Topographic and hydrodynamic controls on barrier retreat and preservation: An example from Dogger Bank, North Sea

Barrier retreat can occur due to in-place drowning, overstepping or rollover, depending on the interplay of controls such as sea-level rise, sediment supply, coastal hydrodynamic regime and topography. Offshore sedimentary archives of barriers active during rapid Holocene sea-level rise provide important records of marine transgression, which are vital analogues to support appropriate mitigation strategies for future coastal realignment under projected relative sea-level rise scenarios. This study analyses the sedimentary archive at Dogger Bank, which is a formerly-glaciated area in the North Sea. Dogger Bank experienced marine transgression due to Early Holocene rapid relative sea-level rise. An integrated dataset of vibrocores and high-resolution seismic reflection data permits a stratigraphic framework to be established, which reveals the buried coastal geomorphology of the southern Dogger Bank for the first time. A transgressive stratigraphy was identified, comprising a topographically complicated basal glacial and terrestrial succession, overlain by two phases of barrier and tidal mudflat deposition, prior to shallow marine sedimentation. Barrier phase A was a recurved barrier drowned in place, and discontinuously overstepped to barrier phase B, which experienced continuous overstepping. By linking barrier elevations to relative sea-level curves, the timing of each barrier phase was established. Both barrier phases retreated during periods of rapid sea-level rise with abundant sediment supply. Coastal hydrodynamics (increasing wave energy) and antecedent topography with spatially variable accommodation are suggested to be the main reason for differing retreat mechanisms, rather than the rate of sea-level rise. Antecedent coastal geomorphology plays a critical role in erosional and depositional patterns during transgression, and therefore on the timing, rate and location of marine inundation, which needs to be included in models that aim to forecast hazards in coastal areas

Relative Impact of Pain and Fatigue on Work Productivity in Patients with Rheumatoid Arthritis from the RA-BEAM Baricitinib Trial

Introduction To explore the relationship of pain and fatigue with daily activity and work productivity in rheumatoid arthritis (RA) patients from the baricitinib clinical trial, RA-BEAM. Methods In RA-BEAM, a double-blind phase 3 study, patients were randomized 3:3:2 to placebo (n = 488), baricitinib 4 mg once daily (n = 487), or adalimumab 40 mg biweekly (n = 330) with background methotrexate. The Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F) measured fatigue and the pain visual analog scale (0–100 mm) assessed pain. Work Productivity and Activity Impairment Questionnaire-RA measured daily activity and work productivity. At weeks 12 and 24, pain was assessed using pain reduction (< 30%, 30% to < 50%, ≥ 50%) and overall pain score; clinically relevant FACIT-F changes were assessed by values < 3.56 and ≥ 3.56 and the FACIT-F normative value score (< 40.1, ≥ 40.1). Pairwise comparisons between pain/fatigue reduction groups were assessed using ANCOVA with pooled data on daily activity and work productivity. A mediator analysis with pain, fatigue, and disease activity measured their contribution to daily activity and work productivity. Data were pooled from all patients for most analyses, and baricitinib-treated patients were assessed as a sensitivity analysis. Results Reductions in pain (≥ 50%) and fatigue (≥ 3.56) had significant (p ≤ 0.001) effects on daily activity and work productivity improvement at weeks 12 and 24. Reductions in pain, fatigue, and disease activity accounted for most of the improvements in daily activity and work productivity. At the lowest levels of remaining pain (≤ 10 mm) at weeks 12 and 24, however, fatigue did not appear to impact work productivity. Similar trends were observed with baricitinib-treated patients. Conclusions Reductions in pain and fatigue were associated with improved daily activity and work productivity for all RA patients and for baricitinib-treated patients in RA-BEAM

Comparative effectiveness of improvement in pain and physical function for baricitinib versus adalimumab, tocilizumab, and tofacitinib monotherapies in rheumatoid arthritis patients who are naïve to treatment with biologic or conventional synthetic disease-modifying antirheumatic drugs: a matching-adjusted indirect comparison

Objective To compare improvement in pain and physical function for patients treated with baricitinib, adalimumab, tocilizumab and tofacitinib monotherapy from randomised, methotrexate (MTX)-controlled trials in conventional synthetic disease-modifying antirheumatic drugs (csDMARDs)/biologic (bDMARD)-naïve RA patients using matching-adjusted indirect comparisons (MAICs). Methods Data were from Phase III trials on patients receiving monotherapy baricitinib, tocilizumab, adalimumab, tofacitinib or MTX. Pain was assessed using a visual analogue scale (0–100 mm) and physical function using the Health Assessment Questionnaire-Disability Index (HAQ-DI). An MAIC based on treatment-arm matching, an MAIC with study-level matching and Bucher’s method without matching compared change in outcomes between therapies. Matching variables included age, gender, baseline disease activity and baseline value of outcome measure. Results With all methods, greater improvements were observed in pain and HAQ-DI at 6 months for baricitinib compared with adalimumab and tocilizumab (p<0.05). Differences in treatment effects (TEs) favouring baricitinib for pain VAS for treatment-arm matching, study-level matching and Bucher’s method, respectively, were −12, −12 and −12 for baricitinib versus adalimumab and −7, −7 and −9 for baricitinib versus tocilizumab; the difference in TEs for HAQ-DI was −0.28, −0.28 and −0.30 for adalimumab and −0.23, −0.23 and −0.26 for tocilizumab. For baricitinib versus tofacitinib, no statistically significant differences for pain improvement were observed except with one of the three methods (Bucher method) and none for HAQ-DI. Conclusions Results suggest greater pain reduction and improved physical function for baricitinib monotherapy compared with tocilizumab and adalimumab monotherapy. No statistically significant differences in pain reduction and improved physical function were observed between baricitinib and tofacitinib with the MAIC analyses

Correction: External validation of risk prediction models for incident colorectal cancer using UK Biobank.

