Standardised data on initiatives—STARDIT: Beta version

Background and objective: There is currently no standardised way to share information across disciplines about initiatives, including fields such as health, environment, basic science, manufacturing, media and international development. All problems, including complex global problems such as air pollution and pandemics require reliable data sharing between disciplines in order to respond effectively. Current reporting methods also lack information about the ways in which different people and organisations are involved in initiatives, making it difficult to collate and appraise data about the most effective ways to involve different people. The objective of STARDIT (Standardised Data on Initiatives) is to address current limitations and inconsistencies in sharing data about initiatives. The STARDIT system features standardised data reporting about initiatives, including who has been involved, what tasks they did, and any impacts observed. STARDIT was created to help everyone in the world find and understand information about collective human actions, which are referred to as ‘initiatives’. STARDIT enables multiple categories of data to be reported in a standardised way across disciplines, facilitating appraisal of initiatives and aiding synthesis of evidence for the most effective ways for people to be involved in initiatives. This article outlines progress to date on STARDIT; current usage; information about submitting reports; planned next steps and how anyone can become involved. Method: STARDIT development is guided by participatory action research paradigms, and has been co-created with people from multiple disciplines and countries. Co-authors include cancer patients, people affected by rare diseases, health researchers, environmental researchers, economists, librarians and academic publishers. The co-authors also worked with Indigenous peoples from multiple countries and in partnership with an organisation working with Indigenous Australians. Results and discussion: Over 100 people from multiple disciplines and countries have been involved in co-designing STARDIT since 2019. STARDIT is the first open access web-based data-sharing system which standardises the way that information about initiatives is reported across diverse fields and disciplines, including information about which tasks were done by which stakeholders. STARDIT is designed to work with existing data standards. STARDIT data will be released into the public domain (CC0) and integrated into Wikidata; it works across multiple languages and is both human and machine readable. Reports can be updated throughout the lifetime of an initiative, from planning to evaluation, allowing anyone to be involved in reporting impacts and outcomes. STARDIT is the first system that enables sharing of standardised data about initiatives across disciplines. A working Beta version was publicly released in February 2021 (ScienceforAll.World/STARDIT). Subsequently, STARDIT reports have been created for peer-reviewed research in multiple journals and multiple research projects, demonstrating the usability. In addition, organisations including Cochrane and Australian Genomics have created prospective reports outlining planned initiatives. Conclusions: STARDIT can help create high-quality standardised information on initiatives trying to solve complex multidisciplinary global problems

Adenosine Triphosphate Stimulates Aquifex aeolicus MutL Endonuclease Activity

BACKGROUND:Human PMS2 (hPMS2) homologues act to nick 5' and 3' to misincorporated nucleotides during mismatch repair in organisms that lack MutH. Mn(++) was previously found to stimulate the endonuclease activity of these homologues. ATP was required for the nicking activity of hPMS2 and yPMS1, but was reported to inhibit bacterial MutL proteins from Thermus thermophilus and Aquifex aeolicus that displayed homology to hPMS2. Mutational analysis has identified the DQHA(X)(2)E(X)(4)E motif present in the C-terminus of PMS2 homologues as important for endonuclease activity. METHODOLOGIES/PRINCIPAL FINDINGS:We examined the effect ATP had on the Mn(++) induced nicking of supercoiled pBR322 by full-length and mutant A. aeolicus MutL (Aae MutL) proteins. Assays were single time point, enzyme titration experiments or reaction time courses. The maximum velocity for MutL nicking was determined to be 1.6+/-0.08x10(-5) s(-1) and 4.2+/-0.3x10(-5) s(-1) in the absence and presence of ATP, respectively. AMPPNP stimulated the nicking activity to a similar extent as ATP. A truncated Aae MutL protein composed of only the C-terminal 123 amino acid residues was found to nick supercoiled DNA. Furthermore, mutations in the conserved C-terminal DQHA(X)(2)E(X)(4)E and CPHGRP motifs were shown to abolish Aae MutL endonuclease activity. CONCLUSIONS:ATP stimulated the Mn(++) induced endonuclease activity of Aae MutL. Experiments utilizing AMPPNP implied that the stimulation did not require ATP hydrolysis. A mutation in the DQHA(X)(2)E(X)(4)E motif of Aae MutL further supported the role of this region in endonclease activity. For the first time, to our knowledge, we demonstrate that changing the histidine residue in the conserved CPHGRP motif abolishes endonucleolytic activity of a hPMS2 homologue. Finally, the C-terminal 123 amino acid residues of Aae MutL were sufficient to display Mn(++) induced nicking activity

