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Many nations use ecological compensation policies to address negative impacts of development projects and achieve No Net Loss (NNL) of biodiversity and ecosystem services. Yet, failures are widely reported. We use spatial simulation models to quantify potential net impacts of alternative compensation policies on biodiversity (indicated by native vegetation) and two ecosystem services (carbon storage, sediment retention) across four case studies (in Australia, Brazil, Indonesia, Mozambique). No policy achieves NNL of biodiversity in any case study. Two factors limit their potential success: the land available for compensation (existing vegetation to protect or cleared land to restore), and expected counterfactual biodiversity losses (unregulated vegetation clearing). Compensation also fails to slow regional biodiversity declines because policies regulate only a subset of sectors, and expanding policy scope requires more land than is available for compensation activities. Avoidance of impacts remains essential in achieving NNL goals, particularly once opportunities for compensation are exhausted. Countries are adopting ecological compensation policies aimed at achieving no net loss of biodiversity and ecosystem services. Here, Sonter and colleagues apply spatial simulation models to case studies in Australia, Brazil, Indonesia, and Mozambique to show that compensation alone is not sufficient to preserve biodiversity.

Loss of habitats or ecosystems arising from development projects (e.g., infrastructure, resource extraction, urban expansion) are frequently addressed through biodiversity offsetting. As currently implemented, offsetting typically requires an outcome of “no net loss” of biodiversity, but only relative to a baseline trajectory of biodiversity decline. This type of “relative” no net loss entrenches ongoing biodiversity loss, and is misaligned with biodiversity targets that require “absolute” no net loss or “net gain.” Here, we review the limitations of biodiversity offsetting, and in response, propose a new framework for compensating for biodiversity losses from development in a way that is aligned explicitly with jurisdictional biodiversity targets. In the framework, targets for particular biodiversity features are achieved via one of three pathways: Net Gain, No Net Loss, or (rarely) Managed Net Loss. We outline how to set the type (“Maintenance” or “Improvement”) and amount of ecological compensation that is appropriate for proportionately contributing to the achievement of different targets. This framework advances ecological compensation beyond a reactive, ad‐hoc response, to ensuring alignment between actions addressing residual biodiversity losses and achievement of overarching targets for biodiversity conservation.

