Efficacy and moderators of efficacy of cognitive behavioural therapies with a trauma focus in children and adolescents: an individual participant data meta-analysis of randomised trials

Background: Existing clinical trials of cognitive behavioural therapies with a trauma focus (CBTs-TF) are underpowered to examine key variables that might moderate treatment effects. We aimed to determine the efficacy of CBTs-TF for young people, relative to passive and active control conditions, and elucidate putative individual-level and treatment-level moderators.   Methods: This was an individual participant data meta-analysis of published and unpublished randomised studies in young people aged 6−18 years exposed to trauma. We included studies identified by the latest UK National Institute of Health and Care Excellence guidelines (completed on Jan 29, 2018) and updated their search. The search strategy included database searches restricted to publications between Jan 1, 2018, and Nov 12, 2019; grey literature search of trial registries ClinicalTrials.gov and ISRCTN; preprint archives PsyArXiv and bioRxiv; and use of social media and emails to key authors to identify any unpublished datasets. The primary outcome was post-traumatic stress symptoms after treatment (<1 month after the final session). Predominantly, one-stage random-effects models were fitted. This study is registered with PROSPERO, CRD42019151954.   Findings: We identified 38 studies; 25 studies provided individual participant data, comprising 1686 young people (mean age 13·65 years [SD 3·01]), with 802 receiving CBTs-TF and 884 a control condition. The risk-of-bias assessment indicated five studies as low risk and 20 studies with some concerns. Participants who received CBTs-TF had lower mean post-traumatic stress symptoms after treatment than those who received the control conditions, after adjusting for post-traumatic stress symptoms before treatment (b=−13·17, 95% CI −17·84 to −8·50, p<0·001, τ2=103·72). Moderation analysis indicated that this effect of CBTs-TF on post-traumatic stress symptoms post-treatment increased by 0·15 units (b=−0·15, 95% CI −0·29 to −0·01, p=0·041, τ2=0·03) for each unit increase in pre-treatment post-traumatic stress symptoms.   Interpretation: This is the first individual participant data meta-analysis of young people exposed to trauma. Our findings support CBTs-TF as the first-line treatment, irrespective of age, gender, trauma characteristics, or carer involvement in treatment, with particular benefits for those with higher initial distress

Predicting attentional allocation in real-world environments: the need to investigate crossmodal semantic guidance

Real-world environments are multisensory, meaningful, and highly complex. To parse these environments in a highly efficient manner, a subset of this information must be selected both within and across modalities. However, the bulk of attention research has been conducted within sensory modalities, with a particular focus on vision. Visual attention research has made great strides, with over a century of research methodically identifying the underlying mechanisms that allow us to select critical visual information. Spatial attention, attention to features, and object-based attention have all been studied extensively. More recently, research has established semantics (meaning) as a key component to allocating attention in real-world scenes, with the meaning of an item or environment affecting visual attentional selection. However, a full understanding of how semantic information modulates real-world attention requires studying more than vision in isolation. The world provides semantic information across all senses, but with this extra information comes greater complexity. Here, we summarize visual attention (including semantic-based visual attention), crossmodal attention, and argue for the importance of studying crossmodal semantic guidance of attention

Probing the mechanism of the dedicated NO sensor [4Fe-4S] NsrR: the effect of cluster ligand environment

NsrR from Streptomyces coelicolor is a bacterial nitric oxide (NO) sensor/nitrosative stress regulator as its primary function, and has been shown to have differential response at low, mid, and high levels of NO. These must correspond to discrete structural changes at the protein-bound [4Fe-4S] cluster in response to stepwise nitrosylation of the cluster. We have investigated the effect of the monohapto carboxylate ligand in the site differentiated [4Fe-4S] cluster cofactor of the protein NsrR on modulating its reactivity to NO with a focus on indentifying mechanistic intermediates. We have prepared a synthetic model [4Fe-4S] cluster complex with tripodal ligand and one single site differentiated site occupied by either thiolate or carboxylate ligand. We report here the mechanistic details of sequential steps of nitrosylation as observed by ESI MS and IR spectroscopy. Parallel non-denaturing mass spectrometry analyses were performed using site-differentiated variants of NsrR with the native aspartic acid, cysteine, or alanine in the position of the forth ligand to the cluster. A mono-nitrosylated synthetic [4Fe-4S] cluster was observed for the first time in a biologically-relevant thiolate-based coordination environment. Combined synthetic and protein data give unprecedented clarity in the modulation of nitrosylation of a [4Fe-4S] cluster

