Pursuing a responsible and sustainable development, the United Nations urged to decouple economic growth from environmental impacts. Several European Union (EU) policies have been implemented towards such goal. Although multiple authors have evaluated the decoupling of the economic growth from the resource use or environmental concerns, the environmental assessment mostly focused on pressures rather than impacts, and used single indicators assumed to be a proxy of the overall effects on the environment. Furthermore, no studies were found using a process-based life cycle approach to quantify the environmental impacts of consumption. To solve such research gap, this paper assesses the decoupling in the EU focusing on potential environmental impacts, complementing a production-based approach with two options for accounting for the impacts of consumption. The aim of this paper is to evaluate the decoupling of the economic growth (in terms of Gross Domestic Product) from the environmental impacts due to EU-28 consumption, assessed by means of life cycle assessment (LCA). The decoupling is then assessed in impact terms rather than limited to pressures by using the Environmental Footprint (EF2017) indicators, which allows assessing 16 different impacts. The Consumption Footprint indicator quantified the environmental impacts of EU apparent consumption, including the territorial impacts (Domestic Footprint) and the embodied impacts in both imports and exports (Trade Footprint). The inventory of pressures for the trade component is compiled either with a bottom-up approach (process-based LCA of representative traded goods) or a top-down approach (input-output-based LCA). Methodological aspects influencing the decoupling assessment and the resulting outputs are presented and discussed. According to the results, the environmental impacts of EU-28 consumption showed decoupling during the last decades (2005–2014), between relative to absolute decoupling depending on the inventory modeling approach taken. Some countries showed higher decoupling levels than others displaying a heterogeneous map of EU-28 decoupling, which was led by acidification, particulate matter, land use and eutrophication impacts. Notwithstanding current limitations, the assessment of decoupling using consumption-based environmental indicators is very promising for supporting policy-making towards addressing the actual impacts driven by the EU production and consumption system. •Comprehensive assessment of the decoupling of environmental impacts of EU-28 consumption from GDP.•A life cycle perspective is taken for the environmental impact modeling.•Decoupling assessment need further refinements to be used for policy support.•Top-down and bottom-up approaches indicated from relative to absolute decoupling.•Decoupling of environmental impacts from human development index is also evaluated. Besides7th EAP)  and the 7th EAP)  are driv7th EAP)  and the 7th EAP)  have rep7th EAP) .1.1when resource use or some environmental pressure either grows at a slower rate than the economic activity that is causing it (relative decoupling) or declines while the economic activity continues to grow (absolute decoupling)” (2 emissions) and environmental impacts . Furthermore, UNEP indicated that human well-being progress should also decouple from the environmental impacts, in line with some authors that proposed using the Human Development Index (HDI) for assessing the progress of environmental policy  urged to decouple economic growth from environmental impacts . Decouplupling)” , p.23. Iupling)” . Based ol policy  or evalul policy .Fig. 1DeBoth resource and environmental decoupling have been largely evaluated in the literature, as detailed in the collection of studies in 2 emissions (2 emissions) assuming to be a proxy of the overall effects on the environment . However, addressing environmental impacts is crucial to comprehensively assess environmental decoupling. In the reviewed studies, the economic output was the driving force originating the environmental pressure: GDP  level and consumption level. The paper evaluates the decoupling of the environmental impacts of consumption in the European Union from GDP.•The environmental assessment is performed in terms of environmental impacts rather than limited to pressures. Multiple impact indicators are used, adopting the Environmental Footprint impact categories and models . Impact •The decoupling assessment is complemented by the evaluation of the decoupling of the HDI from the environmental impacts  to addre•The influence of methodological decisions is addressed to unveil the effect of inventory modeling and normalization.•The consumption impacts are modelled, adding to the production impacts those of import and subtracting those of export. The trade footprint is calculated adopting two alternative approaches: a bottom-up approach (process-based LCA of representative traded goods) and a top-down approach (input-output-based LCA related to trade).In this context, this paper contributes to the decoupling literature in a number ofaspects:1.2The goal of this paper is to evaluate the decoupling of the economic growth (in terms of GDP) from the environmental impacts of EU-28 consumption by employing LCA-based environmental indicators and exploring the methodological aspects that influence the decoupling assessment and resulting outputs. Specific objectives aim to address the following research questions:-Which are the environmental impact categories driving the decoupling? How have the EU environmental policies influenced the decoupling from environmental impacts?-To what extent does life cycle modeling and impact assessment affect the assessment of decoupling?-Which are the environmental issues missing in the current assessment?-How can decoupling be assessed beyond GDP?- How has GDP decoupled from the environmental impacts of EU-28 consumption in the timeframe (2005–2014)? How is the environmental decoupling taking place in the different EU countries in the timeframe (2004–2011)?2The decoupling of GDP from environmental impacts due to EU-28 consumption was evaluated through the decoupling index (DI). The environmental impacts were quantified by adopting the LCA-based Consumption Footprint (CF) set of indicators . The CF 2.1The decoupling can evaluate how resource use or environmental impact are linked to the economy by calculating a specific index, such as proposed by -Absolute decoupling: DI < 0, ΔEI<0, ΔGDP>0. The environmental impact decreases while the economic output keeps growing.-Relative decoupling: 0<DI<1, ΔEI>0, ΔGDP>0. The environmental impact increases although at a slower pace than the economic output.-Non-decoupling: DI > 1, ΔEI > 0, ΔGDP>0. The environmental impact increases more than the economic growth.-Stagnant: DI≠0, ΔEI<±0.1, ΔGDP≤0. The economic output remains stable or decreases while the environmental impact shows a small variation, suggesting that the decoupling is linked to the stagnation of the economy.The environmental decoupling was classified in:The classification has been adjusted from the one proposed by 2.2The Consumption Footprint (CF)  is an LCThe CF takes into account both the impacts associated with domestic activities  (Domestic footprint) and the ones associated with trade (i.e. embedded impacts of imports and exports) (Import and Export footprints).The CF is calculated as:The Domestic Footprint (DF)  quantifi•Consumption Footprint Bottom-up (CF-BU): the DF was combined with trade impacts calculated based on the process-based LCA , 2006b o•Consumption Footprint Top-down (CF-TD): the DF was combined with trade impacts calculated using sectorial-based Multi-Regional Input-Output Tables (MRIOTs), considering the Exiobase database version 3 .Concerning the trade component of the CF, two approaches were followed to build the inventory of emissions and resources related to import and export :•Consump2.2.1This section details the compilation of the inventory data for the DF, CF-BU and CF-TD.Domestic Footprint (DF). The DF relied on a vast inventory consisting of data on emissions and resource extraction and use in EU-28 territory, as detailed in Consumption Footprint Bottom-up (CF-BU) in which the Trade is based on Bottom-up Footprints. The CF-BU built upon the above-described DF, combined with import and export inventories based on process-based LCA of representative products of traded goods selected from Comext statistics . The up-Consumption Footprint Top - Down(CF-TD) in which the Trade is based on Top-Down Footprints. The CF-TD built upon the above-described DF, combined with import and export inventories calculated using sectorial-based and environmentally-extended MRIOTs . The hyb2.2.2The EF LCIA (EF2017) method  was adop2.3-limitations of the top-down data collection: regarding top-down trade and consumption