Governments, businesses, and lenders worldwide are adopting an objective of no net loss (NNL) of biodiversity that is often partly achieved through biodiversity offsetting within a hierarchy of mitigation actions. Offsets aim to balance residual losses of biodiversity caused by development in one location with commensurate gains at another. Although ecological challenges to achieve NNL are debated, the associated gains and losses for local stakeholders have received less attention. International best practice calls for offsets to make people no worse off than before implementation of the project, but there is a lack of clarity concerning how to achieve this with regard to people’s use and nonuse values for biodiversity, especially given the inevitable trade-offs when compensating biodiversity losses with gains elsewhere. This is particularly challenging for countries where poor people depend on natural resources. Badly planned offsets can exacerbate poverty, and development and offset impacts can vary across spatial-temporal scales and by location, gender, and livelihood. We conceptualize the no-worse-off principle in the context of NNL of biodiversity, by exploring for whom and how the principle can be achieved. Changes in the spatial and temporal distribution of biodiversity-related social impacts of a development and its associated offset can lead to social inequity and negatively impact people’s well-being. The level of aggregation (regional, village, interest group, household, and individual) at which these social impacts are measured and balanced can again exacerbate inequity in a system. We propose that a determination that people are no worse off, and preferably better off, after a development and biodiversity offset project than they were before the project should be based on the perceptions of project-affected people (assessed at an appropriate level of aggregation); that their well-being associated with biodiversity losses and gains should be at least as good as it was before the project; and that this level of well-being should be maintained throughout the project life cycle. Employing this principle could help ensure people are no worse off as a result of interventions to achieve biodiversity NNL. Los gobiernos, negocios y financiadores están adoptando el objetivo de biodiversidad sin pérdida neta (NNL, en inglés), el cual comúnmente se logra parcialmente por medio de compensaciones por biodiversidad dentro de una jerarquía de acciones de mitigación. Las compensaciones buscan balancear las pérdidas residuales de la biodiversidad causadas por el desarrollo en una localidad con ganancias conmensuradas en otra localidad. Aunque los obstáculos ecológicos para alcanzar la NNL se debaten hoy en día, las ganancias y pérdidas para los accionistas locales han recibido menos atención. La mejor práctica internacional requiere compensaciones para que las personas no estén peor que antes de la implementación del proyecto, pero existe una falta de claridad con respecto a cómo lograr esto considerando el valor de uso o no de la biodiversidad por parte de las personas, especialmente dadas las compensaciones inevitables cuando se resarcen las pérdidas de biodiversidad con ganancias en otros lugares. Esto es un reto particularmente para los países en donde la gente pobre depende de los recursos naturales. Las compensaciones mal planeadas pueden exacerbar la pobreza, y los impactos del desarrollo y las compensaciones puede variar a lo largo de la escala espacio-temporal y por localidad, género, y sustento. Conceptualizamos el principio de no-peor-que en el contexto de la NNL de biodiversidad explorando para quién y cómo se puede lograr este principio. Los cambios en la distribución especial y temporal de los impactos sociales de un proyecto relacionados con la biodiversidad y sus compensaciones asociadas pueden resultar en una inequidad social e impactar negativamente el bienestar de las personas. El nivel de agregación (regional, aldea, grupo de interés. hogar, individual) en el que se miden y balancean estos impactos sociales también puede exacerbar la inequidad en un sistema. Proponemos que la determinación de que las personas no estén peor que antes, y de preferencia mejor que, después de un proyecto de desarrollo y de compensación por la biodiversidad debería basarse en las percepciones de las personas afectadas por el proyecto (evaluadas en un nivel apropiado de agregación); que su bienestar asociado con las pérdidas y ganancias de biodiversidad debería por lo menos ser tan bueno como era antes del proyecto; y que este nivel de bienestar debería mantenerse durante todo el ciclo de vida del proyecto. Si se emplea este principio, se podría ayudar a asegurarle a las personas que no estén peor que antes como resultado de las intervenciones para alcanzar la NNL de biodiversidad. 世界各国的政府、企业和贷款机构都在努力实现生物多样性无净损失(no net loss, NNL)的巨标，这一目 标一定程度上是通过分级减控行动中的生物多样性补偿实现的。补偿旨在平衡一千地区发展导致的生物多祥性 剩余损失与另ー个地区的同等收益。虽然实现无净损失面临的生态挑战仍受到争议，但当地的利益相关者的相 应收益和损失受到的关注甚至更少。目前，国际上的最优做法要求对人们的补偿应能够保i正其生活水平不会比 项目实施前更低，但就人们对生物多祥性的利用及菲利用价值来说如何达到这一要求还不明确，特別是考虑到 用其它地方的收益来补偿生物多祥性损失时所不可避免地产生的利弊权衡。而这ー问题在贫困人ロ依赖自然资 源生活的国家格外具有挑战性。计划不当的补偿可能会加剧贫困，发展和ネト偿的影响还会随时空尺度、地点、 性别和谋生方式而变化。我们在生物多祥性无净损失的背景下，通过分析无恶化原则将为谁实现、如何实现，构 建了该原则的概念。发展及其补偿所引起的生物多祥性相关的社会影响在时间和空间分布上的变化会导致社 会不平等，并对人们的福祉产生负面影响。在何种聚合程度上（地区、村庄、利益集团、家庭、十人）衡量和平 衡这些社会影响，可能会再次加剧系统中的不平等性。我们认为，发展及生物多祥性补偿项目对人们生活水平影 响(不应比项目开展前更差，最好有所改善)的测定应建立在对受项目影响人群的理解和认识上即在ー个合适 的綜合的水平上进行评估;另外，人们与生物多样性收益及损失相关的福祉也至少要与项目实施前一祥好，且项 目全程都保持这ー水平。采用这个原则有助于确保实现生物多祥性无净损失的干预不会导致人们生活水平下 降。

A global goal of no net loss of natural ecosystems or better has recently been proposed, but such a goal would require equitable translation to country-level contributions. Given the wide variation in ecosystem depletion, these could vary from net gain (for countries where restoration is needed), to managed net loss (in rare circumstances where natural ecosystems remain extensive and human development imperative is greatest). National contributions and international support for implementation also must consider non-area targets (for example, for threatened species) and socioeconomic factors such as the capacity to conserve and the imperative for human development. A framework is presented for achieving global no net loss of biodiversity that accounts for inequity among countries in both pressures and ability to act.