An amendment to this paper has been published and can be accessed via a link at the top of the paper

Human cryptochrome exhibits light-dependent magnetosensitivity

Humans are not believed to have a magnetic sense, even though many animals use the Earth's magnetic field for orientation and navigation. One model of magnetosensing in animals proposes that geomagnetic fields are perceived by light-sensitive chemical reactions involving the flavoprotein cryptochrome (CRY). Here we show using a transgenic approach that human CRY2, which is heavily expressed in the retina, can function as a magnetosensor in the magnetoreception system of Drosophila and that it does so in a light-dependent manner. The results show that human CRY2 has the molecular capability to function as a light-sensitive magnetosensor and reopen an area of sensory biology that is ready for further exploration in humans

Protocadherin 15 suppresses oligodendrocyte progenitor cell proliferation and promotes motility through distinct signalling pathways

Oligodendrocyte progenitor cells (OPCs) express protocadherin 15 (Pcdh15), a member of the cadherin superfamily of transmembrane proteins. Little is known about the function of Pcdh15 in the central nervous system (CNS), however, Pcdh15 expression can predict glioma aggression and promote the separation of embryonic human OPCs immediately following a cell division. Herein, we show that Pcdh15 knockdown significantly increases extracellular signal-related kinase (ERK) phosphorylation and activation to enhance OPC proliferation in vitro. Furthermore, Pcdh15 knockdown elevates Cdc42-Arp2/3 signalling and impairs actin kinetics, reducing the frequency of lamellipodial extrusion and slowing filopodial withdrawal. Pcdh15 knockdown also reduces the number of processes supported by each OPC and new process generation. Our data indicate that Pcdh15 is a critical regulator of OPC proliferation and process motility, behaviours that characterise the function of these cells in the healthy CNS, and provide mechanistic insight into the role that Pcdh15 might play in glioma progression

Achieving Pain Control in Rheumatoid Arthritis with Baricitinib or Adalimumab Plus Methotrexate: Results from the RA-BEAM Trial

The purpose of the study was to assess the proportion of patients who achieve pain relief thresholds, the time needed to reach the thresholds, and the relationship between pain and inflammation among patients with rheumatoid arthritis (RA) and an inadequate response to methotrexate in RA-BEAM (NCT0170358). A randomized, double-blind trial was conducted, comparing baricitinib (N = 487), adalimumab (N = 330), and placebo (N = 488) plus methotrexate. Pain was evaluated by patient’s assessment on a 0–100 mm visual analog scale (VAS). The following were assessed through a 24-week placebo-controlled period: the proportion of patients who achieved ≥30%, ≥50%, and ≥70% pain relief, the time to achieve these pain relief thresholds, remaining pain (VAS ≤ 10 mm, ≤20 mm, or ≤40 mm), and the relationship between inflammation markers and pain relief. Baricitinib-treated patients were more likely (p < 0.05) to achieve ≥30%, ≥50%, and ≥70% pain relief than placebo- and adalimumab-treated patients, as early as Week 1 vs. placebo and at Week 4 vs. adalimumab. A greater proportion of baricitinib-treated patients achieved ≤20 mm or ≤40 mm remaining pain vs. placebo- and adalimumab-treated patients. Baricitinib-treated patients tended to demonstrate consistent pain relief independent of levels of inflammation control. In RA patients with an inadequate response to methotrexate, baricitinib provided greater and more rapid pain relief than adalimumab and placebo. Analyses suggest the relationship between inflammation and pain may be different for baricitinib and adalimumab treatments

Periaxonal and nodal plasticities modulate action potential conduction in the adult mouse brain

Central nervous system myelination increases action potential conduction velocity. However, it is unclearhow myelination is coordinated to ensure the temporally precise arrival of action potentials and facilitate information processing within cortical and associative circuits. Here, we show that myelin sheaths, supportedby mature oligodendrocytes, remain plastic in the adult mouse brain and undergo subtle structural modifications to influence action potential conduction velocity. Repetitive transcranial magnetic stimulation andspatial learning, two stimuli that modify neuronal activity, alter the length of the nodes of Ranvier and thesize of the periaxonal space within active brain regions. This change in the axon-glial configuration is independent of oligodendrogenesis and robustly alters action potential conduction velocity. Because aptitudein the spatial learning task was found to correlate with action potential conduction velocity in the fimbriafornix pathway, modifying the axon-glial configuration may be a mechanism that facilitates learning in theadult mouse brain

Read-through Activation of Transcription in a Cellular Genomic Context

Read-through transcription from the adjacent E1a gene region is required for wild-type (wt) activity of the downstream adenovirus E1b promoter early after infection (read-through activation). However, whether a cellular chromosomal template can support read-through activation is not known. To address this issue, read-through activation was evaluated in the context of stably expressed templates in transfected cells. Inhibition of read-through transcription by insertion of a transcription termination sequence between the E1a and E1b promoters reduced downstream gene expression from stably integrated templates. The results indicate that the mechanism of read-through activation does not depend on the structure of early adenovirus nucleoprotein complexes, a structure that is likely to be different from that of cellular chromatin. Accordingly, this regulatory interaction could participate in the coordinated control of the expression of closely linked cellular genes