Communicating serum chemical concentrations to study participants: follow up survey

<p>Abstract</p> <p>Background</p> <p>A considerable literature now supports the importance of effective communication with study participants, including how best to develop communication plans focusing on the uncertainty of health risks associated with particular environmental exposures. Strategies for communicating individual concentrations of environmental chemicals in human biological samples in the absence of clearly established safe or hazardous levels have been discussed from a conceptual basis and to a lesser extent from an empirical basis. We designed and evaluated an empirically based communication strategy for women of reproductive age who previously participated in a prospective study focusing on persistent environmental chemicals and reproductive outcomes.</p> <p>Methods</p> <p>A cohort of women followed from preconception through pregnancy or up to 12 menstrual cycles without pregnancy was given their individual serum concentrations for lead, dichloro-2,2-bis<it>p</it>-chlorophenyl ethylene, and select polychlorinated biphenyl congeners. Two versions of standardized letters were prepared depending upon women's exposure status, which was characterized as low or high. Letters included an introduction, individual concentrations, population reference values and guidance for minimizing future exposures. Participants were actively monitored for any questions or concerns following receipt of letters.</p> <p>Results</p> <p>Ninety-eight women were sent letters informing them of their individual concentrations to select study chemicals. None of the 89 (91%) participating women irrespective of exposure status contacted the research team with questions or concerns about communicated exposures despite an invitation to do so.</p> <p>Conclusions</p> <p>Our findings suggest that study participants can be informed about their individual serum concentrations without generating unnecessary concern.</p

Impact of PNKP mutations associated with microcephaly, seizures and developmental delay on enzyme activity and DNA strand break repair

Microcephaly with early-onset, intractable seizures and developmental delay (MCSZ) is a hereditary disease caused by mutations in polynucleotide kinase/phosphatase (PNKP), a DNA strand break repair protein with DNA 5'-kinase and DNA 3'-phosphatase activity. To investigate the molecular basis of this disease, we examined the impact of MCSZ mutations on PNKP activity in vitro and in cells. Three of the four mutations currently associated with MCSZ greatly reduce or ablate DNA kinase activity of recombinant PNKP at 30°C (L176F, T424Gfs48X and exon15Δfs4X), but only one of these mutations reduces DNA phosphatase activity under the same conditions (L176F). The fourth mutation (E326K) has little impact on either DNA kinase or DNA phosphatase activity at 30°C, but is less stable than the wild-type enzyme at physiological temperature. Critically, all of the MCSZ mutations identified to date result in ∼10-fold reduced cellular levels of PNKP protein, and reduced rates of chromosomal DNA strand break repair. Together, these data suggest that all four known MCSZ mutations reduce the cellular stability and level of PNKP protein, with three mutations likely ablating cellular DNA 5'-kinase activity and all of the mutations greatly reducing cellular DNA 3'-phosphatase activity

Oceanids C2: An Integrated Command, Control, and Data Infrastructure for the Over-the-Horizon Operation of Marine Autonomous Systems

Long-range Marine Autonomous Systems (MAS), operating beyond the visual line-of-sight of a human pilot or research ship, are creating unprecedented opportunities for oceanographic data collection. Able to operate for up to months at a time, periodically communicating with a remote pilot via satellite, long-range MAS vehicles significantly reduce the need for an expensive research ship presence within the operating area. Heterogeneous fleets of MAS vehicles, operating simultaneously in an area for an extended period of time, are becoming increasingly popular due to their ability to provide an improved composite picture of the marine environment. However, at present, the expansion of the size and complexity of these multi-vehicle operations is limited by a number of factors: (1) custom control-interfaces require pilots to be trained in the use of each individual vehicle, with limited cross-platform standardization; (2) the data produced by each vehicle are typically in a custom vehicle-specific format, making the automated ingestion of observational data for near-real-time analysis and assimilation into operational ocean models very difficult; (3) the majority of MAS vehicles do not provide machine-to-machine interfaces, limiting the development and usage of common piloting tools, multi-vehicle operating strategies, autonomous control algorithms and automated data delivery. In this paper, we describe a novel piloting and data management system (C2) which provides a unified web-based infrastructure for the operation of long-range MAS vehicles within the UK's National Marine Equipment Pool. The system automates the archiving, standardization and delivery of near-real-time science data and associated metadata from the vehicles to end-users and Global Data Assembly Centers mid-mission. Through the use and promotion of standard data formats and machine interfaces throughout the C2 system, we seek to enable future opportunities to collaborate with both the marine science and robotics communities to maximize the delivery of high-quality oceanographic data for world-leading science