Understanding adaptation by natural selection requires understanding the genetic factors that determine which beneficial mutations are available for selection. Here, using experimental evolution of rifampicin-resistant Pseudomonas aeruginosa, we show that different genotypes vary in their capacity for adaptation to the cost of antibiotic resistance. We then use sequence data to show that the beneficial mutations associated with fitness recovery were specific to particular genetic backgrounds, suggesting that genotypes had access to different sets of beneficial mutations. When we manipulated the supply rate of beneficial mutations, by altering effective population size during evolution, we found that it constrained adaptation in some selection lines by restricting access to rare beneficial mutations, but that the effect varied among the genotypes in our experiment. These results suggest that mutational neighbourhood varies even among genotypes that differ by a single amino acid change, and this determines their capacity for adaptation as well as the influence of population biology processes that alter mutation supply rate.

Background Palmoplantar pustulosis is a rare but painful and debilitating disease. It consistently ranks the highest of all psoriasis phenotypic variants in terms of symptoms and functional impairment. Management of plaque-type psoriasis has been revolutionised in the last 10 years with the advent of biologic therapies, but treatment options for pustular psoriasis remain profoundly limited. On the basis of mechanistic findings which suggest a key pathogenic role for interleukin (IL)-1 in pustular psoriasis, we hypothesise that anakinra (IL-1 blockade) will be an efficacious treatment for pustular psoriasis. Methods/design We will conduct a two-stage, adaptive, double-blind, randomised, placebo-controlled trial to test the hypothesis that anakinra, self-administered daily by subcutaneous injection over 8 weeks, will deliver therapeutic benefit in palmoplantar pustular psoriasis, a localised form of pustular psoriasis typically involving the palms and/or soles. Safety outcomes will be collected for 20 weeks. A total of 64 participants will be randomised to anakinra or placebo in a 1:1 ratio. At the end of stage 1, a decision to progress to stage 2 will be made. This decision will take place after 24 participants have been randomised and followed for 8 weeks and will be based on the ordering of the observed mean outcome values in both treatment arms. At the end of stage 1, the reliability of outcome measurements and method to collect the data will also be assessed, and the primary outcome will be confirmed for stage 2. Discussion We have undertaken an adaptive approach in which we will gain proof-of-concept data prior to completing a powered efficacy trial because pustular psoriasis is a rare disease, no validated outcome measures to detect change exist, and limited safety data for anakinra exist in this population. To our knowledge, this will be the first randomised controlled trial that will provide valuable evidence for the efficacy and safety of IL-1 blockade for treatment in pustular psoriasis. Trial registration ISRCTN13127147 . Registered on 1st August 2016. EudraCT, 2015-003600-23 . Registered on 1st April 2016.

Background Current treatment options for Palmoplantar Pustulosis (PPP), a debilitating chronic skin disease which affects the hands and feet, are limited. The Anakinra for Pustular psoriasis: Response in a Controlled Trial (APRICOT) aims to determine the efficacy of anakinra in the treatment of PPP. This article describes the statistical analysis plan for the final analysis of this two-staged trial, which was determined prior to unblinding and database lock. This is an update to the published protocol and stage one analysis plan. Methods APRICOT is a randomised, double-blind, placebo-controlled trial of anakinra versus placebo, with two stages and an adaptive element. Stage one compared treatment arms to ensure proof-of-concept and determined the primary outcome for stage two of the trial. The primary outcome was selected to be the change in Palmoplantar Pustulosis Psoriasis Area and Severity Index (PPPASI) at 8 weeks. Secondary outcomes include other investigator-assessed efficacy measures of disease severity, participant-reported measures of efficacy and safety measures. This manuscript describes in detail the outcomes, sample size, general analysis principles, the pre-specified statistical analysis plan for each of the outcomes, the handling of missing outcome data and the planned sensitivity and supplementary analyses for the second stage of the APRICOT trial. Discussion This statistical analysis plan was developed in compliance with international trial guidelines and is published to increase transparency of the trial analysis. The results of the trial analysis will indicate whether anakinra has a role in the treatment of PPP. Trial registration ISCRTN, ISCRTN13127147 . Registered on 1 August 2016. EudraCT Number 2015-003600-23 . Registered on 1 April 2016.

