What are the effects of macroalgal blooms on the structure and functioning of marine ecosystems? A systematic review protocol

Abstract Background Anthropogenic activities are believed to have caused an increase in the magnitude, frequency, and extent of macroalgal blooms in marine and estuarine environments. These blooms may contribute to declines in seagrasses and non-blooming macroalgal beds, increasing hypoxia, and reductions in the diversity of benthic invertebrates. However, they may also provide other marine organisms with food and habitat, increase secondary production, and reduce eutrophication. The objective of this systematic review will be to quantify the positive and negative impacts of anthropogenically induced macroalgal blooms in order to determine their effects on ecosystem structure and functioning, and to identify factors that cause their effects to vary. Methods We will search a number of online databases to gather empirical evidence from the literature on the impacts of macroalgal blooms on: (1) species richness and other univariate measures of biodiversity; (2) productivity and abundance of algae, plants, and animals; and (3) biogeochemical cycling and other flows of energy and materials, including trophic interactions and cross-ecosystem subsidies. Data from relevant studies will be extracted and used in a random effects meta-analysis in order to estimate the average effect of macroalgal blooms on each response of interest. Where possible, sub-group analyses will be conducted in order to evaluate how the effects of macroalgal blooms vary according to: (1) which part of the ecosystem is being studied (e.g. which habitat type, taxonomic group, or trophic level); (2) the size of blooms; (3) the region in which blooms occurred; (4) background levels of ecosystem productivity; (5) physical and chemical conditions; (6) aspects of study design and quality (e.g. lab vs. field, experimental vs. observational, degree of replication); and (7) whether the blooms are believed to be anthropogenically induced or not

Global goals mapping: the environment-human landscape

The UK Natural Environment Research Council (NERC), The Rockefeller Foundation (RF), and the UK Economic and Social Research Council (ESRC) recognise that the development challenges of the 21st century require both a shift in thinking and actions that prepare us for the future, while enabling more effective development interventions today. These organisations are establishing a new initiative: 'Towards a Sustainable Earth: Environment-human Systems and the UN Global Goals' (TaSE) as part of their commitment to seeing the 17 Sustainable Development Goals (also known as Global Goals) become a reality. The core premise of the TaSE initiative is that environment-human interactions must be central to all development. The TaSE initiative is convening a meeting at The Rockefeller Foundation Bellagio Centre (7-11 November 2016) to identify the major research and innovation questions relevant to the achievement of the overarching ambition of this initiative. To help focus discussions during this meeting, NERC commissioned the Sussex Sustainability Research Programme (SSRP) at the University of Sussex and the UN Environment World Conservation Monitoring Centre (UNEP-WCMC) to produce a “synthesis of past and current research and innovation relating to the policy landscape surrounding the environment-human relationships and systems that interact across the UN Global Goals”. The commissioned work is encapsulated in this report, Global Goals mapping: the environment-human landscape. For each Goal, the first part of this report summarises the role of environment-human interactions and synthesises relevant research evidence, key innovations and policies, and knowledge and research gaps. The syntheses of research evidence, key innovations and policies presented for individual Global Goals show that environment-human interactions are important for the achievement of all of the Goals. However, the number of environment-human interactions, and the extent to which these interactions need to be considered for achieving each Goal, varies among Global Goals. Although research, innovation and policy have advanced substantially since the Millennium Ecosystem Assessment, knowledge and research gaps related to environment-human interactions remain for all Goals. The Global Goals were conceived as an 'indivisible whole'. The Goals relate to and depend on each other, but relationships between Goals need to be better understood. Previous analyses have begun to explore relationships including synergies and possible conflicts between the Goals from a number of different perspectives and differ widely in their conclusions. While many highlight the role of the more environmentally-focused Goals in underpinning sustainable development, none specifically focuses on environment-human interactions, which are the focus of the TaSE initiative and crucial to the achievement of the Goals. This report uses a new analysis to suggest which relationships between Global Goals may be most influenced by environment-human interactions. It is based on a pairwise view of relationships between Goals, assessing the influence that action (research, policy, innovation and/or management) towards one Goal may have on the potential for achieving others. It highlights 20 pairwise relationships between Goals where these influences may be especially strong, and illustrates for some of these how the knowledge and research gaps identified in Part 1 are relevant to the relationships between the Goals. In reality relationships among Goals are more complex and multidimensional than a pairwise analysis can illustrate, but visualising all connections among them is challenging. Further knowledge gaps and challenges related to the trade-offs, synergies and unintended consequences of the relationships among Goals will need to be addressed to achieve all 17 Goals. In order to understand relationships among Global Goals and prioritize action, including research, it is essential to consider multiple cross-cutting factors, including: temporal and spatial scales of action and impact; context for the action, whether local or other; the (multi) directionality of the relationships among Goals; thresholds and tipping points; number and types of people affected; human behaviour; governance, institutions and power; existence and accessibility of different types of knowledge; and the feasibility of obtaining and scaling-up research results and innovations by 2030. Several approaches have attempted to tackle interconnected challenges, including nexus thinking, pathways, leverage points, indigenous and local knowledge, integrated environmental assessments and integrated modelling. However, there is a need for more work and holistic approaches to achieve all 17 Goals. The syntheses of research evidence, innovations and policies regarding environment-human interactions relevant to each Global Goal and the analysis of the relationships among Goals provide a basis for identifying priority areas for new research, innovation and policy. The Bellagio Group has a vital role to play in building on this to help the TaSE initiative identify a research, innovation and research translation agenda in support of the Global Goals

