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Measuring peace : principles, practices, and politics
How can we know if the peace that has been established following a civil war is a stable peace? More than half of all countries that experienced civil war since World War II have suffered a relapse into violent conflict, in some cases more than once. Meanwhile the international community expends billions of dollars and deploys tens of thousands of personnel each year in support of efforts to build peace in countries emerging from violent conflict. 0This book argues that efforts to build peace are hampered by the lack of effective means of assessing progress towards the achievement of a consolidated peace. Rarely, if ever, do peacebuilding organizations and governments seek to ascertain the quality of the peace that they are helping to build and the contribution that their engagement is making (or not) to the consolidation of peace. More rigorous assessments of the robustness of peace are needed. These assessments require clarity about the0characteristics of, and the requirements for, a stable peace. This in turn requires knowledge of the local culture, local history, and the specific conflict dynamics at work in a given conflict situation. Better assessment can inform peacebuilding actors in the reconfiguration and reprioritization of their operations in cases where conditions on the ground have deteriorated or improved. To build a stable peace, it is argued here, it is important to take the measure of peace.
Book
Association between antihypertensive treatment and adverse events: systematic review and meta-analysis
AbstractObjectiveTo examine the association between antihypertensive treatment and specific adverse events.DesignSystematic review and meta-analysis.Eligibility criteriaRandomised controlled trials of adults receiving antihypertensives compared with placebo or no treatment, more antihypertensive drugs compared with fewer antihypertensive drugs, or higher blood pressure targets compared with lower targets. To avoid small early phase trials, studies were required to have at least 650 patient years of follow-up.Information sourcesSearches were conducted in Embase, Medline, CENTRAL, and the Science Citation Index databases from inception until 14 April 2020.Main outcome measuresThe primary outcome was falls during trial follow-up. Secondary outcomes were acute kidney injury, fractures, gout, hyperkalaemia, hypokalaemia, hypotension, and syncope. Additional outcomes related to death and major cardiovascular events were extracted. Risk of bias was assessed using the Cochrane risk of bias tool, and random effects meta-analysis was used to pool rate ratios, odds ratios, and hazard ratios across studies, allowing for between study heterogeneity (τ2).ResultsOf 15 023 articles screened for inclusion, 58 randomised controlled trials were identified, including 280 638 participants followed up for a median of 3 (interquartile range 2-4) years. Most of the trials (n=40, 69%) had a low risk of bias. Among seven trials reporting data for falls, no evidence was found of an association with antihypertensive treatment (summary risk ratio 1.05, 95% confidence interval 0.89 to 1.24, τ2=0.009). Antihypertensives were associated with an increased risk of acute kidney injury (1.18, 95% confidence interval 1.01 to 1.39, τ2=0.037, n=15), hyperkalaemia (1.89, 1.56 to 2.30, τ2=0.122, n=26), hypotension (1.97, 1.67 to 2.32, τ2=0.132, n=35), and syncope (1.28, 1.03 to 1.59, τ2=0.050, n=16). The heterogeneity between studies assessing acute kidney injury and hyperkalaemia events was reduced when focusing on drugs that affect the renin angiotensin-aldosterone system. Results were robust to sensitivity analyses focusing on adverse events leading to withdrawal from each trial. Antihypertensive treatment was associated with a reduced risk of all cause mortality, cardiovascular death, and stroke, but not of myocardial infarction.ConclusionsThis meta-analysis found no evidence to suggest that antihypertensive treatment is associated with falls but found evidence of an association with mild (hyperkalaemia, hypotension) and severe adverse events (acute kidney injury, syncope). These data could be used to inform shared decision making between doctors and patients about initiation and continuation of antihypertensive treatment, especially in patients at high risk of harm because of previous adverse events or poor renal function.RegistrationPROSPERO CRD42018116860.
Journal Article
Soil microbial community responses to climate extremes: resistance, resilience and transitions to alternative states
A major challenge for advancing our understanding of the functional role of soil microbial communities is to link changes in their structure and function under climate change. To address this challenge requires new understanding of the mechanisms that underlie the capacity of soil microbial communities to resist and recover from climate extremes. Here, we synthesize emerging understanding of the intrinsic and extrinsic factors that influence the resistance and resilience of soil microbial communities to climate extremes, with a focus on drought, and identify drivers that might trigger abrupt changes to alternative states. We highlight research challenges and propose a path for advancing our understanding of the resistance and resilience of soil microbial communities to climate extremes, and of their vulnerability to transitions to alternative states, including the use of trait-based approaches. We identify a need for new approaches to quantify resistance and resilience of soil microbial communities, and to identify thresholds for transitions to alternative states. We show how high-resolution time series coupled with gradient designs will enable detecting response patterns to interacting drivers. Finally, to account for extrinsic factors, we suggest that future studies should use environmental gradients to track soil microbial community responses to climate extremes in space and time.
This article is part of the theme issue ‘Climate change and ecosystems: threats, opportunities and solutions’.
