Radiocarbon Chronologies and Extinction Dynamics of the Late Quaternary Mammalian Megafauna of the Taimyr Peninsula, Russian Federation

This paper presents 75 new radiocarbon dates based on late Quaternary mammal remains recovered from eastern Taimyr Peninsula and adjacent parts of the northern Siberian lowlands, Russian Federation, including specimens of woolly mammoth (Mammuthus primigenius), steppe bison (Bison priscus), muskox (Ovibos moschatus), moose (Alces alces), reindeer (Rangifer tarandus), horse (Equus caballus) and wolf (Canis lupus). New evidence permits reanalysis of megafaunal extinction dynamics in the Asian high Arctic periphery. Increasingly, radiometric records of individual species show evidence of a gap at or near the Pleistocene/Holocene boundary (PHB). In the past, the PHB gap was regarded as significant only when actually terminal, i.e., when it marked the apparent ‘‘last’’ occurrence of a species (e.g., current ‘‘last’’ occurrence date for woolly mammoth in mainland Eurasia is 9600 yr BP). However, for high Arctic populations of horses and muskoxen the gap marks an interruption rather than extinction, because their radiocarbon records resume, nearly simultaneously, much later in the Holocene. Taphonomic effects, ΔC14 flux, and biased sampling are unlikely explanations for these hiatuses. A possible explanation is that the gap is the signature of an event, of unknown nature, that prompted the nearly simultaneous crash of many megafaunal populations in the high Arctic and possibly elsewhere in Eurasia.

Automated coronary artery calcification scoring in non-gated chest CT: Agreement and reliability

Objective: To determine the agreement and reliability of fully automated coronary artery calcium (CAC) scoring in a lung cancer screening population. Materials and Methods: 1793 low-dose chest CT scans were analyzed (non-contrast-enhanced, non-gated). To establish the reference standard for CAC, first automated calcium scoring was performed using a preliminary version of a method employing coronary calcium atlas and machine learning approach. Thereafter, each scan was inspected by one of four trained raters. When needed, the raters corrected initially automaticity-identified results. In addition, an independent observer subsequently inspected manually corrected results and discarded scans with gross segmentation errors. Subsequently, fully automatic coronary calcium scoring was performed. Agatston score, CAC volume and number of calcifications were computed. Agreement was determined by calculating proportion of agreement and examining Bland-Altman plots. Reliability was determined by calculating linearly weighted kappa (κ) for Agatston strata and intraclass correlation coefficient (ICC) for continuous values. Results: 44 (2.5%) scans were excluded due to metal artifacts or gross segmentation errors. In the remaining 1749 scans, median Agatston score was 39.6 (P25-P75:0-345.9), median volume score was 60.4 mm3 (P25-P75:0-361.4) and median number of calcifications was 2 (P25-P75:0-4) for the automated scores. The k demonstrated very good reliability (0.85) for Agatston risk categories between the automated and reference scores. The Bland-Altman plots showed underestimation of calcium score values by automated quantification. Median difference was 2.5 (p25-p75:0.0-53.2) for Agatston score, 7.6 (p25-p75:0.0-94.4) for CAC volume and 1 (p25-p75:0-5) for number of calcifications. The ICC was very good for Agatston score (0.90), very good for calcium volume (0.88) and good for number of calcifications (0.64). Discussion: Fully automated coron

Airway tapering: an objective image biomarker for bronchiectasis

Purpose: To estimate airway tapering in control subjects and to assess the usability of tapering as a bronchiectasis biomarker in paediatric populations. Methods: Airway tapering values were semi-automatically quantified in 156 children with control CTs collected in the Normal Chest CT Study Group. Airway tapering as a biomarker for bronchiectasis was assessed on spirometer-guided inspiratory CTs from 12 patients with bronchiectasis and 12 age- and sex-matched controls. Semi-automatic image analysis software was used to quantify intra-branch tapering (reduction in airway diameter along the branch), inter-branch tapering (reduction in airway diameter before and after bifurcation) and airway-artery ratios on chest CTs. Biomarkers were further stratified in small, medium and large airways based on three equal groups of the accompanying vessel size. Results: Control subjects showed intra-branch tapering of 1% and inter-branch tapering of 24–39%. Subjects with bronchiectasis showed significantly reduced intra-branch of 0.8% and inter-branch tapering of 19–32% and increased airway–artery ratios compared with controls (p < 0.01). Tapering measurements were significantly different between diseased and controls across all airway sizes. Difference in airway–artery ratio was only significant in small airways. Conclusion: Paediatric normal values for airway tapering were established in control subjects. Tapering showed to be a promising biomarker for bronchiectasis as subjects with bronchiectasis show significantly less airway tapering across all airway sizes compared with controls. Detecting les