IL-13 is a driver of COVID-19 severity

Immune dysregulation is characteristic of the more severe stages of SARS-CoV-2 infection. Understanding the mechanisms by which the immune system contributes to COVID-19 severity may open new avenues to treatment. Here, we report that elevated IL-13 was associated with the need for mechanical ventilation in 2 independent patient cohorts. In addition, patients who acquired COVID-19 while prescribed Dupilumab, a mAb that blocks IL-13 and IL-4 signaling, had less severe disease. In SARS-CoV-2–infected mice, IL-13 neutralization reduced death and disease severity without affecting viral load, demonstrating an immunopathogenic role for this cytokine. Following anti–IL-13 treatment in infected mice, hyaluronan synthase 1 (Has1) was the most downregulated gene, and accumulation of the hyaluronan (HA) polysaccharide was decreased in the lung. In patients with COVID-19, HA was increased in the lungs and plasma. Blockade of the HA receptor, CD44, reduced mortality in infected mice, supporting the importance of HA as a pathogenic mediator. Finally, HA was directly induced in the lungs of mice by administration of IL-13, indicating a new role for IL-13 in lung disease. Understanding the role of IL-13 and HA has important implications for therapy of COVID-19 and, potentially, other pulmonary diseases. IL-13 levels were elevated in patients with severe COVID-19. In a mouse model of the disease, IL-13 neutralization reduced the disease and decreased lung HA deposition. Administration of IL-13–induced HA in the lung. Blockade of the HA receptor CD44 prevented mortality, highlighting a potentially novel mechanism for IL-13–mediated HA synthesis in pulmonary pathology

Rucaparib maintenance treatment for recurrent ovarian carcinoma after response to platinum therapy (ARIEL3): a randomised, double-blind, placebo-controlled, phase 3 trial

