Can Genetics Predict Response to Complex Behavioral Interventions? Evidence from a Genetic Analysis of the Fast Track Randomized Control Trial.

Early interventions are a preferred method for addressing behavioral problems in high-risk children, but often have only modest effects. Identifying sources of variation in intervention effects can suggest means to improve efficiency. One potential source of such variation is the genome. We conducted a genetic analysis of the Fast Track randomized control trial, a 10-year-long intervention to prevent high-risk kindergarteners from developing adult externalizing problems including substance abuse and antisocial behavior. We tested whether variants of the glucocorticoid receptor gene NR3C1 were associated with differences in response to the Fast Track intervention. We found that in European-American children, a variant of NR3C1 identified by the single-nucleotide polymorphism rs10482672 was associated with increased risk for externalizing psychopathology in control group children and decreased risk for externalizing psychopathology in intervention group children. Variation in NR3C1 measured in this study was not associated with differential intervention response in African-American children. We discuss implications for efforts to prevent externalizing problems in high-risk children and for public policy in the genomic era

Wind-related orientation patterns in diurnal, crepuscular and nocturnal high-altitude insect migrants

Most insect migrants fly at considerable altitudes (hundreds of meters above the ground) where they utilize fast-flowing winds to achieve rapid and comparatively long-distance transport. The nocturnal aerial migrant fauna has been well studied with entomological radars, and many studies have demonstrated that flight orientations are frequently grouped around a common direction in a range of nocturnal insect migrants. Common orientation typically occurs close to the downwind direction (thus ensuring that a large component of the insects' self-powered speed is directed downstream), and in nocturnal insects at least, the downwind headings are seemingly maintained by direct detection of wind-related turbulent cues. Despite being far more abundant and speciose, the day-flying windborne migrant fauna has been much less studied by radar; thus the frequency of wind-related common orientation patterns and the sensory mechanisms involved in their formation remain to be established. Here, we analyze a large dataset of >600,000 radar-detected "medium-sized" windborne insect migrants (body mass from 10 to 70 mg), flying hundreds of meters above southern UK, during the afternoon, in the period around sunset, and in the middle of the night. We found that wind-related common orientation was almost ubiquitous during the day (present in 97% of all “migration events” analyzed), and was also frequent at sunset (85%) and at night (81%). Headings were systematically offset to the right of the flow at night-time (as predicted from the use of turbulence cues for flow assessment), but there was no directional bias in the offsets during the day or at sunset. Orientation "performance” significantly increased with increasing flight altitude throughout the day and night. We conclude by discussing sensory mechanisms which most likely play a role in the selection and maintenance of wind-related flight headings

Environmental behaviour of iron and steel slags in coastal settings

\ua9 The Author(s) 2024. Iron and steel slags have a long history of both disposal and beneficial use in the coastal zone. Despite the large volumes of slag deposited, comprehensive assessments of potential risks associated with metal(loid) leaching from iron and steel by-products are rare for coastal systems. This study provides a national-scale overview of the 14 known slag deposits in the coastal environment of Great Britain (those within 100 m of the mean high-water mark), comprising geochemical characterisation and leaching test data (using both low and high ionic strength waters) to assess potential leaching risks. The seaward facing length of slag deposits totalled at least 76 km, and are predominantly composed of blast furnace (iron-making) slags from the early to mid-20th Century. Some of these form tidal barriers and formal coastal defence structures, but larger deposits are associated with historical coastal disposal in many former areas of iron and steel production, notably the Cumbrian coast of England. Slag deposits are dominated by melilite phases (e.g. gehlenite), with evidence of secondary mineral formation (e.g. gypsum, calcite) indicative of weathering. Leaching tests typically show lower element (e.g. Ba, V, Cr, Fe) release under seawater leaching scenarios compared to deionised water, largely ascribable to the pH buffering provided by the former. Only Mn and Mo showed elevated leaching concentrations in seawater treatments, though at modest levels (<3 mg/L and 0.01 mg/L, respectively). No significant leaching of potentially ecotoxic elements such as Cr and V (mean leachate concentrations <0.006 mg/L for both) were apparent in seawater, which micro-X-Ray Absorption Near Edge Structure (μXANES) analysis show are both present in slags in low valence (and low toxicity) forms. Although there may be physical hazards posed by extensive erosion of deposits in high-energy coastlines, the data suggest seawater leaching of coastal iron and steel slags in the UK is likely to pose minimal environmental risk

High-throughput screen identifies non inflammatory small molecule inducers of trained immunity