footprints, Exiobase data for 2000–2003 period showed multiple outliers in different impact categories while data were not available for the 2011–2014 period and were extrapolated (linear extrapolation excluding outlier years);-limitations of process-based data collection: concerning the bottom-up approach (both trade and consumption footprints), calculations were made for four distinct years . For the remaining years, the trade component was obtained based on interpolation according to the environmental results of the calculated total mass of imported and exported volumes (trade). The interpolated results were added to the calculated DF thereby obtaining an interpolated value for the CF-BU.The geographical and temporal scope depended on the assessment approach and component  . Data ava)maximum inclusion of years available in both top-down (2004–2014) and bottom-up  approaches to allow a comparative assessment;b)maximum time coverage of more robust data available at EU level.Therefore, the criteria to define the timeframe 2005–2014 for this study were:As the top-down approach is dependent on external data sources for the trade component , years beyond 2015 cannot be included in the assessment as extrapolation methods should be used, as already applied for the period 2012–2014. In this sense, enlarging the time period would include further uncertainties to the assessment.2.4The decoupling of the economic output from resource use due to EU consumption was assessed in order to outline the differences between resource and environmental decoupling. The Domestic Material Consumption (DMC) indicator was selected for this purpose, considering the following aspects. First, DMC has already been used in the decoupling literature . Second,2.5Environmental decoupling has been mostly assessed considering the economic growth as reference , as indicated by the Alternatives to GDP were presented and evaluated in the literature . van den3This section illustrates the evaluation of the decoupling related to the environmental impacts of EU consumption. In a first section, the decoupling assessment for the DF, CF-BU and CF-TD is reported. The resource decoupling is also assessed. Moreover, the environmental decoupling is analyzed at the country and impact category level. Finally, decoupling is assessed beyond GDP by employing the HDI indicator.3.1The GDP showed decoupling from the environmental impacts of EU-28 consumption for the period 2005–2014 . While t3.1.1During the assessed period (2005–2014), the single score DF was reduced by 19% following a continuous decrease. Compared to a GDP increase of 8%, the single score DF showed an absolute decoupling between 2005 and 2014. This result indicates the environmental impacts resulting from the consumption in EU-28 were reduced within the borders of the EU, i.e. considering a production- and territorial-based perspective, for the assessed impact categories.3.1.2The single score CF-TD showed a stable trend between 2005 and 2014 (−0.2%) . Two difAssessing trade is crucial to understand the results since the environmental impact of DF showed a constant decrease during the evaluated period, contrarily to the increase of the environmental burdens of imports  and exports . In percentage, the exports had a larger increase than imports. However, the impacts of imports in the CF-TD were two times bigger than those of domestic and exports impacts, in absolute terms. Therefore, the increase of imports drastically affected CF-TD and compensated the decrease of domestic impacts and the increase of embodied environmental impacts exported from EU. Results in absolute terms are reported in the supplementary material (ESM 2).3.1.3The economic growth decoupled from the EU-28 CF-BU in absolute terms, as the single score indicator of the environmental impact decreased by 23% while the GDP grew by 8% . As for 3.1.4The resource use indicators domestic extraction (DE) and DMC were analyzed and both showed a decreasing trend between 2005 and 2014  . The behBoth DE and DF decreased along the assessed period, however DF showed a higher decreased (−19%), outlining that the environmental decoupling was more intense than the resource decoupling. Although having a similar decrease between 2005 and 2014, the trend of both indicators varied along the period. While the DF followed a continuous decrease, the DE increased until 2007, drastically decreased between 2008 and 2010, as a result from the economic crisis, and presented an irregular decrease during the last period (2011–2014). In this sense, the DE had a relative decoupling until 2007 and an absolute decoupling for the rest of the period, apart from years of DE increase .In the same line, CF-BU (−23%) showed an aligned behavior with the DMC (−17%) indicator as both decreased between 2005 and 2014, but this trend was more intense for the environmental impact than for the resource use. As well, while the CF-BU showed a decreasing trend along the entire period, the DMC increased during the first period (until 2009) and decreased from then.The comparison of the pairs DE-DF and DMC-CF-BU unveiled a divergent trend between resource use and environmental impact indicators. This fact highlighted the contrast behavior of (a) single and composite indicators, and (b) resource depletion and environmental impact.3.2The EU-28 as a single entity had a positive trend towards environmental decoupling. However, EU countries showed different and contrasting profiles. 3.2.1Examples of each decoupling group  were evaluated to determine the drivers of the largest changes in the environmental impacts of individual countries. The consumption component, the flows, the economic sectors and the products leading the change in the environmental indicators were identified (ESM 3).2.5 emissions (Estonia) and a decreased trade of manufactured products - particularly with electronic parts  (Slovakia) and of bio-based products   motivated the decreasing trends in the CF-TD of absolute decouplers.Absolute decouplers: Slovakia, Poland, Lithuania and Estonia. A decreased production of electricity from non-renewable sources  (Lithuania), a variation in the domestic PM4.Relative decouplers: Czech Republic. Changes in CF-TD of relative decouplers were produced by increased food exports, reduced hard coal consumption compensated by increased crude oil imports, and enlarged domestic emissions of CO and CHStagnant countries: Greece and Italy. An improved energy mix and reduced food imports , improved wastewater treatment, decreased domestic SOx emissions and increased food imports (Greece) defined the impact trends of stagnant countries.Non-decouplers: Luxemburg, Netherlands and Germany. An increased import of meat , increased import of metal manufactured products (Luxemburg) and increased imports of gold and other industrial minerals (Germany) were the main drivers towards a non-decoupling consumption.3.2.2Regarding the midpoint indicators, CC, PM and MRD had the main role, contributing to between 49% and 57% of the CF-TD weighted score during the entire period. FRD, WU, LU and AC represented more than 5% each for the entire period. While for CF-BU, CC (26–28%), PM (19–20%) and FRD (18–19%) were the most contributing categories to the weighted score for years 2005 and 2010 (ESM 4). The relevance of these categories in the weighted score was also related to the weighting factors adopted in the EF2017 scheme  (ESM 1).During the assessed period, the impact categories showed a decreasing trend  for the CF-TD approach, apart from HTOX_c (+1%) and MRD (+127%). In fact, MRD was the only category that showed no decoupling from the GDP, which is in contrast with the reduction observed for the pressure indicator DMC. On the contrary, all the indicators followed an absolute decoupling trend for the CF-BU, ranging between −1% (LU) and −88% (HTOX_nc) (ESM 5). Furthermore, HTOX_c obtained negative values in the CF-BU, indicating that the embodied impacts in exports were higher than the domestic and imported ones. This is a clear limitation of the representative products currently modelled. Hence, results are illustrative of the possible methdological approach but are still not mature to be used to draw conclusions on the impacts trend.Furthermore, the analysis of DF at the indicator level allows for assessing the possible effects of EU policies acting on the environmental aspects. The effect in the environmental burdens of some policies that entered into force within the considered timeframe or a few years before , 2001 wa3.2.3Concerning the assessment of whether human well-being decoupled from the environmental impacts of consumption and how the result varies from the GDP decoupling, When comparing the use of the two reference indicators (GDP and HDI), some trends were observed. In general, the environmental decoupling employing