Progestogens to prevent preterm birth in twin pregnancies: an individual participant data meta-analysis of randomized trials

<p>Abstract</p> <p>Background</p> <p>Preterm birth is the principal factor contributing to adverse outcomes in multiple pregnancies. Randomized controlled trials of progestogens to prevent preterm birth in twin pregnancies have shown no clear benefits. However, individual studies have not had sufficient power to evaluate potential benefits in women at particular high risk of early delivery (for example, women with a previous preterm birth or short cervix) or to determine adverse effects for rare outcomes such as intrauterine death.</p> <p>Methods/design</p> <p>We propose an individual participant data meta-analysis of high quality randomized, double-blind, placebo-controlled trials of progestogen treatment in women with a twin pregnancy. The primary outcome will be adverse perinatal outcome (a composite measure of perinatal mortality and significant neonatal morbidity). Missing data will be imputed within each original study, before data of the individual studies are pooled. The effects of 17-hydroxyprogesterone caproate or vaginal progesterone treatment in women with twin pregnancies will be estimated by means of a random effects log-binomial model. Analyses will be adjusted for variables used in stratified randomization as appropriate. Pre-specified subgroup analysis will be performed to explore the effect of progestogen treatment in high-risk groups.</p> <p>Discussion</p> <p>Combining individual patient data from different randomized trials has potential to provide valuable, clinically useful information regarding the benefits and potential harms of progestogens in women with twin pregnancy overall and in relevant subgroups.</p

The GPR120 agonist TUG‐891 promotes metabolic health by stimulating mitochondrial respiration in brown fat

Brown adipose tissue (BAT) activation stimulates energy expenditure in human adults, which makes it an attractive target to combat obesity and related disorders. Recent studies demonstrated a role for G protein‐coupled receptor 120 (GPR120) in BAT thermogenesis. Here, we investigated the therapeutic potential of GPR120 agonism and addressed GPR120‐mediated signaling in BAT. We found that activation of GPR120 by the selective agonist TUG‐891 acutely increases fat oxidation and reduces body weight and fat mass in C57Bl/6J mice. These effects coincided with decreased brown adipocyte lipid content and increased nutrient uptake by BAT, confirming increased BAT activity. Consistent with these observations, GPR120 deficiency reduced expression of genes involved in nutrient handling in BAT. Stimulation of brown adipocytes in vitro with TUG‐891 acutely induced O2 consumption, through GPR120‐dependent and GPR120‐independent mechanisms. TUG‐891 not only stimulated GPR120 signaling resulting in intracellular calcium release, mitochondrial depolarization, and mitochondrial fission, but also activated UCP1. Collectively, these data suggest that activation of brown adipocytes with the GPR120 agonist TUG‐891 is a promising strategy to increase lipid combustion and reduce obesity

STRIDER (Sildenafil TheRapy in dismal prognosis early onset fetal growth restriction): An international consortium of randomised placebo-controlled trials

Background: Severe, early-onset fetal growth restriction due to placental insufficiency is associated with a high risk of perinatal mortality and morbidity with long-lasting sequelae. Placental insufficiency is the result of abnormal formation and function of the placenta with inadequate remodelling of the maternal spiral arteries. There is currently no effective therapy available. Some evidence suggests sildenafil citrate may improve uteroplacental blood flow, fetal growth, and meaningful infant outcomes. The objective of the Sildenafil TheRapy In Dismal prognosis Early onset fetal growth Restriction (STRIDER) collaboration is to evaluate the effectiveness of sildenafil versus placebo in achieving healthy perinatal survival through the conduct of randomised clinical trials and systematic review including individual patient data meta-analysis.  Methods: Five national/bi-national multicentre randomised placebo-controlled trials have been launched. Women with a singleton pregnancy between 18 and 30 weeks with severe fetal growth restriction of likely placental origin, and where the likelihood of perinatal death/severe morbidity is estimated to be significant are included. Participants will receive either sildenafil 25 mg or matching placebo tablets orally three times daily from recruitment to 32 weeks gestation.  Discussion: The STRIDER trials were conceived and designed through international collaboration. Although the individual trials have different primary outcomes for reasons of sample size and feasibility, all trials will collect a standard set of outcomes including survival without severe neonatal morbidity at time of hospital discharge. This is a summary of all the STRIDER trial protocols and provides an example of a prospectively planned international clinical research collaboration. All five individual trials will contribute to a pre-planned systematic review of the topic including individual patient data meta-analysis