Trained immunity is characterized by epigenetic and metabolic reprogramming in response to specific stimuli. This rewiring can result in increased cytokine and effector responses to pathogenic challenges, providing nonspecific protection against disease. It may also improve immune responses to established immunotherapeutics and vaccines. Despite its promise for next-generation therapeutic design, most current understanding and experimentation is conducted with complex and heterogeneous biologically derived molecules, such as β-glucan or the Bacillus Calmette-Guérin (BCG) vaccine. This limited collection of training compounds also limits the study of the genes most involved in training responses as each molecule has both training and nontraining effects. Small molecules with tunable pharmacokinetics and delivery modalities would both assist in the study of trained immunity and its future applications. To identify small molecule inducers of trained immunity, we screened a library of 2,000 drugs and drug-like compounds. Identification of well-defined compounds can improve our understanding of innate immune memory and broaden the scope of its clinical applications. We identified over two dozen small molecules in several chemical classes that induce a training phenotype in the absence of initial immune activation—a current limitation of reported inducers of training. A surprising result was the identification of glucocorticoids, traditionally considered immunosuppressive, providing an unprecedented link between glucocorticoids and trained innate immunity. We chose seven of these top candidates to characterize and establish training activity in vivo. In this work, we expand the number of compounds known to induce trained immunity, creating alternative avenues for studying and applying innate immune training

Legacy iron and steel wastes in the UK: Extent, resource potential, and management futures

This is the author accepted manuscript. The final version is available on open access from Elsevier via the DOI in this recordThe iron and steel industry has a long tradition of bulk reuse of slags for a range of construction applications. Growing interest in recent years has seen slag resource recovery options extend to critical raw material recovery and atmospheric carbon capture. Full scale deployment of such technologies is currently limited in part by absent or partial inventories of slag deposit locations, data on composition, and volume estimates in many jurisdictions. This paper integrates a range of spatial information to compile a database of iron and steel slag deposits in mainland United Kingdom (UK) for the first time and evaluate the associated resource potential. Over 190 million tonnes of legacy iron and steel slag are present across current and former iron and steel working regions of the UK, with particular concentrations in the north west and north east of England, and central Scotland. While significant potential stockpiles of blast furnace and basic oxygen furnace slag could provide up to 0.9 million tonnes of vanadium and a cumulative carbon dioxide capture potential of 57–138 million tonnes, major management challenges for resource recovery are apparent. Over one third are located in close proximity to designated conservation areas which may limit resource recovery. Furthermore, land use analyses show that many of the sites have already been redeveloped for housing (nearly 30% urban cover). Deposits from recent decades in current or recently closed steel-working areas may have the greatest potential for resource recovery where such ambitions could be coupled with site restoration and regeneration efforts.Natural Environment Research Council (NERC)Engineering and Physical Sciences Research Council (EPSRC)Economic and Social Research Council (ESRC)UK Department for Business Energy and Industrial Strategy (BEIS

Quantitative fibronectin to help decision-making in women with symptoms of preterm labour (QUIDS) part 1: Individual participant data meta-analysis and health economic analysis.

INTRODUCTION: The aim of the QUIDS study is to develop a decision support tool for the management of women with symptoms and signs of preterm labour, based on a validated prognostic model using quantitative fetal fibronectin (qfFN) concentration, in combination with clinical risk factors. METHODS AND ANALYSIS: The study will evaluate the Rapid fFN 10Q System (Hologic, Marlborough, Massachusetts) which quantifies fFN in a vaginal swab. In part 1 of the study, we will develop and internally validate a prognostic model using an individual participant data (IPD) meta-analysis of existing studies containing women with symptoms of preterm labour alongside fFN measurements and pregnancy outcome. An economic analysis will be undertaken to assess potential cost-effectiveness of the qfFN prognostic model. The primary endpoint will be the ability of the prognostic model to rule out spontaneous preterm birth within 7 days. Six eligible studies were identified by systematic review of the literature and five agreed to provide their IPD (n=5 studies, 1783 women and 139 events of preterm delivery within 7 days of testing). ETHICS AND DISSEMINATION: The study is funded by the National Institute of Healthcare Research Health Technology Assessment (HTA 14/32/01). It has been approved by the West of Scotland Research Ethics Committee (16/WS/0068). PROSPERO REGISTRATION NUMBER: CRD42015027590. VERSION: Protocol version 2, date 1 November 2016

Study protocol: quantitative fibronectin to help decision-making in women with symptoms of preterm labour (QUIDS) part 2, UK Prospective Cohort Study.