Using the Theoretical Domains Framework (TDF) to understand adherence to multiple evidence-based indicators in primary care : a qualitative study

BACKGROUND: There are recognised gaps between evidence and practice in general practice, a setting posing particular implementation challenges. We earlier screened clinical guideline recommendations to derive a set of 'high-impact' indicators based upon criteria including potential for significant patient benefit, scope for improved practice and amenability to measurement using routinely collected data. Here, we explore health professionals' perceived determinants of adherence to these indicators, examining the degree to which determinants were indicator-specific or potentially generalisable across indicators. METHODS: We interviewed 60 general practitioners, practice nurses and practice managers in West Yorkshire, the UK, about adherence to four indicators: avoidance of risky prescribing; treatment targets in type 2 diabetes; blood pressure targets in treated hypertension; and anticoagulation in atrial fibrillation. Interview questions drew upon the Theoretical Domains Framework (TDF). Data were analysed using framework analysis. RESULTS: Professional role and identity and environmental context and resources featured prominently across all indicators whilst the importance of other domains, for example, beliefs about consequences, social influences and knowledge varied across indicators. We identified five meta-themes representing more general organisational and contextual factors common to all indicators. CONCLUSIONS: The TDF helped elicit a wide range of reported determinants of adherence to 'high-impact' indicators in primary care. It was more difficult to pinpoint which determinants, if targeted by an implementation strategy, would maximise change. The meta-themes broadly underline the need to align the design of interventions targeting general practices with higher level supports and broader contextual considerations. However, our findings suggest that it is feasible to develop interventions to promote the uptake of different evidence-based indicators which share common features whilst also including content-specific adaptations

Accuracy of Electronic Health Record Data for Identifying Stroke Cases in Large-Scale Epidemiological Studies: A Systematic Review from the UK Biobank Stroke Outcomes Group

Long-term follow-up of population-based prospective studies is often achieved through linkages to coded regional or national health care data. Our knowledge of the accuracy of such data is incomplete. To inform methods for identifying stroke cases in UK Biobank (a prospective study of 503,000 UK adults recruited in middle-age), we systematically evaluated the accuracy of these data for stroke and its main pathological types (ischaemic stroke, intracerebral haemorrhage, subarachnoid haemorrhage), determining the optimum codes for case identification.We sought studies published from 1990-November 2013, which compared coded data from death certificates, hospital admissions or primary care with a reference standard for stroke or its pathological types. We extracted information on a range of study characteristics and assessed study quality with the Quality Assessment of Diagnostic Studies tool (QUADAS-2). To assess accuracy, we extracted data on positive predictive values (PPV) and-where available-on sensitivity, specificity, and negative predictive values (NPV).37 of 39 eligible studies assessed accuracy of International Classification of Diseases (ICD)-coded hospital or death certificate data. They varied widely in their settings, methods, reporting, quality, and in the choice and accuracy of codes. Although PPVs for stroke and its pathological types ranged from 6-97%, appropriately selected, stroke-specific codes (rather than broad cerebrovascular codes) consistently produced PPVs >70%, and in several studies >90%. The few studies with data on sensitivity, specificity and NPV showed higher sensitivity of hospital versus death certificate data for stroke, with specificity and NPV consistently >96%. Few studies assessed either primary care data or combinations of data sources.Particular stroke-specific codes can yield high PPVs (>90%) for stroke/stroke types. Inclusion of primary care data and combining data sources should improve accuracy in large epidemiological studies, but there is limited published information about these strategies

A systematic review of the effectiveness of liming to mitigate impacts of river acidification on fish and macro-invertebrates