Antiinflammatory Therapy with Canakinumab for Atherosclerotic Disease

Background: Experimental and clinical data suggest that reducing inflammation without affecting lipid levels may reduce the risk of cardiovascular disease. Yet, the inflammatory hypothesis of atherothrombosis has remained unproved. Methods: We conducted a randomized, double-blind trial of canakinumab, a therapeutic monoclonal antibody targeting interleukin-1β, involving 10,061 patients with previous myocardial infarction and a high-sensitivity C-reactive protein level of 2 mg or more per liter. The trial compared three doses of canakinumab (50 mg, 150 mg, and 300 mg, administered subcutaneously every 3 months) with placebo. The primary efficacy end point was nonfatal myocardial infarction, nonfatal stroke, or cardiovascular death. RESULTS: At 48 months, the median reduction from baseline in the high-sensitivity C-reactive protein level was 26 percentage points greater in the group that received the 50-mg dose of canakinumab, 37 percentage points greater in the 150-mg group, and 41 percentage points greater in the 300-mg group than in the placebo group. Canakinumab did not reduce lipid levels from baseline. At a median follow-up of 3.7 years, the incidence rate for the primary end point was 4.50 events per 100 person-years in the placebo group, 4.11 events per 100 person-years in the 50-mg group, 3.86 events per 100 person-years in the 150-mg group, and 3.90 events per 100 person-years in the 300-mg group. The hazard ratios as compared with placebo were as follows: in the 50-mg group, 0.93 (95% confidence interval [CI], 0.80 to 1.07; P = 0.30); in the 150-mg group, 0.85 (95% CI, 0.74 to 0.98; P = 0.021); and in the 300-mg group, 0.86 (95% CI, 0.75 to 0.99; P = 0.031). The 150-mg dose, but not the other doses, met the prespecified multiplicity-adjusted threshold for statistical significance for the primary end point and the secondary end point that additionally included hospitalization for unstable angina that led to urgent revascularization (hazard ratio vs. placebo, 0.83; 95% CI, 0.73 to 0.95; P = 0.005). Canakinumab was associated with a higher incidence of fatal infection than was placebo. There was no significant difference in all-cause mortality (hazard ratio for all canakinumab doses vs. placebo, 0.94; 95% CI, 0.83 to 1.06; P = 0.31). Conclusions: Antiinflammatory therapy targeting the interleukin-1β innate immunity pathway with canakinumab at a dose of 150 mg every 3 months led to a significantly lower rate of recurrent cardiovascular events than placebo, independent of lipid-level lowering. (Funded by Novartis; CANTOS ClinicalTrials.gov number, NCT01327846.

Forgoing life support: How the decision is made in European pediatric intensive care units

Purpose: To determine how decisions to forgo life support are made in European pediatric intensive care units (PICUs). Methods: A multicenter, prospective study, the Eurydice II study, among 45 PICUs: 20 in France, 21 in Northern/Western (N/W) European countries and 4 in Eastern/Central (E/C) Europe. Data were collected between November 2009 and April 2010 through a questionnaire. Results: The decision to forgo life-sustaining treatment was made in 166 (40.6%) out of 409 deceased children (median 42.9%, France 38.2%, N/W European countries 60.0%, E/C European countries 0%; P < 0.001). In the E/C group, more patients died after cardiopulmonary resuscitation (CPR) failure than after forgoing life support (P < 0.001). In all PICUs, caregivers discussed the decision during a formal meeting, after which the medical staff made the final decision. The decision was often documented in the medical record (median 100%). The majority of the parents were informed of the final decision and were at the bedside during their child's death (median 100%). Decision to forgo life-sustaining treatment occurred in 40.6% of children, compared with 33% in Eurydice I. A high percentage of parents from France were now informed about the meeting and its conclusion as compared with Eurydice I (median 100%). Conclusions: The results of this study and comparison with the Eurydice I study (2002) show a trend towards standardization of end-of-life practices across N/W European countries and France in the past decade

The multifaceted mismatch-repair system

By removing biosynthetic errors from newly synthesized DNA, mismatch repair (MMR) improves the fidelity of DNA replication by several orders of magnitude. Loss of MMR brings about a mutator phenotype, which causes a predisposition to cancer. But MMR status also affects meiotic and mitotic recombination, DNA-damage signalling, apoptosis and cell-type-specific processes such as class-switch recombination, somatic hypermutation and triplet-repeat expansion. This article reviews our current understanding of this multifaceted DNA-repair system in human cells