HDI was more dichotomic than when using GDP and countries were absolute decouplers or non-decouplers, apart from Hungary that showed a relative decoupling in both cases . The number of countries which are non-decouplers and absolute decouplers increased compared to the graph illustrating decoupling to GDP. Firstly, those countries with a decreasing environmental impact trend (between −7 and −80%) were absolute decouplers considering both the GDP and the HDI. Furthermore, the group of stagnant countries  disappeared and became absolute decouplers because, contrary to the GDP, the HDI increased for all the EU-28 countries along the assessed period. Secondly, as GDP had growing rates larger than the HDI, the non-decouplers showed the same behavior for GDP and HDI as the environmental impact growth was still higher (between 17 and 76%). Finally, most of the countries with relative decoupling when using GDP had a larger CF-TD growth (5.5–9.4%) than the HDI variation (2.9–4.2%), resulting in non-decouplers when assessing well-being. In this last case, the HDI increase was between 1.4 and 8 times smaller than the GDP one.In terms of population, four out of the six most populated EU countries  were in both cases either decouplers or stagnant . While Germany showed no environmental decoupling in both cases, the GDP of Spain had a relative decoupling from the environmental impacts but the HDI showed no decoupling. Similarly to Spain, some of the mid-populated countries (10–20 million inhabitants) changed from relative decouplers (GDP) to non-decouplers (HDI) , apart from Hungary which remained as relative decoupler in both cases. The rest of mid-populated countries revealed as specific cases: The Netherlands was a non-decoupler in both cases, Portugal was an absolute decoupler for both indicators and Greece changed from stagnant (GDP) to absolute decoupler (HDI). The least populated countries (<3 million inhabitants) showed absolute decoupling in both cases, apart from Luxembourg which resulted in non-decoupler (both GDP and HDI). In absolute terms, assessing the GDP decoupling from the environmental impacts of consumption identified a larger amount of population as decoupler or being stagnant (383 million inhabitants) than when considering HDI (353 million inhabitants). Such trend implied that for each inhabitant having a consumption pattern without decoupling, 3.25 inhabitants were having consumption patterns that showed decoupling when using the GDP as economic indicator and only 2.4 when considering the well-being indicator HDI.44.1The environmental impacts of EU-28 consumption showed decoupling during the last decades (2005–2014) as suggested by the literature for waste generation  and for The assessment stressed the relevance of consumption-based approaches in assessing the decoupling phenomenon as discussed in the literature . DF deco4.24.2.1Input-output LCA and process-based LCA were contrasted by confronting CF-TD and CF-BU, respectively. In both approaches, the CF was higher than the DF and, thus, EU-28 was a net importer of environmental impacts. One of the main divergences between both approaches relied on the MRD impact category. MRD represented only 2% of the impact in CF-BU but was a major driver in CF-TD (from 13% to 24%) as the inventory was highly aggregated in Exiobase and different types of minerals were characterized with a singular characterisation factor, as discussed in -A DF based on statistical data was merged with a trade footprint calculated based on two different modeling approaches: process-based LCA (CF-BU) and input-output-based LCA (CF-TD).-The elementary flows coverage was not the same for these components in the calculation of the environmental impacts of consumption: around 2,000 (DF), around 15,000 (process-based LCA trade footprint in CF-BU) and 78 (input-output-based LCA trade footprint in CF-TD).-The top-down approach (CF-TD) with an input-output-based LCA trade footprint included the impacts of matter-less economic sectors , while these were excluded from the bottom-up approach (process-based LCA).-The top-down approach (CF-TD) was more correlated to monetary flows while the bottom-up (CF-BU) one followed the trend of mass flows. Regarding CF-BU, the decrease of the environmental impact can be related to the fact that more semi-finished materials or finished products are consumed in the EU. This could be the real issue at stake, i.e., the material footprint embedded is higher but the mass which is imported is less. This again my question the represenativness of the selected products.The following differences between the two environmental modeling approaches arose as limitations of this comparison:Therefore, from an inventory perspective, a compromised solution combining the benefits of both approaches might provide with results better mirroring the reality.4.2.2The normalization and weighting of the characterised values and the inclusion of different midpoint impact categories can alter the single footprint outputs and the decoupling assessment. While previous literature showed no normalization steps and used single indicators, the sensitivity analysis of varying these aspects in LCA unveiled a considerable influence. The evaluated results followed a global normalization step to show the evolution of EU-28 environmental impacts compared to global environmental impacts, and included 14 EF categories. However, the assessment at the country level can be also performed applying EU-28 normalization factors to compare the countries with an EU reference. All the 16 EF categories can be assessed for DF  (ESM 6).The sensitivity assessment unveiled some divergences. First, global normalized results were more positive than EU-28 ones as the EU-28 share of the global environmental impacts was limited (<10%). Thus, while globally normalized DF results showed an almost-green map, absolute decouplers were more restricted in EU-normalized ones. Second, using EU-28 normalization sets the average EU-28 trend for a determined timeframe  as the reference behavior, leading to potential opposite trends in the characterized and the normalized values. For example, although the AC impact of all EU-28 countries decreased following the policy implementation against related emissions, Luxemburg's decreasing rate (−4%) was lower than the EU average, resulting in an increasing normalized trend (+28%).Third, the role of each impact category varied regarding the normalization type as the global share of EU-28 impacts depends on the midpoint category: EU-28 had more relevance in IR (68%), PM (12%), CC (9%) and FEU (8%), while a low effect to LU (3%) and MRD (2%) (ESM 6). Thus, the contribution of each country to the midpoint categories can result in a different decoupling output based on the normalization and the number of impact categories included in the assessment . In part4.2.3Defining the temporal scope of a decoupling assessment can influence the results due to specific events  Although the CF-TD showed a stable trend for 2005–2014, the annual decoupling assessment unveiled that decoupling occurred at the beginning (2005–2007) and ending  years while non-decoupling took place along the period 2008–2011, due to the economic crisis and the decreased economic output, and 2013 (ESM 8). Regarding the midpoint categories, none of them followed the same pattern along the entire timeframe and the economic crisis severely affected 2009 and 2010. The categories that showed more years of absolute decoupling were FEU, CC and LU, antagonistically to HTOX_c. The assessment of the annual decoupling is common in literature  and can Regarding DF, robust data was available for the period 2000–2014 (ESM 9), which showed slightly more absolute decoupling in EU-28. Italy and Greece were stagnant in both cases as GDP was stable (0%) or decreasing (recession). While both Finland and Estonia were relative decouplers for 2005–2014 due to an increase of MEU and MRD (Finland), and CC and HTOX_c (Estonia), only Latvia was a relative decoupler for the longer period (2000–2014) due to an increase in CC. Decoupling assessment of longer periods could provide information about the mid- and long-term effects of policy implementation. In this case, EU-28 is leading the development and implementation of environmental policies as observed in the absolute decoupling results for the DF, which were even better for a longer evaluation timeframe.4.2.42 emissions with results indicating a very limited relative decoupling and, thus, the consideration of all GHG emissions could result in a non-decoupling behaviour  encompassed multiple environmental pressures and impacts (at least 14 categories), thereby attempting a comprehensive accounting of the environmental impact of EU-28 consumption. This represents a clear novelty of this work compared to previous studies. In