The major histocompatibility complex (MHC) region is strongly associated with multiple sclerosis (MS) susceptibility. HLA-DRB1*15:01 has the strongest effect, and several other alleles have been reported at different levels of validation. Using SNP data from genome-wide studies, we imputed and tested classical alleles and amino acid polymorphisms in 8 classical human leukocyte antigen (HLA) genes in 5,091 cases and 9,595 controls. We identified 11 statistically independent effects overall: 6 HLA-DRB1 and one DPB1 alleles in class II, one HLA-A and two B alleles in class I, and one signal in a region spanning from MICB to LST1. This genomic segment does not contain any HLA class I or II genes and provides robust evidence for the involvement of a non-HLA risk allele within the MHC. Interestingly, this region contains the TNF gene, the cognate ligand of the well-validated TNFRSF1A MS susceptibility gene. The classical HLA effects can be explained to some extent by polymorphic amino acid positions in the peptide-binding grooves. This study dissects the independent effects in the MHC, a critical region for MS susceptibility that harbors multiple risk alleles.

Background Depression and related disorders represent a significant part of general practitioners (GPs) daily work. Implementing the evidence about what works for depression care into routine practice presents a challenge for researchers and service designers. The emerging consensus is that the transfer of efficacious interventions into routine practice is strongly linked to how well the interventions are based upon theory and take into account the contextual factors of the setting into which they are to be transferred. We set out to develop a conceptual framework to guide change and the implementation of best practice depression care in the primary care setting. Methods We used a mixed method, observational approach to gather data about routine depression care in a range of primary care settings via: audit of electronic health records; observation of routine clinical care; and structured, facilitated whole of organisation meetings. Audit data were summarised using simple descriptive statistics. Observational data were collected using field notes. Organisational meetings were audio taped and transcribed. All the data sets were grouped, by organisation, and considered as a whole case. Normalisation Process Theory (NPT) was identified as an analytical theory to guide the conceptual framework development. Results Five privately owned primary care organisations (general practices) and one community health centre took part over the course of 18 months. We successfully developed a conceptual framework for implementing an effective model of depression care based on the four constructs of NPT: coherence, which proposes that depression work requires the conceptualisation of boundaries of who is depressed and who is not depressed and techniques for dealing with diffuseness; cognitive participation, which proposes that depression work requires engagement with a shared set of techniques that deal with depression as a health problem; collective action, which proposes that agreement is reached about how care is organised; and reflexive monitoring, which proposes that depression work requires agreement about how depression work will be monitored at the patient and practice level. We describe how these constructs can be used to guide the design and implementation of effective depression care in a way that can take account of contextual differences. Conclusions Ideas about what is required for an effective model and system of depression care in primary care need to be accompanied by theoretically informed frameworks that consider how these can be implemented. The conceptual framework we have presented can be used to guide organisational and system change to develop common language around each construct between policy makers, service users, professionals, and researchers. This shared understanding across groups is fundamental to the effective implementation of change in primary care for depression.

Invasive non‐native species (INNS) are recognized as a major threat to island biodiversity, ecosystems, and economies globally. Preventing high‐risk INNS from being introduced is the most cost‐effective way to avoid their adverse impacts. We applied a horizon scanning approach to identify potentially INNS in the United Kingdom Overseas Territories (OTs), ranging from Antarctica to the Caribbean, and from the Pacific to the Atlantic. High‐risk species were identified according to their potential for arrival, establishment, and likely impacts on biodiversity and ecosystem function, economies, and human health. Across OTs, 231 taxa were included on high‐risk lists. The highest ranking species were the Asian green mussel (Perna viridis), little fire ant (Wasmannia auropunctata), brown rat (Rattus norvegicus), and mesquite tree (Prosopis juliflora). Shipping containers were identified as the introduction pathway associated with the most species. The shared high‐risk species and pathways identified provide a guide for other remote islands and archipelagos to focus ongoing biosecurity and surveillance aimed at preventing future incursions.