11.5% versus 6.1%) after lay resuscitation for OHCA of all causes except trauma/ bleeding to death, hypoxia, and sepsis.
Resuscitation by laypersons is associated with an improved result regarding the endpoint 30 days' survival/discharged alive in cases of OHCA caused by cardiac events and intoxication. These two groups account for 81% of the resuscitation patients in the study. Because there was also a tendency towards higher survival rates following OHCA of other causes (except hypoxia), laypersons should continue to be encouraged to attempt resuscitation in all cases of OHCA, whatever the cause.
Antibiotic treatments have detrimental effects on the microbiome and lead to antibiotic resistance. To develop a phage therapy against a diverse range of clinically relevant Escherichia coli, we ...screened a library of 162 wild-type (WT) phages, identifying eight phages with broad coverage of E. coli, complementary binding to bacterial surface receptors, and the capability to stably carry inserted cargo. Selected phages were engineered with tail fibers and CRISPR-Cas machinery to specifically target E. coli. We show that engineered phages target bacteria in biofilms, reduce the emergence of phage-tolerant E. coli and out-compete their ancestral WT phages in coculture experiments. A combination of the four most complementary bacteriophages, called SNIPR001, is well tolerated in both mouse models and minipigs and reduces E. coli load in the mouse gut better than its constituent components separately. SNIPR001 is in clinical development to selectively kill E. coli, which may cause fatal infections in hematological cancer patients.
Diffuse large B cell lymphoma (DLBCL) is one of the most common types of aggressive lymphoid malignancies. Here, we explore the contribution of RNA editing to DLBCL pathogenesis. We observed that DNA ...mutations and RNA editing events are often mutually exclusive, suggesting that tumors can modulate pathway outcomes by altering sequences at either the genomic or the transcriptomic level. RNA editing targets transcripts within known disease-driving pathways such as apoptosis, p53 and NF-κB signaling, as well as the RIG-I-like pathway. In this context, we show that ADAR1-mediated editing within MAVS transcript positively correlates with MAVS protein expression levels, associating with increased interferon/NF-κB signaling and T cell exhaustion. Finally, using targeted RNA base editing tools to restore editing within MAVS 3′UTR in ADAR1-deficient cells, we demonstrate that editing is likely to be causal to an increase in downstream signaling in the absence of activation by canonical nucleic acid receptor sensing.
Display omitted
•RNA editing targets transcripts within DLBCL disease-driving pathways•RNA editing may represent a mechanism complementary to that of DNA mutation•MAVS editing directly correlates with its protein levels and downstream signaling•Targeted restoration of editing within MAVS restores downstream pathway signaling
Genetics; Molecular biology; Epigenetics; Omics; Transcriptomics
PDF