the literature, most of the analysis focused on a single environmental impact and the environmental modeling was very limited. For instance, some studies assessing climate change only accounted for COour e.g. .The extensive impact assessment conducted in this study was highly data demanding, and it relied on a wide variety of sources and models to populate the underpinning environmental pressures. For calculating the inventory of emissions and resources, data were retrieved from: public statistics, environmental modelling for data gap filling, life cycle inventories, multi-regional input-output databases, as detailed in Besides, there is an increasing awareness of the level of impacts posed by current patterns of production and consumption, e.g. leading to an unprecedented decrease in biodiversity at global level  and in b5This paper evaluates the decoupling of GDP from the environmental impacts of EU-28 consumption by employing LCA-based environmental indicators and exploring the methodological aspects that influence the decoupling assessment and resulting outputs. The methodological approach and results contribute to the literature by adopting an LCA perspective that assesses environmental decoupling in impact terms rather than pressures, as well as using a set of multiple impact categories.The environmental impacts of EU-28 consumption showed decoupling during the last decades (2005–2014), behaving as between relative (−0.2% change) and absolute (−23%) decoupler, depending on the environmental modeling approach taken. However, decoupling had a different intensity along the EU territory. Some countries showed higher decoupling levels compared to others, thereby displaying a heterogeneous map of the decoupling in the EU-28. In general, southern countries showed better results  than northern countries, apart from water consumption.Trade variation and the economic crisis of started in 2008 had a strong effect on the results. The CF was higher than the DF highlighting the role of EU as a net importer of environmental burdens. The imports of meat, minerals for manufacturing products, manufactured products, and non-renewable energy sources were the main contributors to increased environmental burdens in non-decoupling countries. The economic crisis severely affected trade patterns and the environmental burdens decreased during the following two years due to a lower consumption in EU countries. This positively affected the decreasing trend for the assessed period. Towards exploring the economic changes behind the trend of the environmental impacts, a decomposition analysis could shed light on whether structural changes, technology progress or trade patterns were the main contributors e.g., .The decoupling of GDP from environmental impacts of EU consumption was led by acidification, particulate matter, land use, and eutrophication impacts. The results stressed out the need to assess decoupling from a consumption perspective towards including the environmental burdens taking place in developing countries where environmental policy is less strict. Accordingly, environmental policy could force changes beyond the EU-28 territory by considering traded products. This would broaden the current positive effect in the EU territory, according to the assessment of implemented EU policies and the trend of the affected environmental impact categories.Methodologically, the top-down approach showed higher values of environmental impact in absolute terms and a stable trend along the assessed period. Input-output-based LCA considers all the economic activities, including the immaterial ones . However, the quantification of the environmental burdens is less accurate than in process-based LCA due to the constraints of the environmental extensions. On the contrary, the bottom-up approach showed better results and trade had larger relevance than domestic impacts. Process-based LCA excludes the services of the environmental modeling and it is based on representative products. Since both approaches show drawbacks, a more accurate accounting of the environmental decoupling might be situated between the top-down and the bottom-up approaches.Furthermore, the way of modeling the environmental impacts was key in the assessment of decoupling and further improvements might be performed to better mirror the reality. In the same line, data availability and origin influenced the robustness of the calculations as different completeness of data added uncertainty to the results. On the other hand, the paper discussed how life cycle modeling and impact assessment can affect the results by observing the sensitivity to different normalization , number of indicators  and timeframe. EU-28 role in global environmental impacts as well as the weighting scheme of EF2017 were revealed as key aspects in the total outputs. As well, the impact assessment method employed (EF2017) missed some environmental impacts related to consumption . Further research might address the modeling of these missing environmental aspects related to consumption in life cycle assessment.Following discussions about the relevance of GDP but the constraint vision of this economic indicator to track progress, the study employs HDI to evaluate the decoupling of human well-being from environmental impacts. Assessing decoupling beyond GDP allows exploring the environmental decoupling of human well-being by considering social sustainability aspects rather than exclusively economic development. While the HDI can be a useful indicator for this purpose with available annual worldwide data, the Genuine Progress Indicator (GPI)  would beHowever, to assess sustainability of production and consumption, the decoupling assessment is not enough. Understanding to which extent the impacts transgress planetary boundaries it is essential to ensure that the decoupling is not only a measure of eco-efficiency but an effective indication of an improved sustainability.


In the last few years click chemistry reactions, and in particular copper-catalyzed cycloadditions, have been used intensively for the preparation of new bioconjugate molecules and materials applicable to biomedical and pharmaceutical areas. This review will be focused on conjugates of the tripeptide Arg-Gly-Asp formed by means of click chemistry reactions. This sequence is a well known binding motif for specific transmembrane proteins and is involved in cellular adhesion to the extracellular matrix, allowing the selective recognition of the biomolecule or polymer in which it is incorporated. The reactions must be modular, wide in scope, give very high yields, generate only inoffensive byproducts that can be removed by nonchromatographic methods, and be stereospecific. The required process characteristics include simple reaction conditions , readily available starting materials and reagents, the use of no solvent or a solvent that is benign (such as water) or easily removed, and simple product isolation.” These are the set of general criteria indicated by Kolb, Finn and Sharpless in 2001 to define a “click chemistry” reaction Fluorobenzaldehyde ([18F]FB-CHO) was prepared from the 4-formyl-N,N,N-trimethylanilium precursor via direct no-carrier-added 18F-fluorination and, after purification, it was coupled to aminooxy-functionalized peptides with an overall radiochemical yield (decay corrected) of up to 40%  PET tracer as a prosthetic group for the synthesis of 18F-labelled peptides. Gambhir and co-workers synthesized two labelled RGD-containing peptides 4 and 5via chemo-selective oxime ligation FDG [18F]FDG was obtained by HPLC separation from excess glucose of the [18F]FDGTUM prepared from routine in-house synthesis at the Technische Universität München (TUM). The corresponding conjugate was obtained in yields of up to 93% (decay corrected) and activities up to 37MBq -ONH[18F]FDG . No-carrto 37MBq .in vivo biodistribution study in M21 melanoma-bearing nude mice, [18F]FDG-RGD showed increased tumor accumulation compared to [18F]-galacto-RGD, the only integrin-ligand presently in clinical studies  cycloaddition-retro-Diels-Alder reaction (crDA) to form stable triazole-linked compounds. As this reaction can be performed in aqueous media, at ambient temperature, and in absence of copper, it represents a valid alternative to the classical Huisgen azide-alkyne cycloaddition. Moreover, oxanorbornadiene derivatives possess an increased reactivity towards azides compared to the corresponding electron-deficient alkynes. Although both double bonds can react, the 1,4,5-substituted triazoles were predominantly formed  10via oxanorbornadiene derivatives (vβ3 (IC50 = 192 nM) and favourable pharmacokinetics.The absence of copper during the conjugation step is particularly useful for the introduction of ligands for radiolabelling such as DTPA. A DTPA radiolabel was conjugated to a