Background: Rucaparib, a poly(ADP-ribose) polymerase inhibitor, has anticancer activity in recurrent ovarian carcinoma harbouring a BRCA mutation or high percentage of genome-wide loss of heterozygosity. In this trial we assessed rucaparib versus placebo after response to second-line or later platinum-based chemotherapy in patients with high-grade, recurrent, platinum-sensitive ovarian carcinoma. Methods: In this randomised, double-blind, placebo-controlled, phase 3 trial, we recruited patients from 87 hospitals and cancer centres across 11 countries. Eligible patients were aged 18 years or older, had a platinum-sensitive, high-grade serous or endometrioid ovarian, primary peritoneal, or fallopian tube carcinoma, had received at least two previous platinum-based chemotherapy regimens, had achieved complete or partial response to their last platinum-based regimen, had a cancer antigen 125 concentration of less than the upper limit of normal, had a performance status of 0–1, and had adequate organ function. Patients were ineligible if they had symptomatic or untreated central nervous system metastases, had received anticancer therapy 14 days or fewer before starting the study, or had received previous treatment with a poly(ADP-ribose) polymerase inhibitor. We randomly allocated patients 2:1 to receive oral rucaparib 600 mg twice daily or placebo in 28 day cycles using a computer-generated sequence (block size of six, stratified by homologous recombination repair gene mutation status, progression-free interval after the penultimate platinum-based regimen, and best response to the most recent platinum-based regimen). Patients, investigators, site staff, assessors, and the funder were masked to assignments. The primary outcome was investigator-assessed progression-free survival evaluated with use of an ordered step-down procedure for three nested cohorts: patients with BRCA mutations (carcinoma associated with deleterious germline or somatic BRCA mutations), patients with homologous recombination deficiencies (BRCA mutant or BRCA wild-type and high loss of heterozygosity), and the intention-to-treat population, assessed at screening and every 12 weeks thereafter. This trial is registered with ClinicalTrials.gov, number NCT01968213; enrolment is complete. Findings: Between April 7, 2014, and July 19, 2016, we randomly allocated 564 patients: 375 (66%) to rucaparib and 189 (34%) to placebo. Median progression-free survival in patients with a BRCA-mutant carcinoma was 16·6 months (95% CI 13·4–22·9; 130 [35%] patients) in the rucaparib group versus 5·4 months (3·4–6·7; 66 [35%] patients) in the placebo group (hazard ratio 0·23 [95% CI 0·16–0·34]; p&lt;0·0001). In patients with a homologous recombination deficient carcinoma (236 [63%] vs 118 [62%]), it was 13·6 months (10·9–16·2) versus 5·4 months (5·1–5·6; 0·32 [0·24–0·42]; p&lt;0·0001). In the intention-to-treat population, it was 10·8 months (8·3–11·4) versus 5·4 months (5·3–5·5; 0·36 [0·30–0·45]; p&lt;0·0001). Treatment-emergent adverse events of grade 3 or higher in the safety population (372 [99%] patients in the rucaparib group vs 189 [100%] in the placebo group) were reported in 209 (56%) patients in the rucaparib group versus 28 (15%) in the placebo group, the most common of which were anaemia or decreased haemoglobin concentration (70 [19%] vs one [1%]) and increased alanine or aspartate aminotransferase concentration (39 [10%] vs none). Interpretation: Across all primary analysis groups, rucaparib significantly improved progression-free survival in patients with platinum-sensitive ovarian cancer who had achieved a response to platinum-based chemotherapy. ARIEL3 provides further evidence that use of a poly(ADP-ribose) polymerase inhibitor in the maintenance treatment setting versus placebo could be considered a new standard of care for women with platinum-sensitive ovarian cancer following a complete or partial response to second-line or later platinum-based chemotherapy. Funding: Clovis Oncology

Ocean data product integration through innovation-the next level of data interoperability

In the next decade the pressures on ocean systems and the communities that rely on them will increase along with impacts from the multiple stressors of climate change and human activities. Our ability to manage and sustain our oceans will depend on the data we collect and the information and knowledge derived from it. Much of the uptake of this knowledge will be outside the ocean domain, for example by policy makers, local Governments, custodians, and other organizations, so it is imperative that we democratize or open the access and use of ocean data. This paper looks at how technologies, scoped by standards, best practice and communities of practice, can be deployed to change the way that ocean data is accessed, utilized, augmented and transformed into information and knowledge. The current portal-download model which requires the user to know what data exists, where it is stored, in what format and with what processing, limits the uptake and use of ocean data. Using examples from a range of disciplines, a web services model of data and information flows is presented. A framework is described, including the systems, processes and human components, which delivers a radical rethink about the delivery of knowledge from ocean data. A series of statements describe parts of the future vision along with recommendations about how this may be achieved. The paper recommends the development of virtual test-beds for end-to-end development of new data workflows and knowledge pathways. This supports the continued development, rationalization and uptake of standards, creates a platform around which a community of practice can be developed, promotes cross discipline engagement from ocean science through to ocean policy, allows for the commercial sector, including the informatics sector, to partner in delivering outcomes and provides a focus to leverage long term sustained funding. The next 10 years will be “make or break” for many ocean systems. The decadal challenge is to develop the governance and co-operative mechanisms to harness emerging information technology to deliver on the goal of generating the information and knowledge required to sustain oceans into the future

