Future climate response to Antarctic Ice Sheet melt caused by anthropogenic warming

© The Author(s), 2020. This article is distributed under the terms of the Creative Commons Attribution License. The definitive version was published in Sadai, S., Condron, A., DeConto, R., & Pollard, D. Future climate response to Antarctic Ice Sheet melt caused by anthropogenic warming. Science Advances, 6(39), (2020): eaaz1169, doi:10.1126/sciadv.aaz1169.Meltwater and ice discharge from a retreating Antarctic Ice Sheet could have important impacts on future global climate. Here, we report on multi-century (present–2250) climate simulations performed using a coupled numerical model integrated under future greenhouse-gas emission scenarios IPCC RCP4.5 and RCP8.5, with meltwater and ice discharge provided by a dynamic-thermodynamic ice sheet model. Accounting for Antarctic discharge raises subsurface ocean temperatures by >1°C at the ice margin relative to simulations ignoring discharge. In contrast, expanded sea ice and 2° to 10°C cooler surface air and surface ocean temperatures in the Southern Ocean delay the increase of projected global mean anthropogenic warming through 2250. In addition, the projected loss of Arctic winter sea ice and weakening of the Atlantic Meridional Overturning Circulation are delayed by several decades. Our results demonstrate a need to accurately account for meltwater input from ice sheets in order to make confident climate predictions.This research was supported by the NSF Office of Polar Programs through NSF grant 1443347, the Biological and Environmental Research (BER) division of the U.S. Department of Energy through grant DE-SC0019263, the NSF through ICER 1664013, and by a grant to the NASA Sea Level Science Team 80NSSC17K0698

Social marketing to encourage initiation and continuation of breastfeeding in Penhill and Pinehurst, Swindon

Executive Summary• NHS Swindon has targets to increase the initiation and duration of breastfeeding to 6-8 weeks and beyond. A number of interventions have been implemented to increase local breastfeeding prevalence, including the UNICEF Baby Friendly Initiative and the family nurse partnership. • Traditional health education approaches on their own do not appear to have much impact. Our own work and indicative results elsewhere position co-creation as a potentially highly effective strategy to use within deprived communities; its potential to embed behaviour change sustainably is clear. • Integrating programmes that address cultural perceptions of breastfeeding with targeted work aimed directly at vulnerable segments, which in turn are co-ordinated with strong ante and post-natal support, education programmes and peer supported group sessions will maximise the chances of increasing breastfeeding. • The UWE project team recruited women and some family members to individual interviews and women from four different categories (pregnant, did not breastfeed, tried breastfeeding but gave up and breastfed beyond 6-8 weeks) to focus groups. In total, 28 individuals took part in the project. Participants were asked a range of questions designed to elicit information about norms surrounding infant feeding, how decisions about feeding were reached, individual’s knowledge concerning the benefits of breastfeeding and social and private attitudes towards breastfeeding. • The norm in both Pinehurst and Penhill is to bottle feed babies. Mothers gained knowledge about breastfeeding for a range of sources, but the timing and volume of NHS leaflets could be problematic. The main reason given for breastfeeding was the associated health benefits for babies. The main reason given for bottle feeding were convenience and ease of feeding in public. • Following these interviews, six professionals involved in services for mothers and babies were interviewed. This cohort was selected to include managers and practitioners from the midwifery and health visiting services for Penhill and Pinehurst. • Lack of support for breastfeeding women is a problem. Contributing factors were thought to include lack of resources in the wider health and social care context, particularly with regard to home visits in the first month after birth. Provision of information appears to rely heavily on written literature, which women may not read. A coherent and integrated service was seen as the ideal to support and promote breastfeeding, but there was some concern expressed about how well the support workers and healthcare professionals worked together. • The general consensus is that there is very little community engagement in these areas and many women are unwilling to access locally based groups where they might learn about breastfeeding or observe other mothers breastfeeding. • Co-creation as an approach depends upon engaging and involving community members, and with levels of involvement and interaction in these communities so low, it was agreed to proceed with a continued focus on breastfeeding interventions, with Uscreates leading on designing and developing ideas, making and directing decisions and activity, and audience members contributing feedback and thoughts. The co-creation process was adapted to be delivered one to one with mobile researchers visiting mothers at home. • A design exercise facilitated mothers to build up a description of the ideal support service along a number of descriptors. This activity led to the plan to re-design and re-launch the Breastmates service. This existing breastfeeding support service satisfied most of the requirements for an ideal service that mothers had described. These characteristics guided the re-design of the Breastmates offering to include home visits, and to promote both online and telephone support for urgent needs. • Uscreates carried out a co-creation process with women in order to re-design the existing Breastmates brand and marketing materials. The marketing combined several support avenues and channels within one identity, presenting a more united front, and giving women a choice of how to access support. • The overall recommendation after the pilot phase is to continue to use the co-created Breastmates brand, and roll this out across Swindon. With face to face engagement and promotion having the biggest impact on uptake and attendance, continue with this as the primary focus for promotion activities. • The other attendant promotion components (Facebook, Breastmates site, Textmagic) should be tweaked as per the recommendations above, and continue as low cost methods to increase general awareness of Breastmates, and provide a professional and unified means of reinforcing messages delivered by the face to face activity