ivatives  21]. Pr. PrN-δ-a111In was selected because of its long half-life: 67.2 h and its stability in the DTPA chelate) was determined, confirming specific accumulation of the conjugate in αvβ3-integrin-expressing tissues  via 1,3-dipolar cycloaddition thus generating a fluorescent high avidity binding agent -Gly-Xaa-] -workers . The syn3-Gly-Gly-Arg(Pbf)-Gly-Asp-propargyl) was synthesized by standard solid-phase peptide synthesis strategy on resin. The cyclization was performed in solution and a variety of reaction conditions were evaluated to optimize the process. The best results were obtained employing 1/3 mol per cent of CuBr/DBU as the catalyst and dichloromethane as the solvent. The cytotoxic activity of all the cyclopetide analogues was evaluated using MTT method, showing, in some cases, activities comparable to cRGDfK that was employed as the positive control.The linear peptide analogue  catalyst (vs. cyclic monomers). The process resulted independent of the peptide sequence but the need for a long and flexible chain was confirmed by the fact that peptides shorter than hexamers were predominantly converted to cyclic monomers . Th. Thv intmonomers .NTGA) 14.The preparation of a glycosylated RGD derivative in order to evaluate the value of a triazole moiety as an amide isostere in terms of electronic properties and atom placement has been recently described by Rutjes and co-workers . The autN-1-β-gluco-Asn]) 15. Moreover, biodistribution studies indicated that the glycosylated peptide showed improved pharmacological properties compared to more hydrophobic/lipophilic peptides such as c(RGDyV).The presence of the triazole analogue increased the chemical stability of the compound with respect to the amide linked c (PEG), a hydrophilic polymer able to absorb large amounts of water and showing low immunogenicity represents a good substitute. Yang and co-workers prepared biodegradable PEG-peptide hydrogels containing the RGD sequence as potential cell delivery vehicles . A stablvia copper-mediated cycloaddition in ambient conditions. Due to the fact that all the reaction by-products had a high solubility in aqueous solution, the purification of the gel was performed successfully by simple washing. The density on the hydrogel surface of both peptides was good, as well as the increased extent of mineralization of the BMS cell, obtained by the synergistic action of RGD and BMP peptides.Analogously, Jabbari and co-workers took advantage of the combination of RGD peptides and hydrogel substrates to develop engineered scaffolds. The aim of the work was the grafting of the RGD peptide and BMP-2 (bone morphogenetic protein-2) peptide onto biodegradable inert hydrogels, and their use as scaffolds for the regeneration of skeletal tissues through osteogenic differentiation and mineralization of bone marrow stromal (BMS) cells . The hydClick chemistry reactions have been largely used also for the functionalization of self-assembled monolayers (SAMs). A SAM is an organized layer of amphiphilic molecules formed on a variety of inert surfaces, including glass, silicon, gold diamond and amorphous carbon. The amphiphilic layer terminates with a head group showing special affinity for a substrate. Due to the capacity of controlling surface properties, such as bioinertness or biomolecule presentation, SAMs have emerged as helpful tools in the study of biochemical interactions.Following this concept, Hudalla and Murphy prepared SAMs formed from the mixed coordination of different alkanethiolates onto a gold-coated substrate. In particular the authors used azide-terminated hexa(ethylene glycol) alkanethiolate and tri(ethylene glycol) alkanethiolate to prepare a SAM presenting groups to allow for a click chemistry conjugation. Immersion of the functionalized gold substrate into a solution containing the peptide Arg-Gly-Asp-Ser-Pro bearing a terminal alkyne moiety and the catalytic mixture CuBr and sodium ascorbate led rapidly and quantitatively to the chemoselective linkage of the peptide to SAM through the CuAAC reaction . Terminavia copper-catalyzed triazole cycloaddition  groups of alkanethiol chains were functionalized with phenoxy squarate, which is able to couple covalently at pH 5.5 with ectively b. Peptidon assay .The previuos examples have demonstrated that the incorporation of the RGD sequence onto a polymer or a substrate is a quick method to produce innovative materials able to promote cell adhesion and growth. The following examples will extend to the usefulness of click chemistry for other types of functionalized materials and in particular the use of CuAAC as a successful way to introduce the well-recognized adhesive RGD motif.via click triazole synthesis of the RGD motif [co-lactide) with a hydrophilic PEG functionalized with azide groups. The amphiphilic polymer obtained presented azide moieties on the surface for further modification with the alkyne-KGRGDS peptide by CuAAC  have allowed the conjugation of a number of different biomolecules, thus obtaining large and complex systems with tailored properties. Among these bioconjugate compounds, structures containing the highly recognized RGD tripeptide motif have obtained remarkable interest. The ability to bind selectively to transmembrane proteins on the cell surface and to involve cellular adhesion has allowed RGD to be a useful tool for the functionalization of (bio)materials and for the transfer of particular properties. Selective molecular probes carrying radiolabel atoms or fluorescent moieties have been prepared and used for the identification of specific target cells. In the biopolymer area, new materials able to act as cell attachment and proliferation points have opened the route to new and attractive possibilities of bioconjugation. Undoubtedly that the beneficial effects of click chemistry for the synthesis of biomolecules containing the RGD system will ensure the growth of this area in the future.


Catheter-associated asymptomatic bacteriuria (CAABU) is frequent in intensive care units (ICUs) and contributes to the routine use of antibiotics and to antibiotic-resistant infections. While nurses are responsible for the implementation of CAABU-prevention guidelines, variability in how individual nurses contribute to CAABU-free rates in ICUs has not been previously explored. This study’s objective was to examine the variability in CAABU-free outcomes of individual ICU nurses. This observational cross-sectional study used shift-level nurse-patient data from the electronic health records from two ICUs in a tertiary medical center in the US between July 2015 and June 2016. We included all adult (18+) catheterized patients with no prior CAABU during the hospital encounter and nurses who provided their care. The CAABU-free outcome was defined as a 0/1 indicator identifying shifts where a previously CAABU-free patient remained CAABU-free (absence of a confirmed urine sample) 24–48 hours following end of shift. The analytical approach used Value-Added Modeling and a split-sample design to estimate and validate nurse-level CAABU-free rates while adjusting for patient characteristics, shift, and ICU type. The sample included 94 nurses, 2,150 patients with 256 confirmed CAABU cases, and 21,729 patient shifts. Patients were 55% male, average age was 60 years. CAABU-free rates of individual nurses varied between 94 and 100 per 100 shifts  and were robust in cross-validation analyses . Learning and disseminating effective CAABU-avoidance strategies from top-performers throughout the nursing teams could improve quality of care in ICUs. Catheter-associated urinary tract infections (CAUTI) are the most common hospital-acquired infection, contributing to increased mortality, morbidity, and costs in the United States and internationally , 2. In iCatheter-associated asymptomatic bacteriuria (CAABU) is the most important risk factor for CAUTI in ICUs. Urinary catheters are used routinely in ICUs for patients with limited mobility, especially if urine must be kept away from wounds , and for accurate monitoring of urinary output . FifteenNurses comprise the majority of the clinical workforce in ICUs and are directly responsible for catheter insertion, care, and surveillance. Recognizing the importance of nurses in infection prevention, the National Quality Forum, the leading non-profit organization focusing on healthcare quality in the US, includes CAUTI among nurse-sensitive infection measures . While tExisting studies linking reduced hospital-acquired infections to nursing care in ICUs have focused on nurse staffing and the work environment characteristics measured at the aggregated hospital- or unit-level –23. HoweThis retrospective observational cross-sectional exploratory analysis of data from electronic health records (EHR) used a split-sample design for estimation and cross-validation