Antarctic climate, Southern Ocean circulation patterns, and deep water formation during the Eocene

We assess early-to-middle Eocene seawater neodymium (Nd) isotope records from seven Southern Ocean deep-sea drill sites to evaluate the role of Southern Ocean circulation in long-term Cenozoic climate change. Our study sites are strategically located on either side of the Tasman Gateway and are positioned at a range of shallow (Nd(t) = −9.3 ± 1.5). IODP Site U1356 off the coast of Adélie Land, a locus of modern-day Antarctic Bottom Water production, is identified as a site of persistent deep water formation from the early Eocene to the Oligocene. East of the Tasman Gateway an additional local source of intermediate/deep water formation is inferred at ODP Site 277 in the SW Pacific Ocean (εNd(t) = −8.7 ± 1.5). Antarctic-proximal shelf sites (ODP Site 1171 and Site U1356) reveal a pronounced erosional event between 49 and 48 Ma, manifested by ~2 εNd unit negative excursions in seawater chemistry toward the composition of bulk sediments at these sites. This erosional event coincides with the termination of peak global warmth following the Early Eocene Climatic Optimum and is associated with documented cooling across the study region and increased export of Antarctic deep waters, highlighting the complexity and importance of Southern Ocean circulation in the greenhouse climate of the Eocene

Concurrent Intrathecal and Intravenous Nivolumab in Leptomeningeal Disease: Phase 1 Trial Interim Results

There is a critical need for effective treatments for leptomeningeal disease (LMD). Here, we report the interim analysis results of an ongoing single-arm, first-in-human phase 1/1b study of concurrent intrathecal (IT) and intravenous (IV) nivolumab in patients with melanoma and LMD. The primary endpoints are determination of safety and the recommended IT nivolumab dose. The secondary endpoint is overall survival (OS). Patients are treated with IT nivolumab alone in cycle 1 and IV nivolumab is included in subsequent cycles. We treated 25 patients with metastatic melanoma using 5, 10, 20 and 50 mg of IT nivolumab. There were no dose-limiting toxicities at any dose level. The recommended IT dose of nivolumab is 50 mg (with IV nivolumab 240 mg) every 2 weeks. Median OS was 4.9 months, with 44% and 26% OS rates at 26 and 52 weeks, respectively. These initial results suggest that concurrent IT and IV nivolumab is safe and feasible with potential efficacy in patients with melanoma LMD, including in patients who had previously received anti-PD1 therapy. Accrual to the study continues, including in patients with lung cancer. ClinicalTrials.gov registration: NCT03025256

Author Correction: Drivers of seedling establishment success in dryland restoration efforts

1 Pág. Correción errata.In the version of this Article originally published, the surname of author Tina Parkhurst was incorrectly written as Schroeder. This has now been corrected.Peer reviewe

Adjunctive rifampicin for Staphylococcus aureus bacteraemia (ARREST): a multicentre, randomised, double-blind, placebo-controlled trial.

BACKGROUND: Staphylococcus aureus bacteraemia is a common cause of severe community-acquired and hospital-acquired infection worldwide. We tested the hypothesis that adjunctive rifampicin would reduce bacteriologically confirmed treatment failure or disease recurrence, or death, by enhancing early S aureus killing, sterilising infected foci and blood faster, and reducing risks of dissemination and metastatic infection. METHODS: In this multicentre, randomised, double-blind, placebo-controlled trial, adults (≥18 years) with S aureus bacteraemia who had received ≤96 h of active antibiotic therapy were recruited from 29 UK hospitals. Patients were randomly assigned (1:1) via a computer-generated sequential randomisation list to receive 2 weeks of adjunctive rifampicin (600 mg or 900 mg per day according to weight, oral or intravenous) versus identical placebo, together with standard antibiotic therapy. Randomisation was stratified by centre. Patients, investigators, and those caring for the patients were masked to group allocation. The primary outcome was time to bacteriologically confirmed treatment failure or disease recurrence, or death (all-cause), from randomisation to 12 weeks, adjudicated by an independent review committee masked to the treatment. Analysis was intention to treat. This trial was registered, number ISRCTN37666216, and is closed to new participants. FINDINGS: Between Dec 10, 2012, and Oct 25, 2016, 758 eligible participants were randomly assigned: 370 to rifampicin and 388 to placebo. 485 (64%) participants had community-acquired S aureus infections, and 132 (17%) had nosocomial S aureus infections. 47 (6%) had meticillin-resistant infections. 301 (40%) participants had an initial deep infection focus. Standard antibiotics were given for 29 (IQR 18-45) days; 619 (82%) participants received flucloxacillin. By week 12, 62 (17%) of participants who received rifampicin versus 71 (18%) who received placebo experienced treatment failure or disease recurrence, or died (absolute risk difference -1·4%, 95% CI -7·0 to 4·3; hazard ratio 0·96, 0·68-1·35, p=0·81). From randomisation to 12 weeks, no evidence of differences in serious (p=0·17) or grade 3-4 (p=0·36) adverse events were observed; however, 63 (17%) participants in the rifampicin group versus 39 (10%) in the placebo group had antibiotic or trial drug-modifying adverse events (p=0·004), and 24 (6%) versus six (2%) had drug interactions (p=0·0005). INTERPRETATION: Adjunctive rifampicin provided no overall benefit over standard antibiotic therapy in adults with S aureus bacteraemia. FUNDING: UK National Institute for Health Research Health Technology Assessment

