DAS28(3)CRP is a reliable measure of disease activity in pregnant women with rheumatoid arthritis

OBJECTIVES: The disease activity of rheumatoid arthritis (RA) in pregnancy is most commonly assessed with the modified Disease Activity Score (DAS)-28, the DAS28(3)CRP. However, the performance of the DAS28(3)CRP in pregnancy has not been compared to musculoskeletal ultrasound (MSK-US) as a gold standard. We performed a prospective pilot study to test the hypothesis that pregnancy-related factors limit the reliability of the DAS28(3)CRP. METHODS: Pregnant women with RA were recruited from an Obstetric Rheumatology clinic and assessed during pregnancy (second (T2) and third (T3) trimesters) and postpartum with DAS28(3)CRP and MSK-US scores, with quantification of power Doppler (PD) signal in small joints (hands and feet). Age-matched non-pregnant women with RA underwent equivalent assessments. PD scores were calculated as mean scores of all joints scanned. RESULTS: We recruited 27 pregnant and 20 non-pregnant women with RA. DAS28(3)CRP was sensitive and specific for active RA in pregnancy and postpartum as defined by positive PD signal, but not in non-pregnancy. There were significant correlations between DAS28(3)CRP and PD scores throughout pregnancy (T2, r=0.82 (95% CI [0.42, 0.95], p<0.01); T3, r=0.68 (95% CI [0.38, 0.86], p<0.01)) and postpartum, r=0.84 (95% CI [0.60, 0.94], p<0.01), while this correlation in non-pregnancy was weaker (r=0.47 (95% CI [0, 0.77], p<0.05). CONCLUSIONS: This pilot study found that DAS28(3)CRP is a reliable measure of disease activity in pregnant women with RA. Based on these data, pregnancy does not appear to confound clinical evaluation of the tender and/or swollen joint counts

Early evolution of the angiosperm clade Asteraceae in the Cretaceous of Antarctica

The Asteraceae (sunflowers and daisies) are the most diverse family of flowering plants. Despite their prominent role in extant terrestrial ecosystems, the early evolutionary history of this family remains poorly understood. Here we report the discovery of a number of fossil pollen grains preserved in dinosaur-bearing deposits from the Late Cretaceous of Antarctica that drastically pushes back the timing of assumed origin of the family. Reliably dated to ∼76–66 Mya, these specimens are about 20 million years older than previously known records for the Asteraceae. Using a phylogenetic approach, we interpreted these fossil specimens as members of an extinct early diverging clade of the family, associated with subfamily Barnadesioideae. Based on a molecular phylogenetic tree calibrated using fossils, including the ones reported here, we estimated that the most recent common ancestor of the family lived at least 80 Mya in Gondwana, well before the thermal and biogeographical isolation of Antarctica. Most of the early diverging lineages of the family originated in a narrow time interval after the K/P boundary, 60–50 Mya, coinciding with a pronounced climatic warming during the Late Paleocene and Early Eocene, and the scene of a dramatic rise in flowering plant diversity. Our age estimates reduce earlier discrepancies between the age of the fossil record and previous molecular estimates for the origin of the family, bearing important implications in the evolution of flowering plants in general.Los datos utilizados en este trabajo pueden accederse haciendo clic en "Documentos relacionados".Facultad de Ciencias Naturales y Muse

Uppermost Triassic to Lower Jurassic sediments of the island of Ireland and its surrounding basins

The uppermost Triassic to Lower Jurassic interval has not been extensively studied across the island of Ireland. This paper seeks to redress that situation and presents a synthesis of records of the uppermost Triassic and Lower Jurassic from both onshore and offshore basins as well as describing the sedimentological characteristics of the main lithostratigraphical units encountered. Existing data have been supplemented with a re-examination and logging of some outcrops and the integration of data from recent hydrocarbon exploration wells and boreholes. The Late Triassic Penarth Group and Early Jurassic Lias Group can be recognised across the Republic of Ireland and Northern Ireland. In some onshore basins, almost 600 m of strata are recorded, however in offshore basins thicknesses in excess of two kilometres for the Lower Jurassic have now been recognised, although little detailed information is currently available. The transition from the Triassic to the Jurassic was a period of marked global sea-level rise and climatic change (warming) and this is reflected in the lithostratigraphical record of these sediments in the basins of Northern Ireland and offshore basins of the Republic of Ireland. In general, the sediments of this interval are thicker than those in Great Britain and have potential for detailed study of climatic and sea-level fluctuation

Paleoecologic and paleoceanographic interpretation of δ18O variability in Lower Ordovician conodont species