of individual nurse CAABU-avoidance rates. We estimated nurse-level variability by applying an individual performance measurement method from the field of education economics, called Value Added Modeling (VAM) . This meFor each individual patient, data elements included: 1) a list of all ICU shifts where the patient had a catheter inserted or indwelling during the shift, with the date and an indicator of day/night shift, 2) nurse login identifiers by shift during ICU stay, 3) if any, a confirmed positive laboratory report of bacteriuria with the timestamp, 4) if any, a confirmed CAUTI report with the timestamp, and 5) patient clinical and demographic characteristics. There were no missing data.The study site was a 559 bed academic medical center in the Midwestern US with 8 ICUs and approximately 7,500 annual adult ICU encounters. Two adult ICUs, a medical ICU (MICU) and a neurological ICU (NeuroICU), with the most frequent use of indwelling catheters and highest CAABU rates were nominated by the site’s infection prevention team for inclusion in this study. During the data extraction period, the two study ICUs were similar . The ICU length of stay (LOS) was higher in the MICU than in NeuroICU (5.5 vs 4.6 days). The hospital used 12-hour nursing shifts (7 a.m. to 7 p.m.) as their ICU staffing schedule and a 1 nurse to 2 patients ICU staffing ratio. The hospital had a nurse-driven decatheterization protocol  in placeThe hospital used standard United States Center for Disease Control and Prevention (CDC) criteria for CAABU/CAUTI identification . For CAAWe included all inpatient admissions to the MICU and NeuroICU between July 1 2015 and June 31 2016 for patients who were 18 or older at the time of admission and had an indwelling or intermittent urinary catheter while in ICU. The study sample included 2,184 patients and 21,729 ICU patient-shift encounters, defined as a patient occupying a bed during a 12 hour shift. Each patient-shift encounter represented a data point for the analyses. Because the study focused on CAABU prevention activities in ICUs, we excluded 34 patients who had a report of positive CAABU or CAUTI prior to or at admission to the ICU. For patients who had a report of a positive CAABU or CAUTI at any point during the ICU stay, we retained only patient-shift encounters that occurred prior to the date and time of the report. The final analysis sample included 17,331 patient-shift encounters . ICU patient-shift encounters with hospitalization discharge dates during the first six months of the data extraction timeframe from July 1 to December 31 of 2015  were used as the estimation dataset; the second six months of data from January 1 to June 31 2016  were used for cross-validating the estimates.The nurse sample included 110 full-time registered nurses  who provided care during the ICU patient-shift encounters included in the final sample. Float nurses were excluded. We conducted post-hoc power analysis for the minimum number of patient-shift encounters per nurse required to detect an individual nurse effect on CAABU equal to 0.05705 . Using a one-sample proportion test against the alternative of 0.000001 (approximating zero), 45 patient-shift encounters per nurse were required to achieve 0.80 power and 0.05 one-tailed significance in the estimation dataset. We excluded 16 nurses who were linked with fewer than 45 patient shifts during the first six months of the study since this presented too few encounters to appropriately classify their CAABU-free outcomes, thus yiedling the final nurse sample of 94 registered nurses (45 from Neuro ICU and 49 from MICU). Of the 94 nurses in the estimation set, 89 were also in the validation set (5.6% loss to follow-up).For each patient-shift encounter, the CAABU-free outcome was defined as a 0/1 indicator variable equal to 1 if there was no record in the patient’s EHR of a confirmed CAABU-positive urine sample collected between 24–48 hours following the end of the encounter, and zero otherwise (if there was a record of a positive CAABU specimen). The event window of 24–48 hours after the end of shift is consistent with the CDC’s infection location attribution rule for multiple transfers that specifies a 24 hour minimum gap and a 48 hour maximum limit on infection attribution . There wPer the VAM methodology described below, individual nurses were the exposures. Each nurse was assigned a unique anonymous indicator variable differentiating the nurse from the other nurses in the sample . For every patient-shift encounter, the nurse indicators of all nurses who provided care to the patient during the encounter were set to 1, the indicators of all other nurses (who did not take care of the patient during the shift) were set to 0.Descriptive statistics for the sample were calculated as means and standard deviations for continuous variables and counts and percentages for categorical variables.The CAABU-free outcomes of individual nurses were estimated on the estimation dataset of 8,572 patient-shift encounters linked to 94 nurses in the 2015 sample.The estimation model followed the VAM methodology –26. The Because the likelihood of developing CAABU can depend on a patient’s internal factors, we adjusted for patient clinical acuity and demographic factors, including: an indicator for the male gender [female gender was the reference category], a continuous variable for age (in years), twenty-one indicators for the patient’s Major Diagnostic Category (MDC) from primary discharge ICD-9/10 codes [MDC = “DDs of Nervous System” was the reference category],–31 an inTo adjust for correlated effects in CAABU occurrence in space proximity and over time, we included shift-level control variables: a continuous variable for the number of hours the patient was in the ICU prior to the beginning of the shift, six indicators for the day of the week [Sunday was the reference category], and an indicator for a day shift [night shift was the reference category]. We also included an indicator for the MICU [NEURO was the reference category] to adjust the model for any differences in CAABU occurrence attributable to unit-level structure and care processes . The model was estimated with clustering at the patient-shift and the ICU- level refer to .We then calculated the nurses’ CAABU-free rates. Using the fully adjusted VAM estimates of the regression coefficients of the nurse indicator variables, we computed CAABU-free rates as the predictive margins of responses for the nurse indicator variables , 33. TheWe examined the sampling frequency distribution of the nurse-level CAABU-free rates and reported their mean, standard deviation, skewness, kurtosis, and the Kolmogorov-Smirnov normality test.To test the role of nurse variability for the CAABU outcome, we conducted two tests. First, using Cohen’s Chi-squared joint test of significance , we testBefore applying the cross-validation approach, we tested for random, versus selective, assignment of nurses to patients. If higher-performing nurses (higher CAABU-free rates) were selectively assigned to lower acuity patients, the VAM estimation approach would over-estimate nurse-level outcome differences. Vice versa, if higher-performing nurses were selectively assigned to higher-acuity patients, the estimated distribution of nurse-level CAABU rates from the VAM approach would understate true nurse-level outcome variability. Either biases would reduce the validity of the VAM estimates. Therefore, we tested the null hypothesis that the nurses’ CAABU-free rates from 2015 were not associated with the characteristics of the nurses’ assigned patients in 2016 (random assignment), using a Chi-square test for the patient’s MDC and insurance type and t-tests for all other patient variables. Failure to reject the null hypothesis of random assignment would support validity of the VAM measurement approach.We then examined the concordance of nurse-level CAABU-free rate estimates generated by the VAM approach in the two independent patient samples (2015 and 2016). To do so, we estimated a second set of adjusted individual nurse CAABU-free rates using the 8,579 patient-shift encounters linked to the 89 nurses in both the 2015 and 2016 patient samples refer to  and calcnd, 3rd, and 4th quartile; first quartile was the reference category). We then calculated predictive margins of responses for the 2015 quartiles on each of the 2016 quartile transitions (including same-quartile transitions) and their 95% confidence intervals. For each of the transitions, we tested the null hypothesis that the probability of transition was equal to 0.25, against the alternative that it was greater than 0.25, using a one-tailed Chi-square test at the 5% significance level. The premise of the test was that if the observed differences in the nurses’ 2015 CAABU-free outcomes occurred due to chance, the nurses would