Journal Article
Stuck on sugars – how carbohydrates regulate cell adhesion, recognition, and signaling
We have explored the fundamental biological processes by which complex carbohydrates expressed on cellular glycoproteins and glycolipids and in secretions of cells promote cell adhesion and signaling. We have also explored processes by which animal pathogens, such as viruses, bacteria, and parasites adhere to glycans of animal cells and initiate disease. Glycans important in cell signaling and adhesion, such as key O-glycans, are essential for proper animal development and cellular differentiation, but they are also involved in many pathogenic processes, including inflammation, tumorigenesis and metastasis, and microbial and parasitic pathogenesis. The overall hypothesis guiding these studies is that glycoconjugates are recognized and bound by a growing class of proteins called glycan-binding proteins (GBPs or lectins) expressed by all types of cells. There is an incredible variety and diversity of GBPs in animal cells involved in binding N- and O-glycans, glycosphingolipids, and proteoglycan/glycosaminoglycans. We have specifically studied such molecular determinants recognized by selectins, galectins, and many other C-type lectins, involved in leukocyte recruitment to sites of inflammation in human tissues, lymphocyte trafficking, adhesion of human viruses to human cells, structure and immunogenicity of glycoproteins on the surfaces of human parasites. We have also explored the molecular basis of glycoconjugate biosynthesis by exploring the enzymes and molecular chaperones required for correct protein glycosylation. From these studies opportunities for translational biology have arisen, involving production of function-blocking antibodies, anti-glycan specific antibodies, and synthetic glycoconjugates, e.g. glycosulfopeptides, that specifically are recognized by GBPs. This invited short review is based in part on my presentation for the IGO Award 2019 given by the International Glycoconjugate Organization in Milan.
Journal Article
11 years' follow-up of trastuzumab after adjuvant chemotherapy in HER2-positive early breast cancer: final analysis of the HERceptin Adjuvant (HERA) trial
Clinical trials have shown that trastuzumab, a recombinant monoclonal antibody against HER2 receptor, significantly improves overall survival and disease-free survival in women with HER2-positive early breast cancer, but long-term follow-up data are needed. We report the results of comparing observation with two durations of trastuzumab treatment at a median follow-up of 11 years, for patients enrolled in the HERA (HERceptin Adjuvant) trial.
HERA (BIG 1-01) is an international, multicentre, open-label, phase 3 randomised trial of 5102 women with HER2-positive early breast cancer, who were enrolled from hospitals in 39 countries between Dec 7, 2001, and June 20, 2005. After completion of all primary therapy (including, surgery, chemotherapy, and radiotherapy as indicated), patients were randomly assigned (1:1:1) to receive trastuzumab for 1 year (once at 8 mg/kg of bodyweight intravenously, then 6 mg/kg once every 3 weeks) or for 2 years (with the same dose schedule), or to the observation group. Primary endpoint is disease-free survival, and analyses are in the intention-to-treat population. Hazard ratios (HRs) were estimated from Cox models, and survival curves were estimated by the Kaplan-Meier method. Comparison of 2 years versus 1 year of trastuzumab is based on 366-day landmark analyses. This study is registered with ClinicalTrials.gov (NCT00045032).
Of the 5102 women randomly assigned in the HERA trial, three patients had no evidence of having provided written informed consent to participate. We followed up the intention-to-treat population of 5099 patients (1697 in observation, 1702 in 1-year trastuzumab, and 1700 in 2-years trastuzumab groups). After a median follow-up of 11 years (IQR 10·09–11·53), random assignment to 1 year of trastuzumab significantly reduced the risk of a disease-free survival event (HR 0·76, 95% CI 0·68–0·86) and death (0·74, 0·64–0·86) compared with observation. 2 years of adjuvant trastuzumab did not improve disease free-survival outcomes compared with 1 year of this drug (HR 1·02, 95% CI 0·89–1·17). Estimates of 10-year disease-free survival were 63% for observation, 69% for 1 year of trastuzumab, and 69% for 2 years of trastuzumab. 884 (52%) patients assigned to the observation group selectively crossed over to receive trastuzumab. Cardiac toxicity remained low in all groups and occurred mostly during the treatment phase. The incidence of secondary cardiac endpoints was 122 (7·3%) in the 2-years trastuzumab group, 74 (4·4%) in the 1-year trastuzumab group, and 15 (0·9%) in the observation group.
1 year of adjuvant trastuzumab after chemotherapy for patients with HER2-positive early breast cancer significantly improves long-term disease-free survival, compared with observation. 2 years of trastuzumab had no additional benefit.
F Hoffmann-La Roche (Roche).
Journal Article
The ubiquitin–26S proteasome system at the nexus of plant biology
Key Points
The ubiquitin-26S proteasome system (UPS) is one of the most complex and pervasive pathways of intracellular protein regulation in plants.
Genomic estimates indicate that as much as 6% of the
Arabidopsis thaliana
transcriptome is devoted to expressing UPS components, with most of these genes encoding ubiquitin ligases (>1,400 loci).
Genetic analyses have recently connected the UPS to much of plant hormone signalling, regulation of chromatin structure and transcription, tailoring morphogenesis, responses to environmental challenges, self recognition and the war between pathogens and their plant hosts.
In several signalling pathways, components involved in ubiquitin ligation have been shown to act as receptors for hormones and light.
Recent proteomic studies have identified a catalogue of plant proteins that are modified by ubiquitylation
in planta
and have identified various types of polyubiquitin chains.
Why the UPS system is so large in plants is currently unclear. Possibilities include their sessile growth habit, which might require additional levels of regulation, the ancient genome duplications common during plant evolution, roles of the UPS in innate immunity and, for annual plants, their reliance on the UPS to confine their life cycle to short growing seasons.
The ubiquitin–26S proteasome system is one of the most pervasive pathways of intracellular protein regulation in plants. It controls hormone signalling, chromatin structure and transcription, tailoring morphogenesis, responses to environmental challenges, self-recognition and the battle between pathogens and their plant hosts.
Plants, like other eukaryotes, rely on proteolysis to control the abundance of key regulatory proteins and enzymes. Strikingly, genome-wide studies have revealed that the ubiquitin-26S proteasome system (UPS) in particular is an exceedingly large and complex route for protein removal, occupying nearly 6% of the
Arabidopsis thaliana
proteome. But why is the UPS so pervasive in plants? Data accumulated over the past few years now show that it targets numerous intracellular regulators that have central roles in hormone signalling, the regulation of chromatin structure and transcription, tailoring morphogenesis, responses to environmental challenges, self recognition and battling pathogens.
Journal Article