Conodont δ18O is increasingly used to reconstruct Paleozoic–Triassic seawater temperature changes. Less attention has been paid to δ18O variation in time slices across paleoenvironments, within sample assemblages, or for reconstructing the thermal structure of Paleozoic oceans. Furthermore, there have been few independent tests of conodont ecologic models based on biofacies and lithofacies distributions. Here we present the rst test of ecologic models for conodonts based on δ18O values of a Laurentian Lower Ordovician (Floian) shelf edge–upper slope assemblage in debrites of the proximal lower slope Shallow Bay Formation, Cow Head Group, western Newfoundland. Nine species yield a 1.6–1.8‰ intra-sample δ18O variability based on mixed tissue and white matter-only analyses, equivalent to an ~7–8 °C range. Lin- ear mixed models demonstrate statistically signi cant differences between the δ18O of some species, supporting the interpretation that an isotopic and temperature gradient is preserved. By considering conodont δ18O in a geologic context, we propose an integrated paleoecologic and paleoceanographic model with species tiered pelagically through the water column, and con rm the utility of conodonts for water-mass characterization within Paleozoic oceans

The genetic heterogeneity and mutational burden of engineered melanomas in zebrafish models.

BACKGROUND: Melanoma is the most deadly form of skin cancer. Expression of oncogenic BRAF or NRAS, which are frequently mutated in human melanomas, promote the formation of nevi but are not sufficient for tumorigenesis. Even with germline mutated p53, these engineered melanomas present with variable onset and pathology, implicating additional somatic mutations in a multi-hit tumorigenic process. RESULTS: To decipher the genetics of these melanomas, we sequence the protein coding exons of 53 primary melanomas generated from several BRAF(V600E) or NRAS(Q61K) driven transgenic zebrafish lines. We find that engineered zebrafish melanomas show an overall low mutation burden, which has a strong, inverse association with the number of initiating germline drivers. Although tumors reveal distinct mutation spectrums, they show mostly C > T transitions without UV light exposure, and enrichment of mutations in melanogenesis, p53 and MAPK signaling. Importantly, a recurrent amplification occurring with pre-configured drivers BRAF(V600E) and p53-/- suggests a novel path of BRAF cooperativity through the protein kinase A pathway. CONCLUSION: This is the first analysis of a melanoma mutational landscape in the absence of UV light, where tumors manifest with remarkably low mutation burden and high heterogeneity. Genotype specific amplification of protein kinase A in cooperation with BRAF and p53 mutation suggests the involvement of melanogenesis in these tumors. This work is important for defining the spectrum of events in BRAF or NRAS driven melanoma in the absence of UV light, and for informed exploitation of models such as transgenic zebrafish to better understand mechanisms leading to human melanoma formation

British Society of Gastroenterology guidance for management of inflammatory bowel disease during the COVID-19 pandemic.

The COVID-19 pandemic is putting unprecedented pressures on healthcare systems globally. Early insights have been made possible by rapid sharing of data from China and Italy. In the UK, we have rapidly mobilised inflammatory bowel disease (IBD) centres in order that preparations can be made to protect our patients and the clinical services they rely on. This is a novel coronavirus; much is unknown as to how it will affect people with IBD. We also lack information about the impact of different immunosuppressive medications. To address this uncertainty, the British Society of Gastroenterology (BSG) COVID-19 IBD Working Group has used the best available data and expert opinion to generate a risk grid that groups patients into highest, moderate and lowest risk categories. This grid allows patients to be instructed to follow the UK government's advice for shielding, stringent and standard advice regarding social distancing, respectively. Further considerations are given to service provision, medical and surgical therapy, endoscopy, imaging and clinical trials

Identifying the domains of context important to implementation science: a study protocol