have a random 25% chance of transitioning from any of the 2015 CAABU-free quartiles to any other the 2016 quartiles, and a 25% chance of staying in the same outcome quartile in both years. On the other hand, a same-quartile transition probability greater than the 25% random chance was interpreted as persistent individual nurse effects on the CAABU-free patient outcome.As the final validation analysis, we explored nurse transitions from having low CAABU-free outcomes to having high outcomes, and vice versa, between 2015 and 2016. We estimated a transition probability matrix  and examAll statistical analyses were performed in Stata15.0 statistical software. The programming code for replicating the analyses is included as a Supporting Information File  of the adjusted nurseCAABU-free rates, the average negative deviation from the sample median was -1.76 (SD = 0.67) CAABU-free cases per 100 shifts; among the 23 nurses in the highest quartile (98.77 to 100), the average positive deviation was 1.20 (SD = 0.45) CAABU-free cases per 100 patient-shifts. The cumulative density function  was apprIn cross-validation analyses using 89 nurses who cared for patients in both 2015 and 2016, 2015 nurse productivity was non-significantly associated with patient characteristics , failing to reject random patient-nurse assignment in this sample. CAABU-free rates obtained using the 2016 validation set were significantly and positively correlated with the rates obtained using the 2015 testing set . Exploratory cluster analysis  identifiResults of the transition probability analysis are displayed in We found evidence of significant variation in CAABU-free outcomes of individual nurses. While all nurses had very high CAABU-free rates (average CAABU-free rate of 98 per 100 catheter ICU patient shifts), the nurses in the top quartile had fewer than 1 new CAABUs per 100 shifts and the nurses in the bottom quartile had 3 to 5 new CAABUs per 100 patient-shifts. In cross-validation analysis using two independent patient samples, the association of individual nurse CAABU-free rates across independent patient samples was strong and a tendency toward persistently suboptimal outcomes in the lowest CAABU-free quartile was also evident.Although the observational nature of the study limits causal inference, the preponderance of evidence in this study supports individual nurse-level differences in achieving infection-free outcomes in ICUs. This finding is important because it can mean that some patients may have a lower or higher risk of developing bacteriuria, and possibly CAUTI, owing to individual nurses who provide their care. Few of the nurses had 100 percent CAABU-free outcomes and transition analysis revealed no consistent pattern of the same nurse being a superior performer in both years, suggesting a limit to how many adverse outcomes can be avoided even with most excellent nursing care. However, low infection-avoidance performance appeared to persist for some nurses over time, thus identifying a potential area for targeted individual intervention and improvement.Scaling up the findings to the hospital level, our results indicate that bringing nurses in the lowest CAABU-free quartile up to the median might have helped avoid 93 of the observed 124 CAABU cases  for a 75 percent relative reduction during the six-month estimation sampling timeframe. Therefore, although a 100 percent infection prevention effectiveness is probably unachievable, reducing the lowest-end variability could have a significant positive impact on the overall quality of ICU care.The observed variability in individual nurse CAABU-free outcomes might be interpreted through the lens of earlier evidence documenting variability in the use of evidence-based practice at the bedside. Nearly uniform (≥95%) infection prevention practice use by nurses is essential to the success of these efforts , 14, 37,To that extent, the results of our study highlight the need to recognize individual nurses as each being a unique and integral component of the care-delivery process. High individual CAABU-prevention effectiveness could be related to the consistent use of evidence-based practice, but it could also result from multiple other factors, including effective coping strategies to avoid burn-out and stress, teamwork and communication skills, and “work-arounds”, which make highly effective nurses thrive in the same environment where others might struggle. Being able to objectively measure and identify the entire distribution of nurse-level outcomes could inform periodic evaluation reviews while also providing the nursing team an opportunity to learn from nurses who have consistently high outcomes. Achieving high-quality patient care will require that high-performing nurses are recognized as role models with unique knowledge specific to the context of their unit, which they can share with the rest of the ICU nursing team.The theoretical construct of individual clinician’s value-added contribution to patient outcomes has yet to be broadly applied to the interaction between nurses and patients. In the discipline of economics, VAM methods have found practical applications in educational assessment of teacher effectiveness . With diThis study was a novel application of the Value-Added Modeling method from the field of economics to the measurement of risk-adjusted variability in infection-prevention outcomes of ICU nurses. Grounded in the fundamental economic construct of “Value-added”, or incremental increase in the value of output directly attributable to a productive input, we applied the method to the nurse-patient relationship by conceptualizing the contribution of a nurse’s care as value added to the quality patient outcome. This is a major innovation because it advances the study of healthcare workforce  beyond examining its aggregated measures like skill mix, education, or experience, to measuring the quality contributions of individual clinicians. Although bedside nursing care is provided by one nurse to one patient at a time, our study is the first to actually measure the value of the nursing infection-prevention practice at the individual nurse-patient level. An additional strength of the study is the use of time-stamped patient and nurse data which allowed for establishing direct linkages between individual patients and the specific nurses who provided their direct care throughout hospitalization, and to also correctly place each nurse’s care in relation to the time of occurrence of an adverse patient event. The use of the CDC’s infection attribution time window and access to verified CAABU data lend further strengths to our study methods and findings.Nonetheless, there are several limitations that should be mentioned. First, unmeasured confounding is an issue in all observational studies. In our prior work in acute care settings, we found that higher-productivity nurses were assigned to higher-acuity patients , 39, 40.Second, it is extremely difficult, if not impossible, to discern which nurse or nurses contributed the most to the prevention of bacteriuria in a particular patient, because nursing care is 24 hours 7 days a week and fluid. Therefore, the approach of attributing a CAABU-free outcome to all of the nurses who cared for the patient during the prior 24–48 hours is consistent with how nursing care is delivered. At the same time, the equal distribution of credit for a CAABU outcome likely means that we report variability in individual nurse CAABU-prevention effectiveness conservatively.The small number of confirmed CAUTIs in this sample precluded us from examining the association between individual nurses and CAUTI outcomes. Most likely owning to a routine treatment of CAABU with antibiotics, only 3 out of the 261 confirmed CAABU cases in our sample progressed to a CAUTI diagnosis. While being effective in avoiding a symptomatic infection, antibiotics also produce side effects and drug interactions, and their use contributes to development of antibiotic-resistant infections in hospitals  = category excluded from model; [omitted] = category dropped due to collinearity and combined with the reference category during estimation.(XLSX)Click here for additional data file.S3 TableThe table presents the regression betas (coefficients of the log-likelihood model) obtained from the validation set, 2016. Estimates are obtained using a logistic regression with clustering at the patient-shift encounter level. [ref] = category excluded from model; [omitted] = category dropped due to collinearity and combined with the reference category during estimation.(XLSX)Click here for additional data file.S1 TextInstitutional Review Board for the Protection of Human Subjects. Loyola University Chicago Health Sciences Division.(DOC)Click here for additional data file.S2 Text(TXT)Click here for additional data file.