The addition of calcium carbonate to catchments or watercourses – liming – has been used widely to mitigate freshwater acidification but the abatement of acidifying emissions has led to questions about its effectiveness and necessity. We conducted a systematic review and meta-analysis of the impact of liming streams and rivers on two key groups of river organisms: fish and invertebrates. On average, liming increased the abundance and richness of acid-sensitive invertebrates and increased overall fish abundance, but benefits were variable and not guaranteed in all rivers. Where B-A-C-I designs (before-after-control-impact) were used to reduce bias, there was evidence that liming decreased overall invertebrate abundance. This systematic review indicates that liming has the potential to mitigate the symptoms of acidification in some instances, but effects are mixed. Future studies should use robust designs to isolate recovery due to liming from decreasing acid deposition, and assess factors affecting liming outcome

Using models to inform policies to meet multiple objectives. Sustainable development, climate change mitigation and biodiversity conservation in Central Africa : Assessing the contribution of brazil's forest code to biodiversity conservation

Land-use change models can help to develop a holistic understanding of the range of potential impacts of different land-use related policy options, and so can strengthen development and implementation of policies to meet a range of objectives, including biodiversity conservation, climate change mitigation, sustainable development and food security. Brazil’s Native Vegetation Protection Act, commonly known as the Forest Code (FC), is one example of a policy that can be used to achieve several objectives. Using land-use modelling to inform ongoing decisions on how the provisions of the FC are put into practice can help to increase its effectiveness in meeting multiple objectives and commitments. Model projections show that the full implementation of the provisions of the FC will both reduce emissions of greenhouse gases and contribute to conserving biodiversity in Brazil. They further highlight the importance for biodiversity conservation of implementing the Environmental Reserve Tradable Certificate (CRAi in Portuguese) mechanism quickly and effectively. Model results also show the need to put in place additional measures to protect areas, such as the Caatinga forests and grassy savanna in the Cerrado,which may suffer increased land-use pressures as a result of the FC.La modélisation des changements d’affectation des terres peut contribuer à développer une vision globale de l’ensemble des impacts potentiels exercés par les différentes actions possibles concernant l’utilisation des sols. Cela permet également de renforcer l’élaboration et la mise en oeuvre des politiques en vue d’atteindre un certain nombre d’objectifs, concernant notamment le développement durable, l’atténuation du changement climatique, la sécurité alimentaire et la protection de la biodiversité. Les pays membres de la Commission des forêts d’Afrique centrale (COMIFAC) se sont engagés à assurer une gestion durable des espaces forestiers de la région, notamment dans le cadre du « Plan de convergence » de la COMIFAC, et à accomplir les objectifs de développement durable (ODD). La réalisation de ces objectifs est subordonnée à l’élaboration et à l’application des politiques et approches nationales nouvelles et existantes. Les prévisions basées sur la modélisation de l’affectation des terres mettent en lumière de possibles synergies et compromis dans la réalisation des ODD, selon différents scénarios de politiques macroéconomiques et d’utilisation des sols. Elles soulignent en particulier l’importance de protéger efficacement certaines zones et concessions forestières pour la conservation des grands singes et d’autres espèces menacées, et montrent que le maintien de ces zones exerce un impact négligeable sur la production agricole de la région. Au vu du développement continu de la région, étendre les zones protégées pourrait permettre de réduire considérablement le nombre d’espèces perdant une grande partie de leur habitat. Toutefois, l’expansion des zones protégées doit être bien planifiée afin d’éviter de produire des effets néfastes pour certaines espèces ou des troubles sociétaux, tels que l’insécurité alimentaire

383 Durable responses with intratumoral electroporation of plasmid interleukin 12 plus pembrolizumab in patients with advanced melanoma progressing on an anti-PD-1 antibody: updated data from keynote 695