Background There is growing recognition that “context” can and does modify the effects of implementation interventions aimed at increasing healthcare professionals’ use of research evidence in clinical practice. However, conceptual clarity about what exactly comprises “context” is lacking. The purpose of this research program is to develop, refine, and validate a framework that identifies the key domains of context (and their features) that can facilitate or hinder (1) healthcare professionals’ use of evidence in clinical practice and (2) the effectiveness of implementation interventions. Methods/design A multi-phased investigation of context using mixed methods will be conducted. The first phase is a concept analysis of context using the Walker and Avant method to distinguish between the defining and irrelevant attributes of context. This phase will result in a preliminary framework for context that identifies its important domains and their features according to the published literature. The second phase is a secondary analysis of qualitative data from 13 studies of interviews with 312 healthcare professionals on the perceived barriers and enablers to their application of research evidence in clinical practice. These data will be analyzed inductively using constant comparative analysis. For the third phase, we will conduct semi-structured interviews with key health system stakeholders and change agents to elicit their knowledge and beliefs about the contextual features that influence the effectiveness of implementation interventions and healthcare professionals’ use of evidence in clinical practice. Results from all three phases will be synthesized using a triangulation protocol to refine the context framework drawn from the concept analysis. The framework will then be assessed for content validity using an iterative Delphi approach with international experts (researchers and health system stakeholders/change agents). Discussion This research program will result in a framework that identifies the domains of context and their features that can facilitate or hinder: (1) healthcare professionals’ use of evidence in clinical practice and (2) the effectiveness of implementation interventions. The framework will increase the conceptual clarity of the term “context” for advancing implementation science, improving healthcare professionals’ use of evidence in clinical practice, and providing greater understanding of what interventions are likely to be effective in which contexts

Mutational processes molding the genomes of 21 breast cancers

All cancers carry somatic mutations. The patterns of mutation in cancer genomes reflect the DNA damage and repair processes to which cancer cells and their precursors have been exposed. To explore these mechanisms further, we generated catalogs of somatic mutation from 21 breast cancers and applied mathematical methods to extract mutational signatures of the underlying processes. Multiple distinct single- and double-nucleotide substitution signatures were discernible. Cancers with BRCA1 or BRCA2 mutations exhibited a characteristic combination of substitution mutation signatures and a distinctive profile of deletions. Complex relationships between somatic mutation prevalence and transcription were detected. A remarkable phenomenon of localized hypermutation, termed "kataegis," was observed. Regions of kataegis differed between cancers but usually colocalized with somatic rearrangements. Base substitutions in these regions were almost exclusively of cytosine at TpC dinucleotides. The mechanisms underlying most of these mutational signatures are unknown. However, a role for the APOBEC family of cytidine deaminases is proposed

Mutational processes molding the genomes of 21 breast cancers

All cancers carry somatic mutations. The patterns of mutation in cancer genomes reflect the DNA damage and repair processes to which cancer cells and their precursors have been exposed. To explore these mechanisms further, we generated catalogs of somatic mutation from 21 breast cancers and applied mathematical methods to extract mutational signatures of the underlying processes. Multiple distinct single- and double-nucleotide substitution signatures were discernible. Cancers with BRCA1 or BRCA2 mutations exhibited a characteristic combination of substitution mutation signatures and a distinctive profile of deletions. Complex relationships between somatic mutation prevalence and transcription were detected. A remarkable phenomenon of localized hypermutation, termed “kataegis,” was observed. Regions of kataegis differed between cancers but usually colocalized with somatic rearrangements. Base substitutions in these regions were almost exclusively of cytosine at TpC dinucleotides. The mechanisms underlying most of these mutational signatures are unknown. However, a role for the APOBEC family of cytidine deaminases is proposed

First large-scale quantification study of DNA preservation in insects from natural history collections using genome-wide sequencing

Insect declines are a global issue with significant ecological and economic ramifications. Yet, we have a poor understanding of the genomic impact these losses can have. Genome-wide data from historical specimens have the potential to provide baselines of population genetic measures to study population change, with natural history collections representing large repositories of such specimens. However, an initial challenge in conducting historical DNA data analyses is to understand how molecular preservation varies between specimens. Here, we highlight how Next-Generation Sequencing methods developed for studying archaeological samples can be applied to determine DNA preservation from only a single leg taken from entomological museum specimens, some of which are more than a century old. An analysis of genome-wide data from a set of 113 red-tailed bumblebee Bombus lapidarius specimens, from five British museum collections, was used to quantify DNA preservation over time. Additionally, to improve our analysis and further enable future research, we generated a novel assembly of the red-tailed bumblebee genome. Our approach shows that museum entomological specimens are comprised of short DNA fragments with mean lengths below 100 base pairs (BP), suggesting a rapid and large-scale post-mortem reduction in DNA fragment size. After this initial decline, however, we find a relatively consistent rate of DNA decay in our dataset, and estimate a mean reduction in fragment length of 1.9 bp per decade. The proportion of quality filtered reads mapping to our assembled reference genome was around 50%, and decreased by 1.1% per decade. We demonstrate that historical insects have significant potential to act as sources of DNA to create valuable genetic baselines. The relatively consistent rate of DNA degradation, both across collections and through time, mean that population-level analyses—for example for conservation or evolutionary studies—are entirely feasible, as long as the degraded nature of DNA is accounted for