Finishing the euchromatic sequence of the human genome

The sequence of the human genome encodes the genetic instructions for human physiology, as well as rich information about human evolution. In 2001, the International Human Genome Sequencing Consortium reported a draft sequence of the euchromatic portion of the human genome. Since then, the international collaboration has worked to convert this draft into a genome sequence with high accuracy and nearly complete coverage. Here, we report the result of this finishing process. The current genome sequence (Build 35) contains 2.85 billion nucleotides interrupted by only 341 gaps. It covers ∼99% of the euchromatic genome and is accurate to an error rate of ∼1 event per 100,000 bases. Many of the remaining euchromatic gaps are associated with segmental duplications and will require focused work with new methods. The near-complete sequence, the first for a vertebrate, greatly improves the precision of biological analyses of the human genome including studies of gene number, birth and death. Notably, the human enome seems to encode only 20,000-25,000 protein-coding genes. The genome sequence reported here should serve as a firm foundation for biomedical research in the decades ahead

Physical activity in people with multiple myeloma: associated factors and exercise program preferences

People with multiple myeloma (MM) often experience disease symptoms and treatment toxicities that can be alleviated through physical activity (PA). However, the majority of people with MM are insufficiently active. This study explored PA among people with MM, including differences by treatment stage, symptoms and demographics, and programming preferences. Overall, 126 people with MM (77% response rate) completed the survey. Pre-diagnosis, 25.4% were sufficiently active, with 12.0% remaining active after treatment. Respondents who were physically active pre-diagnosis were 46.7 times (95% confidence intervals CI: 2.03, 1072.1) more likely to meet PA guidelines following an MM diagnosis compared to people not meeting guidelines pre-diagnosis. Experiencing MM symptoms and receiving PA advice from healthcare professionals were not associated with meeting PA guidelines. People with MM were interested in exercise programs (55%) that are low-cost (77%), offered at flexible times (74%), and at locations close to home (69%), both during active treatment and remission (57%), and supervised by an exercise oncology specialist (48%). People with MM, particularly those insufficiently active prior to diagnosis, should be offered convenient, low-cost exercise programs supervised by an exercise oncology specialist to increase PA participation

Imprinted gene alterations in the kidneys of growth restricted offspring may be mediated by a long non-coding RNA

ABSTRACTAltered epigenetic mechanisms have been previously reported in growth restricted offspring whose mothers experienced environmental insults during pregnancy in both human and rodent studies. We previously reported changes in the expression of the DNA methyltransferase Dnmt3a and the imprinted genes Cdkn1c (Cyclin-dependent kinase inhibitor 1C) and Kcnq1 (Potassium voltage-gated channel subfamily Q member 1) in the kidney tissue of growth restricted rats whose mothers had uteroplacental insufficiency induced on day 18 of gestation, at both embryonic day 20 (E20) and postnatal day 1 (PN1). To determine the mechanisms responsible for changes in the expression of these imprinted genes, we investigated DNA methylation of KvDMR1, an imprinting control region (ICR) that includes the promoter of the antisense long non-coding RNA Kcnq1ot1 (Kcnq1 opposite strand/antisense transcript 1). Kcnq1ot1 expression decreased by 51% in growth restricted offspring compared to sham at PN1. Interestingly, there was a negative correlation between Kcnq1ot1 and Kcnq1 in the E20 growth restricted group (Spearman’s ρ = 0.014). No correlation was observed between Kcnq1ot1 and Cdkn1c expression in either group at any time point. Additionally, there was a 11.25% decrease in the methylation level at one CpG site within KvDMR1 ICR. This study, together with others in the literature, supports that long non-coding RNAs may mediate changes seen in tissues of growth restricted offspring