The Oxford Handbook of Human Symbolic Evolution

The biological and neurological capacity to symbolize, and the products of behavioral, cognitive, sociocultural, linguistic, and technological uses of symbols (symbolism), are fundamental to every aspect of human life. The Oxford Handbook of Human Symbolic Evolution explores the origins of our characteristically human abilities - our ability to speak, create images, play music, and read and write. The book investigates how symbolization evolved in human evolution and how symbolism is expressed across the various areas of human life. The field is intrinsically interdisciplinary - considering findings from fossil studies, scientific research from primatology, developmental psychology, and of course linguistics. Written by world leading experts, thirty-nine topical chapters are grouped into six thematic parts that respectively focus on epistemological, psychological, anthropological, ethological, linguistic, and social-technological aspects of human symbolic evolution. The handbook presents an in-depth but comprehensive and interdisciplinary overview of the of the state of the art in the science of human symbolic evolution. This work will be of interest to academics and students active in all fields contributing to the study of human evolution

EGFR/MAPK signaling pathway acts as a potential therapeutic target for sulforaphane-rescued heart tube malformation induced by various concentrations of PhIP exposure

Background: 2-Amino-1-methyl-6-phenylimidazo [4,5-b] pyrimidine (PhIP) is a known carcinogen generated mainly from cooking meat and environmental pollutants. It is worth exploring the potential of natural small-molecule drugs to protect against adverse effects on embryonic development. Purpose: In this study, we investigated the potential toxicological effects of PhIP on embryonic heart tube formation and the effect of Sulforaphane (SFN) administration on the anti-toxicological effects of PhIP on embryonic cardiogenesis. Study design and methods: First, the chicken embryo model was used to investigate the different phenotypes of embryonic heart tubes induced by various concentrations of PhIP exposure. We also proved that SFN rescues PhIP-induced embryonic heart tube malformation. Second, immunofluorescence, western blot, Polymerase Chain Reaction (PCR) and flow cytometry experiments were employed to explore the mechanisms by which SFN protects cardiac cells from oxidative damage in the presence of PhIP. We used RNA-seq analysis, molecular docking, in situ hybridization, cellular thermal shift assay and solution nuclear magnetic resonance spectroscopy to explore whether SFN protects cardiogenesis through the EGFR/MAPK signaling pathway. Results: The study showed that PhIP might dose-dependently interfere with the C-looping heart tube (mild) or the fusion of a pair of bilateral endocardial tubes (severe) in chick embryos, while SFN administration prevented cardiac cells from oxidative damage in the presence of high-level PhIP. Furthermore, we found that excessive reactive oxygen species (ROS) production and subsequent apoptosis were not the principal mechanisms by which low-level PhIP induced malformation of heart tubes. This is due to PhIP-disturbed Mitogen-activated protein kinase (MAPK) signaling pathway could be corrected by SFN administration. Conclusions: This study provided novel insight that PhIP exposure could increase the risk of abnormalities in early cardiogenesis and that SFN could partially rescue various concentrations of PhIP-induced abnormal heart tube formation by targeting EGFR and mediating EGFR/MAPK signaling pathways

Cover crops in cereal rotations: A quantitative review

The use of cover crops in conventional agriculture is not fully accepted. This is probably due to the substantial variability in outcomes reported and is complicated by the conflation of a host of techniques under the same umbrella term, often without the appropriate benchmarking. This review addresses these issues with a quantitative synthesis of the last 11 years of research on cover crops in cereal rotations in temperate climates. Strict inclusion criteria focus the scope of the review to studies offering comparisons with an equally treated bare fallow control. Coded variables included duration, fertiliser, irrigation and tillage regime, cover and cash crop type and termination mode. The result is a quantitative review of 100 parameters covered by multiple publications, with an additional overview on 124 parameters covered by single studies. The investigated response variables range from microbiology and chemical parameters to hydrology, soil structure, weed and pest control and crop performance. Relevant trends were identified regarding strengths and weaknesses of cover cropping, with predictions formulated about the conditions necessary for their successful implementation. Additionally, trade-offs specific to cover cropping are discussed, together with the variables at play in determining the final balance of net gain or loss. The main findings are that cash crop performance is best enhanced by legume cover crops and in low-tillage regimes, and the soil biotic effects of cover crops tend to be short-lived, fading by the end of the season. Most importantly, a positive effect of cover cropping on soil carbon is potentially offset by increased GHG emissions