Protocol for developing a core outcome set for male infertility research:an international consensus development study

Abstract STUDY QUESTION We aim to develop, disseminate and implement a minimum data set, known as a core outcome set, for future male infertility research. WHAT IS KNOWN ALREADY Research into male infertility can be challenging to design, conduct and report. Evidence from randomized trials can be difficult to interpret and of limited ability to inform clinical practice for numerous reasons. These may include complex issues, such as variation in outcome measures and outcome reporting bias, as well as failure to consider the perspectives of men and their partners with lived experience of fertility problems. Previously, the Core Outcome Measure for Infertility Trials (COMMIT) initiative, an international consortium of researchers, healthcare professionals and people with fertility problems, has developed a core outcome set for general infertility research. Now, a bespoke core outcome set for male infertility is required to address the unique challenges pertinent to male infertility research. STUDY DESIGN, SIZE, DURATION Stakeholders, including healthcare professionals, allied healthcare professionals, scientists, researchers and people with fertility problems, will be invited to participate. Formal consensus science methods will be used, including the modified Delphi method, modified Nominal Group Technique and the National Institutes of Health’s consensus development conference. PARTICIPANTS/MATERIALS, SETTING, METHODS An international steering group, including the relevant stakeholders outlined above, has been established to guide the development of this core outcome set. Possible core outcomes will be identified by undertaking a systematic review of randomized controlled trials evaluating potential treatments for male factor infertility. These outcomes will be entered into a modified Delphi method. Repeated reflection and re-scoring should promote convergence towards consensus outcomes, which will be prioritized during a consensus development meeting to identify a final core outcome set. We will establish standardized definitions and recommend high-quality measurement instruments for individual core outcomes. STUDY FUNDING/COMPETING INTEREST(S) This work has been supported by the Urology Foundation small project award, 2021. C.L.R.B. is the recipient of a BMGF grant and received consultancy fees from Exscentia and Exceed sperm testing, paid to the University of Dundee and speaking fees or honoraria paid personally by Ferring, Copper Surgical and RBMO. S.B. received royalties from Cambridge University Press, Speaker honoraria for Obstetrical and Gynaecological Society of Singapore, Merk SMART Masterclass and Merk FERRING Forum, paid to the University of Aberdeen. Payment for leadership roles within NHS Grampian, previously paid to self, now paid to University of Aberdeen. An Honorarium is received as Editor in Chief of Human Reproduction Open. M.L.E. is an advisor to the companies Hannah and Ro. B.W.M. received an investigator grant from the NHMRC, No: GNT1176437 is a paid consultant for ObsEva and has received research funding from Ferring and Merck. R.R.H. received royalties from Elsevier for a book, consultancy fees from Glyciome, and presentation fees from GryNumber Health and Aytu Bioscience. Aytu Bioscience also funded MiOXYS systems and sensors. Attendance at Fertility 2020 and Roadshow South Africa by Ralf Henkel was funded by LogixX Pharma Ltd. R.R.H. is also Editor in Chief of Andrologia and has been an employee of LogixX Pharma Ltd. since 2020. M.S.K. is an associate editor with Human Reproduction Open. K.Mc.E. received an honoraria for lectures from Bayer and Pharmasure in 2019 and payment for an ESHRE grant review in 2019. His attendance at ESHRE 2019 and AUA 2019 was sponsored by Pharmasure and Bayer, respectively. The remaining authors declare no competing interests. TRIAL REGISTRATION NUMBER Core Outcome Measures in Effectiveness Trials (COMET) initiative registration No: 1586. Available at www.comet-initiative.org/Studies/Details/1586. TRIAL REGISTRATION DATE N/A. DATE OF FIRST PATIENT’S ENROLMENT N/A

Ultrafiltration and size exclusion chromatography combined with asymmetrical-flow field-flow fractionation for the isolation and characterisation of extracellular vesicles from urine

Extracellular vesicles (EVs) have a great potential in clinical applications. However, their isolation from different bodily fluids and their characterisation are currently not optimal or standardised. Here, we report the results of examining the performance of ultrafiltration combined with size exclusion chromatography (UF-SEC) to isolate EVs from urine. The results reveal that UF-SEC is an efficient method and provides high purity. Furthermore, we introduce asymmetrical-flow field-flow fractionation coupled with a UV detector and multi-angle light-scattering detector (AF4/UV-MALS) as a characterisation method and compare it with current methods. We demonstrate that AF4/UV-MALS is a straightforward and reproducible method for determining size, amount and purity of isolated urinary EVs