INTRODUCTION: The aim of the QUIDS study is to develop a decision support tool for the management of women with symptoms and signs of preterm labour, based on a validated prognostic model using quantitative fetal fibronectin (fFN) concentration, in combination with clinical risk factors. METHODS AND ANALYSIS: The study will evaluate the Rapid fFN 10Q System (Hologic, Marlborough, Massachusetts, USA) which quantifies fFN in a vaginal swab. In QUIDS part 2, we will perform a prospective cohort study in at least eight UK consultant-led maternity units, in women with symptoms of preterm labour at 22+0 to 34+6 weeks gestation to externally validate a prognostic model developed in QUIDS part 1. The effects of quantitative fFN on anxiety will be assessed, and acceptability of the test and prognostic model will be evaluated in a subgroup of women and clinicians (n=30). The sample size is 1600 women (with estimated 96-192 events of preterm delivery within 7 days of testing). Clinicians will be informed of the qualitative fFN result (positive/negative) but be blinded to quantitative fFN result. Research midwives will collect outcome data from the maternal and neonatal clinical records. The final validated prognostic model will be presented as a mobile or web-based application. ETHICS AND DISSEMINATION: The study is funded by the National Institute of Healthcare Research Health Technology Assessment (HTA 14/32/01). It has been approved by the West of Scotland Research Ethics Committee (16/WS/0068). VERSION: Protocol V.2, Date 1 November 2016. TRIAL REGISTRATION NUMBER: ISRCTN 41598423andCPMS: 31277

Accuracy of magnetic resonance studies in the detection of chondral and labral lesions in femoroacetabular impingement : systematic review and meta-analysis

Background: Several types of Magnetic resonance imaging (MRI) are commonly used in imaging of femoroacetabular impingement (FAI), however till now there are no clear protocols and recommendations for each type. The aim of this meta-analysis is to detect the accuracy of conventional magnetic resonance imaging (cMRI), direct magnetic resonance arthrography (dMRA) and indirect magnetic resonance arthrography (iMRA) in the diagnosis of chondral and labral lesions in femoroacetabular impingement (FAI). Methods: A literature search was finalized on the 17th of May 2016 to collect all studies identifying the accuracy of cMRI, dMRA and iMRA in diagnosing chondral and labral lesions associated with FAI using surgical results (arthroscopic or open) as a reference test. Pooled sensitivity and specificity with 95% confidence intervals using a random-effects meta-analysis for MRI, dMRA and iMRA were calculated also area under receiver operating characteristic (ROC) curve (AUC) was retrieved whenever possible where AUC is equivocal to diagnostic accuracy. Results: The search yielded 192 publications which were reviewed according inclusion and exclusion criteria then 21 studies fulfilled the eligibility criteria for the qualitative analysis with a total number of 828 cases, lastly 12 studies were included in the quantitative meta-analysis. Meta-analysis showed that as regard labral lesions the pooled sensitivity, specificity and AUC for cMRI were 0.864, 0.833 and 0.88 and for dMRA were 0.91, 0.58 and 0.92. While in chondral lesions the pooled sensitivity, specificity and AUC for cMRI were 0.76, 0.72 and 0.75 and for dMRA were 0.75, 0.79 and 0.83, while for iMRA were sensitivity of 0.722 and specificity of 0.917. Conclusions: The present meta-analysis showed that the diagnostic test accuracy was superior for dMRA when compared with cMRI for detection of labral and chondral lesions. The diagnostic test accuracy was superior for labral lesions when compared with chondral lesions in both cMRI and dMRA. Promising results are obtained concerning iMRA but further studies still needed to fully assess its diagnostic accuracy

Prognostic markers in cancer: the evolution of evidence from single studies to meta-analysis, and beyond

In oncology, prognostic markers are clinical measures used to help elicit an individual patient's risk of a future outcome, such as recurrence of disease after primary treatment. They thus facilitate individual treatment choice and aid in patient counselling. Evidence-based results regarding prognostic markers are therefore very important to both clinicians and their patients. However, there is increasing awareness that prognostic marker studies have been neglected in the drive to improve medical research. Large protocol-driven, prospective studies are the ideal, with appropriate statistical analysis and clear, unbiased reporting of the methods used and the results obtained. Unfortunately, published prognostic studies rarely meet such standards, and systematic reviews and meta-analyses are often only able to draw attention to the paucity of good-quality evidence. We discuss how better-quality prognostic marker evidence can evolve over time from initial exploratory studies, to large protocol-driven primary studies, and then to meta-analysis or even beyond, to large prospectively planned pooled analyses and to the initiation of tumour banks. We highlight articles that facilitate each stage of this process, and that promote current guidelines aimed at improving the design, analysis, and reporting of prognostic marker research. We also outline why collaborative, multi-centre, and multi-disciplinary teams should be an essential part of future studies