Maximum tolerable daily dose of mirror movement therapy ankle exercises after stroke: an early phase dose screening study

Background: Mirror movement therapy may reduce lower limb motor impairment after stroke, but the optimal dose is unknown. Objective: identify the maximum tolerable dose a day (MTD) of lower limb mirror movement therapy Design: 3+3 cohort rule-based, dose escalation/de-escalation study. After undertaking baseline measures participants performed mirror movement therapy for 14 consecutive days. Participants then undertook outcome measures. Cohort One trained for 15 minutes daily. Subsequent cohorts exercised at a dose set according to pre-set rules and the modified Fibonacci sequence. The study stopped when the difference between set doses for consecutive cohorts was 10% or less. Setting: Participants’ homes (intervention) and a movement analysis laboratory (measures). Participants: Adults discharged from statutory stroke rehabilitation services. Intervention: Mirror movement therapy ankle exercises. Outcome measures: Motricity Index (primary) and bilateral time symmetry from movement onset to peak activation of Tibialis Anterior muscles during standardised sit- to-stand (secondary). Results: Five cohorts of three participants were included (n=15). Mean (SD) age and time after stroke were 61 (9) years and 35 (42) months respectively. Set daily doses for the five cohorts were: 15, 30, 50, 40 then 35 minutes. The set dose for a subsequent cohort (six) would have been 38 minutes thus the difference from cohort five would have been three minutes i.e., 9% different. Therefore, the study stopped Conclusion: The identified MTD of lower limb mirror therapy was 35 minutes daily when frequency was set at seven days a week and duration as two weeks

EULAR recommendations for the management of systemic lupus erythematosus: 2023 update

Objectives: To update the EULAR recommendations for the management of systemic lupus erythematosus (SLE) based on emerging new evidence. Methods: An international Task Force formed the questions for the systematic literature reviews (January 2018-December 2022), followed by formulation and finalisation of the statements after a series of meetings. A predefined voting process was applied to each overarching principle and recommendation. Levels of evidence and strengths of recommendation were assigned, and participants finally provided their level of agreement with each item. Results: The Task Force agreed on 5 overarching principles and 13 recommendations, concerning the use of hydroxychloroquine (HCQ), glucocorticoids (GC), immunosuppressive drugs (ISDs) (including methotrexate, mycophenolate, azathioprine, cyclophosphamide (CYC)), calcineurin inhibitors (CNIs, cyclosporine, tacrolimus, voclosporin) and biologics (belimumab, anifrolumab, rituximab). Advice is also provided on treatment strategies and targets of therapy, assessment of response, combination and sequential therapies, and tapering of therapy. HCQ is recommended for all patients with lupus at a target dose 5 mg/kg real body weight/day, considering the individual's risk for flares and retinal toxicity. GC are used as 'bridging therapy' during periods of disease activity; for maintenance treatment, they should be minimised to equal or less than 5 mg/day (prednisone equivalent) and, when possible, withdrawn. Prompt initiation of ISDs (methotrexate, azathioprine, mycophenolate) and/or biological agents (anifrolumab, belimumab) should be considered to control the disease and facilitate GC tapering/discontinuation. CYC and rituximab should be considered in organ-threatening and refractory disease, respectively. For active lupus nephritis, GC, mycophenolate or low-dose intravenous CYC are recommended as anchor drugs, and add-on therapy with belimumab or CNIs (voclosporin or tacrolimus) should be considered. Updated specific recommendations are also provided for cutaneous, neuropsychiatric and haematological disease, SLE-associated antiphospholipid syndrome, kidney protection, as well as preventative measures for infections, osteoporosis, cardiovascular disease. Conclusion: The updated recommendations provide consensus guidance on the management of SLE, combining evidence and expert opinion