Genomic properties of variably methylated retrotransposons in mouse

Background: Transposable elements (TEs) are enriched in cytosine methylation, preventing their mobility within the genome. We previously identified a genome-wide repertoire of candidate intracisternal A particle (IAP) TEs in mice that exhibit interindividual variability in this methylation (VM-IAPs) with implications for genome function. Results: Here we validate these metastable epialleles and discover a novel class that exhibit tissue specificity (tsVM-IAPs) in addition to those with uniform methylation in all tissues (constitutive- or cVM-IAPs); both types have the potential to regulate genes in cis . Screening for variable methylation at other TEs shows that this phenomenon is largely limited to IAPs, which are amongst the youngest and most active endogenous retroviruses. We identify sequences enriched within cVM-IAPs, but determine that these are not sufficient to confer epigenetic variability. CTCF is enriched at VM-IAPs with binding inversely correlated with DNA methylation. We uncover dynamic physical interactions between cVM-IAPs with low methylation ranges and other genomic loci, suggesting that VM-IAPs have the potential for long-range regulation. Conclusion: Our findings indicate that a recently evolved interplay between genetic sequence, CTCF binding, and DNA methylation at young TEs can result in inter-individual variability in transcriptional outcomes with implications for phenotypic variation

Neonatal outcomes associated with time from a high fetal blood lactate concentration to operative delivery

Introduction: Adjunctive technologies to cardiotocography intend to increase the specificity of the diagnosis of fetal hypoxia. If correctly diagnosed, time to delivery could affect neonatal outcome. In the present study, we aimed to investigate the effect of time from when fetal distress is indicated by a high fetal blood sample (FBS) lactate concentration to operative delivery on the risk of adverse neonatal outcomes. Material and methods: We conducted a prospective observational study. Deliveries with a singleton fetus in cephalic presentation at 36+0weeks of gestation or later were included. Adverse neonatal outcomes, related to decision-to-delivery interval (DDI), were investigated in operative deliveries indicated by an FBS lactate concentration of at least 4.8 mmol/L. We applied logistic regression to estimate crude and adjusted odds ratios (aOR) of various adverse neonatal outcomes, with associated 95% confidence intervals (CI), for a DDI exceeding 20 minutes, compared with a DDI of 20 minutes or less. ClinicalTrials.gov Identifier: NCT04779294. Results: The main analysis included 228 women with an operative delivery indicated by an FBS lactate concentration of 4.8 mmol/L or greater. The risk of all adverse neonatal outcomes was significantly increased for both DDI groups compared with the reference group (deliveries with an FBS lactate below 4.2 mmol/L within 60 minutes before delivery). In operative deliveries indicated by an FBS lactate concentration of 4.8 mmol/L or more, there was a significantly increased risk of a 5-minute Apgar score less than 7 if the DDI exceeded 20 minutes, compared with a DDI of 20 minutes or less (aOR 8.1, 95% CI 1.1–60.9). We found no statistically significant effect on other short-term outcomes for deliveries with DDI longer than 20 minutes, compared with those with DDI of 20 minutes or less (pH ≤7.10: aOR 2.0, 95% CI 0.5–8.4; transfer to the neonatal intensive care unit: aOR 1.1, 95% CI 0.4–3.5). Conclusions: After a high FBS lactate measurement, the increased risk of adverse neonatal outcome is further augmented if the DDI exceeds 20 minutes. These findings give support to current Norwegian guidelines for intervention in cases of fetal distress.publishedVersio

Accuracy of physicians in differentiating type 1 and type 2 myocardial infarction based on clinical information