Early Detection of Erlotinib Treatment Response in NSCLC by 3′-Deoxy-3′-[18F]-Fluoro-L-Thymidine ([18F]FLT) Positron Emission Tomography (PET)

Background: Inhibition of the epidermal growth factor receptor (EGFR) has shown clinical success in patients with advanced non-small cell lung cancer (NSCLC). Somatic mutations of EGFR were found in lung adenocarcinoma that lead to exquisite dependency on EGFR signaling; thus patients with EGFR-mutant tumors are at high chance of response to EGFR inhibitors. However, imaging approaches affording early identification of tumor response in EGFR-dependent carcinomas have so far been lacking. Methodology/Principal Findings: We performed a systematic comparison of 3′-Deoxy-3′-[$^{18}F$]-fluoro-L-thymidine ([$^{18}F$]FLT) and 2-[$^{18}F$]-fluoro-2-deoxy-D-glucose ([$^{18}F$]FDG) positron emission tomography (PET) for their potential to identify response to EGFR inhibitors in a model of EGFR-dependent lung cancer early after treatment initiation. While erlotinib-sensitive tumors exhibited a striking and reproducible decrease in [$^{18}F$]FLT uptake after only two days of treatment, [$^{18}F$]FDG PET based imaging revealed no consistent reduction in tumor glucose uptake. In sensitive tumors, a decrease in [$^{18}F$]FLT PET but not [$^{18}F$]FDG PET uptake correlated with cell cycle arrest and induction of apoptosis. The reduction in [$^{18}F$]FLT PET signal at day 2 translated into dramatic tumor shrinkage four days later. Furthermore, the specificity of our results is confirmed by the complete lack of [$^{18}F$]FLT PET response of tumors expressing the T790M erlotinib resistance mutation of EGFR. Conclusions: [$^{18}F$]FLT PET enables robust identification of erlotinib response in EGFR-dependent tumors at a very early stage. [$^{18}F$]FLT PET imaging may represent an appropriate method for early prediction of response to EGFR TKI treatment in patients with NSCLC

SARS-CoV-2 Omicron is an immune escape variant with an altered cell entry pathway

Vaccines based on the spike protein of SARS-CoV-2 are a cornerstone of the public health response to COVID-19. The emergence of hypermutated, increasingly transmissible variants of concern (VOCs) threaten this strategy. Omicron (B.1.1.529), the fifth VOC to be described, harbours multiple amino acid mutations in spike, half of which lie within the receptor-binding domain. Here we demonstrate substantial evasion of neutralization by Omicron BA.1 and BA.2 variants in vitro using sera from individuals vaccinated with ChAdOx1, BNT162b2 and mRNA-1273. These data were mirrored by a substantial reduction in real-world vaccine effectiveness that was partially restored by booster vaccination. The Omicron variants BA.1 and BA.2 did not induce cell syncytia in vitro and favoured a TMPRSS2-independent endosomal entry pathway, these phenotypes mapping to distinct regions of the spike protein. Impaired cell fusion was determined by the receptor-binding domain, while endosomal entry mapped to the S2 domain. Such marked changes in antigenicity and replicative biology may underlie the rapid global spread and altered pathogenicity of the Omicron variant

Effects of antiplatelet therapy on stroke risk by brain imaging features of intracerebral haemorrhage and cerebral small vessel diseases: subgroup analyses of the RESTART randomised, open-label trial

Background Findings from the RESTART trial suggest that starting antiplatelet therapy might reduce the risk of recurrent symptomatic intracerebral haemorrhage compared with avoiding antiplatelet therapy. Brain imaging features of intracerebral haemorrhage and cerebral small vessel diseases (such as cerebral microbleeds) are associated with greater risks of recurrent intracerebral haemorrhage. We did subgroup analyses of the RESTART trial to explore whether these brain imaging features modify the effects of antiplatelet therapy