Detecting the limits of regulatory element conservation and divergence estimation using pairwise and multiple alignments

BACKGROUND: Molecular evolutionary studies of noncoding sequences rely on multiple alignments. Yet how multiple alignment accuracy varies across sequence types, tree topologies, divergences and tools, and further how this variation impacts specific inferences, remains unclear. RESULTS: Here we develop a molecular evolution simulation platform, CisEvolver, with models of background noncoding and transcription factor binding site evolution, and use simulated alignments to systematically examine multiple alignment accuracy and its impact on two key molecular evolutionary inferences: transcription factor binding site conservation and divergence estimation. We find that the accuracy of multiple alignments is determined almost exclusively by the pairwise divergence distance of the two most diverged species and that additional species have a negligible influence on alignment accuracy. Conserved transcription factor binding sites align better than surrounding noncoding DNA yet are often found to be misaligned at relatively short divergence distances, such that studies of binding site gain and loss could easily be confounded by alignment error. Divergence estimates from multiple alignments tend to be overestimated at short divergence distances but reach a tool specific divergence at which they cease to increase, leading to underestimation at long divergences. Our most striking finding was that overall alignment accuracy, binding site alignment accuracy and divergence estimation accuracy vary greatly across branches in a tree and are most accurate for terminal branches connecting sister taxa and least accurate for internal branches connecting sub-alignments. CONCLUSION: Our results suggest that variation in alignment accuracy can lead to errors in molecular evolutionary inferences that could be construed as biological variation. These findings have implications for which species to choose for analyses, what kind of errors would be expected for a given set of species and how multiple alignment tools and phylogenetic inference methods might be improved to minimize or control for alignment errors

Continuing or adding IL-2 in patients treated with antiretroviral therapy (ACTG Protocol A5051, a rollover trial of ACTG Protocol A328)

<p>Abstract</p> <p>Background</p> <p>Effective antiretroviral therapy reduces HIV-1 RNA levels, improves CD4 T-cell counts, and lowers the risk of opportunistic infections and malignancies. Interleukin-2 (IL-2) has been shown to increase CD4 T-cell numbers mainly by expanding CD4 cells and by prolonging their half-lives. HIV-infected patients previously enrolled into A328 had been randomized to antiretroviral therapy (ART) alone or ART followed by IL-2. In A5051, 53 patients from A328 who had previously received IL-2 were allowed to continue IL-2 for an additional 80 weeks; 27 patients who had received ART alone received IL-2 for 80 weeks.</p> <p>Results</p> <p>The patients previously receiving IL-2 continued to have elevated CD4 levels with extended use of IL-2. The prior ART-alone recipients had increases in CD4 levels to comparable levels as the prior IL-2 recipients (median 804 versus 847 cells/mm³at week 72; 60% versus 9% had >50% increase in A5051 to week 72, p < 0.001). Those who had previously received IL-2 required fewer IL-2 cycles to maintain their CD4 T-cell counts compared to those newly initiating IL-2. The treatments were well tolerated with no significant differences in toxicity or discontinuations between those newly versus previously receiving IL-2. There were few clinical events observed.</p> <p>Conclusions</p> <p>Although sustained CD4 T-cell count increases were seen with IL-2 administration as in other studies, the absence of clinical benefit in two recent randomized trials has demonstrated no apparent role for IL-2 as a therapy in HIV disease.</p> <p>Trial Registration</p> <p>A5051 ClinicalTrials.gov Identifier: NCT00000923.</p

MONKEY: identifying conserved transcription-factor binding sites in multiple alignments using a binding site-specific evolutionary model

We introduce a method (MONKEY) to identify conserved transcription-factor binding sites in multispecies alignments. MONKEY employs probabilistic models of factor specificity and binding-site evolution, on which basis we compute the likelihood that putative sites are conserved and assign statistical significance to each hit. Using genomes from the genus Saccharomyces, we illustrate how the significance of real sites increases with evolutionary distance and explore the relationship between conservation and function

Widespread Discordance of Gene Trees with Species Tree in Drosophila: Evidence for Incomplete Lineage Sorting