Background Electroporated plasmid interleukin-12 (pIL-12-EP; tavokinogene telseplasmid; TAVO) induces sustained intratumoral expression of IL-12, a cytokine that is integral for response to anti-PD-1 antibodies. Here, we present updated safety and response duration data from KEYNOTE 695, a Phase 2, multicenter, open-label trial of pIL-12-EP in combination with pembrolizumab in patients with stage III/IV melanoma immediately following confirmed progression on an anti-PD-1 antibody. Methods Patients with confirmed disease progression after ≥12 weeks‘ treatment with an anti-PD-1 antibody alone or in combination were eligible. Patients received intratumoral pIL-12-EP on days 1, 5 and 8 every 6 weeks and pembrolizumab 200 mg every 3 weeks. Responses were assessed by the investigator at 12-week intervals using RECIST v1.1; overall survival (OS) and duration of response (DoR) assessments were conducted using the Kaplan-Meier method. Results Of the first 56 patients treated, 50% had visceral disease (M1b-d), 80% had received 1–2 and 20% ≥3 prior lines of therapy, 27% had prior ipilimumab and 21% prior BRAF/MEK inhibitors. 61% of patients were primary refractory to anti-PD-1. 54 patients were efficacy evaluable, defined as patients who had at least one post-treatment scan. The investigator-assessed objective response rate (ORR) per RECIST was 27.8% (4 CR, 11 PR); ORR per iRECIST was 29.6%. In patients with M1b-d staging, ORR was 33.3% (n=9/27), and in those receiving prior ipilimumab, ORR was 33.3% (n=5/15). Seven patients had 100% reduction in target lesions, and regression was observed in non-injected lesions. The median DoR had not been reached. With a median follow up of 19.3 months, the median OS (95% CI) was 24.5 (14.4, NR) months (figure 1). The study is now fully enrolled. In 105 patients with safety data, there were no Grade 4/5 treatment-related adverse events (TRAEs) reported. Grade 3 TRAEs occurred in 5.7% and comprised cellulitis in two patients and arthralgia, pneumonitis, enteritis, keratoacanthoma, lichen planus and musculoskeletal chest pain in one patient each. The Grade 1/2 TRAEs in ≥10% patients were fatigue (27.6%), procedural pain (20.0%), diarrhea (17.1%), nausea (10.5%) and pruritus (10.5%). ORR by blinded independent central review has commenced and a global phase 3 trial is planned. Abstract 383 Figure 1 Overall survival in patients treated with pIL-12-EP in combination with pembrolizumab. Dark grey bars: time on study treatment, light grey bars: end of treatment to death or censoring Conclusions Patients with anti-PD-1 therapy refractory advanced melanoma can achieve deep, durable responses in both injected and non-injected lesions with pIL-12-EP plus pembrolizumab. Intratumoral pIL-12-EP in combination with pembrolizumab was generally well tolerated, with minimal Grade 3 and no Grade 4/5 TRAEs. Trial Registration NCT03132675 Ethics Approval The study was approved by a central IRB and/or local institutional IRB/Ethics Committee as required for each participating institution. Consent Written informed consent was obtained from the patients participating in the trial; the current abstract does not include information requiring additional consen

Segregation of a missense mutation in the amyloid precursor protein gene with familial Alzheimer's disease

A locus segregating with familial Alzheimer's disease (AD) has been mapped to chromosome 21, close to the amyloid precursor protein (APP) gene. Recombinants between the APP gene and the AD locus have been reported which seemed to exclude it as the site of the mutation causing familial AD. But recent genetic analysis of a large number of AD families has demonstrated that the disease is heterogeneous. Families with late-onset AD do not show linkage to chromosome 21 markers. Some families with early-onset AD show linkage to chromosome 21 markers, but some do not. This has led to the suggestion that there is non-allelic genetic heterogeneity even within early onset familial AD. To avoid the problems that heterogeneity poses for genetic analysis, we have examined the cosegregation of AD and markers along the long arm of chromosome 21 in a single family with AD confirmed by autopsy. Here we demonstrate that in this kindred, which shows linkage to chromosome 21 markers, there is a point mutation in the APP gene. This mutation causes an amino-acid substitution (Val----Ile) close to the carboxy terminus of the beta-amyloid peptide. Screening other cases of familial AD revealed a second unrelated family in which this variant occurs. This suggests that some cases of AD could be caused by mutations in the APP gene

Somatic mosaicism and common genetic variation contribute to the risk of very-early-onset inflammatory bowel disease

Very-early-onset inflammatory bowel disease (VEO-IBD) is a heterogeneous phenotype associated with a spectrum of rare Mendelian disorders. Here, we perform whole-exome-sequencing and genome-wide genotyping in 145 patients (median age-at-diagnosis of 3.5 years), in whom no Mendelian disorders were clinically suspected. In five patients we detect a primary immunodeficiency or enteropathy, with clinical consequences (XIAP, CYBA, SH2D1A, PCSK1). We also present a case study of a VEO-IBD patient with a mosaic de novo, pathogenic allele in CYBB. The mutation is present in ~70% of phagocytes and sufficient to result in defective bacterial handling but not life-threatening infections. Finally, we show that VEO-IBD patients have, on average, higher IBD polygenic risk scores than population controls (99 patients and 18,780 controls; P < 4 × 10-10), and replicate this finding in an independent cohort of VEO-IBD cases and controls (117 patients and 2,603 controls; P < 5 × 10-10). This discovery indicates that a polygenic component operates in VEO-IBD pathogenesis