Background Physicians commonly judge whether a myocardial infarction (MI) is type 1 (thrombotic) vs type 2 (supply/demand mismatch) based on clinical information. Little is known about the accuracy of physicians’ clinical judgement in this regard. We aimed to determine the accuracy of physicians’ judgement in the classification of type 1 vs type 2 MI in perioperative and nonoperative settings. Methods We performed an online survey using cases from the Optical Coherence Tomographic Imaging of Thrombus (OPTIMUS) Study, which investigated the prevalence of a culprit lesion thrombus based on intracoronary optical coherence tomography (OCT) in patients experiencing MI. Four MI cases, 2 perioperative and 2 nonoperative, were selected randomly, stratified by etiology. Physicians were provided with the patient’s medical history, laboratory parameters, and electrocardiograms. Physicians did not have access to intracoronary OCT results. The primary outcome was the accuracy of physicians' judgement of MI etiology, measured as raw agreement between physicians and intracoronary OCT findings. Fleiss’ kappa and Gwet’s AC1 were calculated to correct for chance. Results The response rate was 57% (308 of 536). Respondents were 62% male; median age was 45 years (standard deviation ± 11); 45% had been in practice for > 15 years. Respondents’ overall accuracy for MI etiology was 60% (95% confidence interval [CI] 57%-63%), including 63% (95% CI 60%-68%) for nonoperative cases, and 56% (95% CI 52%-60%) for perioperative cases. Overall chance-corrected agreement was poor (kappa = 0.05), consistent across specialties and clinical scenarios. Conclusions Physician accuracy in determining MI etiology based on clinical information is poor. Physicians should consider results from other testing, such as invasive coronary angiography, when determining MI etiology

Development of guidance for non-market approaches in the Paris Agreement: operationalizing Articles 6.8 and 6.9 of the Paris Agreement

While market-based forms of cooperation are enshrined in Articles 6.2–6.7, Article 6.8 of the Paris Agreement recognizes the importance of non-market approaches (NMAs) in international cooperation on climate change mitigation and adaptation in a variety of fields. Article 6.9 establishes the NMA framework that promotes NMAs described in Article 6.8. The Parties to the Paris Agreement are currently negotiating a work program to further elaborate on this. If properly designed, fostering the accelerated diffusion of non-market based international cooperation on technology development and transfer, capacity-building and finance in both adaptation and mitigation can provide a relevant contribution to NDC implementation and ratcheting up of ambition. Having that goal in mind, this report provides recommendations on the operationalization of the NMA framework and the work program and the identification of concrete NMAs for consideration by the negotiating Parties. We provide concrete examples of NMAs in various fields Parties have identified as relevant under the framework, including forests, resilience, removals, energy efficiency and the cross cutting topics mentioned above. The NMA work program should be designed as a meaningful addition to ongoing work under the United Nations Framework Convention on Climate Change. The focus must be on activities that are not duplicating ongoing efforts, not implementable through markets, transformative, and have so far been side-lined by international public climate finance. The NMAs’ relevance will ultimately depend on Parties’ active engagement in the identification of concrete NMAs and their submission to the NMA forum envisaged in the latest iterations of the Presidency draft texts from COP25. The NMA forum should operate in a flexible but results-oriented manner to allow for the consideration of emerging concepts and pilot activities. In the end, the role of finance will also be pivotal for the work program’s relevance. According to the current status of negotiations, the work program will not have own financial resources but the consideration of finance is essential to avoid that the NMA work program becomes a mere ‘talk shop’

Editorial: Mechanisms underlying plant-pollinator-herbivore interactions

not applicabl

The Role of Discretion in the Criminal Justice System

Although a substantial body of research suggests that the discretion of discretion of actors in the criminal justice system is important, there is disagreement in the existing empirical literature over its role. Studies in this literature generally hypothesize that discretion plays one of two roles: either it serves as the means by which changing broad social norms against crime causes changes in sentencing patterns, or it serves as the means by which internal social norms of the criminal justice system prevent the implementation of formal changes in laws. We reject both of these hypotheses using data on the sentencing of California prisoners before and after Proposition 8, which provided for sentence enhancements for those convicted of certain serious' crimes with qualifying' criminal histories. We find that an increase in the statutory sentence for a given crime can increase sentence length for those who are charged with the crime, and also for those who are charged with factually 'similar' crimes, where a 'similar' crime is defined as one that has legal elements in common with the given crime. These spillovers are consistent with neither broad social norms nor internal social norms, so we conclude that discretion takes a less-well studied form, which we call 'prosecutorial maximization.'