The phylogenetic relationship of the now fully sequenced species Drosophila erecta and D. yakuba with respect to the D. melanogaster species complex has been a subject of controversy. All three possible groupings of the species have been reported in the past, though recent multi-gene studies suggest that D. erecta and D. yakuba are sister species. Using the whole genomes of each of these species as well as the four other fully sequenced species in the subgenus Sophophora, we set out to investigate the placement of D. erecta and D. yakuba in the D. melanogaster species group and to understand the cause of the past incongruence. Though we find that the phylogeny grouping D. erecta and D. yakuba together is the best supported, we also find widespread incongruence in nucleotide and amino acid substitutions, insertions and deletions, and gene trees. The time inferred to span the two key speciation events is short enough that under the coalescent model, the incongruence could be the result of incomplete lineage sorting. Consistent with the lineage-sorting hypothesis, substitutions supporting the same tree were spatially clustered. Support for the different trees was found to be linked to recombination such that adjacent genes support the same tree most often in regions of low recombination and substitutions supporting the same tree are most enriched roughly on the same scale as linkage disequilibrium, also consistent with lineage sorting. The incongruence was found to be statistically significant and robust to model and species choice. No systematic biases were found. We conclude that phylogenetic incongruence in the D. melanogaster species complex is the result, at least in part, of incomplete lineage sorting. Incomplete lineage sorting will likely cause phylogenetic incongruence in many comparative genomics datasets. Methods to infer the correct species tree, the history of every base in the genome, and comparative methods that control for and/or utilize this information will be valuable advancements for the field of comparative genomics

Cost-effectiveness of structured education in children with type-1 diabetes mellitus

Objectives: Kids in Control OF Food (KICk-OFF) is a 5-day structured education program for 11- to 16-year-olds with type 1 diabetes mellitus (T1DM) who are using multiple daily insulin injections. This study evaluates the cost-effectiveness of the KICk-OFF education program compared with the usual care using data from the KICk-OFF trial. Methods: The short-term within-trial analysis covers the 2-year postintervention period. Data on glycated hemoglobin (HbA1c), severe hypoglycemia, and diabetic ketoacidosis (DKA) were collected over a 2-year follow-up period. Sub-group analyses have been defined on the basis of baseline HbA1c being below 7.5 percent (58.5 mmol/mol) (low group), between 7.5 percent and 9.5 percent (80.3 mmol/mol) (medium group), and over 9.5 percent (high group). The long-term cost-effectiveness evaluation has been conducted by using The Sheffield Type 1 Diabetes Policy Model, which is a patient-level simulation model on T1DM. It includes long-term microvascular (retinopathy, neuropathy, and nephropathy) and macrovascular (myocardial infarction, stroke, revascularization, and angina) diabetes-related complications and acute adverse events (severe hypoglycemia and DKA). Results: The most favorable within-trial scenario for the KICk-OFF arm led to an incremental cost-effectiveness ratio (ICER) of £23,688 (base year 2009) with a cost-effectiveness probability of 41.3 percent. Simulating the long-term complications using the full cohort data, the mean ICER for the base case was £28,813 (base year 2011) and the probability of the KICk-OFF intervention being cost-effective at £20,000/QALY threshold was 42.6 percent, with considerable variation due to treatment effect duration. For the high HbA1c sub-group, the KICk-OFF arm was “dominant” (meaning it provided better health gains at lower costs than usual care) over the usual care arm in each scenario considered. Conclusions: For the whole study population, the cost-effectiveness of KICk-OFF depends on the assumption for treatment effect duration. For the high baseline HbA1c sub-group, KICk-OFF arm was estimated to be dominant over the usual care arm regardless of the assumption on the treatment effect duration

Engineering cancer selective virotherapies: are the pieces of the puzzle falling into place?

Advances in gene therapy, synthetic biology, cancer genomics and patient-derived cancer models have expanded the repertoire of strategies for targeting human cancers using viral vectors. Novel capsids, synthetic promoters and therapeutic payloads, are being developed and assessed via approaches such as rational design, pooled library screening and directed evolution. Ultimately, the goal is to generate precision-engineered viruses that target different facets of tumour cell biology, without compromising normal tissue and organ function. Here, we briefly review the opportunities for engineering cancer selectivity into viral vectors at both the cell extrinsic and intrinsic level. Such stringently tumour-targeted vectors can subsequently act as platforms for the delivery of potent therapeutic transgenes, including the exciting prospect of immunotherapeutic payloads. These have the potential to eradicate non-transduced cells through stimulation of systemic anti-cancer immune responses, thereby side-stepping the inherent challenge of achieving gene delivery to the entire cancer cell population. We discuss the importance of using advanced primary human cellular models, such as patient-derived cultures and organoids, to enable rapid screening and triage of novel candidates using disease-relevant human cellular models. We believe this combination of improved delivery and selectivity, through novel capsids and promoters, coupled with more potent choices for the combinations of immunotherapy-based payloads seems capable of finally delivering innovative new gene therapies for oncology. Many pieces of the puzzle of how to build a virus capable of targeting human cancers appear to be falling into place