Tobacco is a major public health concern. A 12-week standard smoking cessation program is available in Japan; however, it requires face-to-face clinic visits, which has been one of the key obstacles to completing the program, leading to a low smoking cessation success rate. Telemedicine using internet-based video counseling instead of regular clinic visits could address this obstacle.This study aimed to evaluate the efficacy and feasibility of an internet-based remote smoking cessation support program compared with the standard face-to-face clinical visit program among patients with nicotine dependence.This study was a randomized, controlled, open-label, multicenter, noninferiority trial. We recruited nicotine-dependent adults from March to June 2018. Participants randomized to the telemedicine arm received internet-based video counseling, whereas control participants received standard face-to-face clinic visits at each time point in the smoking cessation program. Both arms received a CureApp Smoking Cessation smartphone app with a mobile exhaled carbon monoxide checker. The primary outcome was a continuous abstinence rate (CAR) from weeks 9 to 12. Full analysis set was used for data analysis.We randomized 115 participants with nicotine dependence: 58 were allocated to the telemedicine (internet-based video counseling) arm and 57, to the control  arm. We analyzed all 115 participants for the primary outcome. Both telemedicine and control groups had similar CARs from weeks 9 to 12 , and the lower limit of the difference between groups (–12.8%) was greater than the prespecified limit (–15%).The application of telemedicine using internet-based video counseling as a smoking cessation program had a similar CAR from weeks 9 to 12 as that of the standard face-to-face clinical visit program. The efficacy of the telemedicine-based smoking cessation program was not inferior to that of the standard visit–based smoking cessation program.University Hospital Medical Information Network Clinical Trials Registry: UMIN000031620; https://upload.umin.ac.jp/cgi-open-bin/ctr_e/ctr_view.cgi?recptno=R000035975. Tobacco is a major public health concern and the biggest preventable cause of a variety of disorders such as cerebro- and cardiovascular diseases, malignant tumors, and chronic obstructive pulmonary disease ,2. In JaTo help quit smoking, Japan provides a smoking cessation program for patients with nicotine dependence. This 12-week program mainly consists of face-to-face clinic visits, involving counseling with a primary physician, checking exhaled carbon monoxide (CO) concentration, and prescribing smoking cessation medications . Face-toRecently, telemedicine, defined as remote delivery of health care via the internet, was considered one of the useful methods for providing medical care to patients ,9. TelemIn this study, we tested the clinical efficacy and feasibility of telemedicine using internet-based Web counseling compared to a standard face-to-face clinical visit in the smoking cessation program among patients with nicotine dependence.This trial was a randomized, controlled, open-label, multicenter, noninferiority trial. Details of the trial protocol have been described elsewhere . In brieWe recruited individuals with nicotine dependence from March to June 2018. We conducted follow-up for 24 weeks. Only the participants who met all the inclusion criteria were included; those who met any of the exclusion criteria were excluded . BrieflyPrimary physicians at each clinic obtained written informed consent from all trial participants. We confirmed that clinics participating in this trial could provide the standard smoking cessation support program and had the necessary equipment to provide Web-based telemedicine . We conducted this trial in compliance with the Declaration of Helsinki, Medical Device Good Clinical Practice guidelines, and all other applicable laws and guidelines in Japan. The trial protocol was approved by the Tokyo-Eki Center-Building Clinic institutional review board. We reported the trial according to CONSORT-EHEALTH (V 1.6.1). This trial was registered at the University Hospital Medical Information Network Clinical Trials Registry (UMIN000031620).We used the stratified-block randomization (four blocks) method with a 1:1 allocation ratio to achieve equal assignment to two arms with stratification of the trial sites. Participants were allocated to either the telemedicine arm or the control arm. The randomization was performed by the staff at each participating clinic at the time of participants’ registration, using a computer-generated random sequence.Participants allocated to the telemedicine arm received internet-based Web counseling for the smoking cessation program. Participants assigned to the control arm received the conventional face-to-face clinic visits for the smoking cessation program. Both arms also received the CASC smartphone app and a mobile exhaled CO checker during the trial period (24 weeks).The standard smoking cessation program in Japan consists of five face-to-face clinic visits lasting for 12 weeks, including doctor consultations and exhaled CO checks at a registered institution or clinic . All stuFollowing the first visit, telemedicine participants were supposed to receive counseling via the internet-based video counseling system with a standardized telemedicine platform application  instead The CASC system was developed by CureApp, Inc. . Details of the system have been demonstrated elsewhere . The CASThe primary outcome was the biochemically validated CAR from weeks 9-12, which was consistent with the previous clinical trial of varenicline in Japan . This meFrom previous pilot studies of a CASC smartphone app, the difference in CAR from 9-12 weeks between the CASC smartphone app group (78%) and historical control groups  is 24% -22. TherWe compared all endpoints between the telemedicine and control groups. Baseline characteristics were described by means and SDs, medians and interquartile ranges (for continuous variables), or proportions . We analyzed the primary outcome using the full analysis set (excluding participants who violated the inclusion or exclusion criteria). In case a patient discontinued an allocated treatment, the case was considered as smoking cessation failure. We compared CARs between telemedicine and the control groups using a logistic regression model with crude odds ratios (ORs). For all outcomes, summary statistics and group difference measures  were presented with 95% CIs. We also tested if the CAR from 9-12 weeks of telemedicine and the control condition varied by subgroups. We assessed interactions of CAR from 9-12 weeks with each variable (greater than vs less than the median for continuous variables) and calculated ORs with 95% CIs in each subgroup. We used the Wilcoxon signed-rank test for comparing the scores regarding nicotine dependence between baseline and at weeks 12 and 24 in each group. R version 3.4.1  was used for all the analyses.We randomized 115 participants to the telemedicine arm or control arm . Each arBiochemically validated CARs from weeks 9-12 were 81.0% (95% CI 71-91) in the telemedicine group and 78.9% (95% CI 68-89) in the control group . The absNext, we demonstrated the efficacy of the telemedicine on CAR from weeks 9-12 by subgroup. Although the KTSND had a moderate interaction with the outcome, we found little evidence of significant interactions for any of the subgroup analyses .We also assessed the evolution of scores by MPSS, FTCQ-12, KTSND, and NDCS . During In this randomized trial, we assessed the efficacy and feasibility of an internet-based remote smoking cessation program compared to the standard face-to-face clinical visit program among patients with nicotine dependence. We found that (1) CARs from weeks 9-12 were relatively high in both groups (81.0% in the telemedicine and 78.9% in the face-to-face control groups) and (2) the clinical efficacy of the telemedicine group was not significantly greater than that of the face-to-face control group in terms of CAR from weeks 9-12.This trial has several important findings. First, CARs from weeks 9-12 were relatively high. CARs from weeks 9-24 also reached favorable results in both groups (74.1% in telemedicine and 71.9% in control). Compared to other countries -25, thesSecond, the dropout rates of the smoking cessation program were low even at week 24 in both groups, indicating potential improvement in the overall smoking cessation success rates. The Japanese national survey on the efficacy of nicotine-dependence treatment showed a linear relationship between the number of patient visits to outpatient clinics and the treatment success rate . We usedThird, most of the scores for nicotine dependence in the trial were significantly decreased in both groups. This result indicated that the telemedicine-based and face-to-face smoking cessation programs with the CASC system were effective in improving the status of nicotine dependence and ameliorating craving for smoking over time in the smoking cessation program. However, mood symptoms  of the MPSS did not change during the trial. This outcome may be because the baseline median scores of these symptoms were already low  and continuously stabilized during the trial period.The strength of this trial was that it was the first randomized controlled trial to test the efficacy and feasibility of telemedicine using internet-based video counseling directly compared with face-to-face clinical visit in patients with nicotine dependence. This trial had a few limitations. First, the prespecified limit value of 15% might not be conservative. However, CARs from weeks 9-12 in both groups were almost what we expected (both around 80%), and we considered 65% of CAR from weeks 9-12 to be a reasonable threshold for checking the clinical relevance of the telemedicine program compared with the face-to-face clinic visit program in accordance with previous reports . Second,Telemedicine using internet-based video counseling for the smoking cessation program had a similar CAR from weeks 9-12 as that of the standard face-to-face clinic visit program. The efficacy of the telemedicine-based smoking cessation program was noninferior to that of the standard clinic visit–based smoking cessation program. The results of this trial demonstrated that internet-based counselling might be a viable alternative to standard clinic visits for smoking cessation.


N = 10) or to an Attention Control Condition . After the training, the dot-probe task was administered again to assess changes in the attentional bias toward trauma-relevant pictures. Injured workers who underwent the ABMT, but not those who underwent the ACC, showed a significant reduction of the attentional bias from pre- to post-training. Overall, these results support previous findings reporting an association between traumatic occupational accidents and cognitive dysfunctions. More importantly, these preliminary findings add to a growing body of evidence suggesting the effectiveness of a short ABMT in reducing the attentional bias after a traumatic workplace accident.Individuals who experienced traumatic work-related accidents frequently show cognitive deficits and biased processing of trauma-relevant information, which, in turn, could increase the risk of further accidents. The attention bias modification training (ABMT) is designed to reduce hypervigilance toward and enhance attentional disengagement from threat stimuli. The aim of the present study was to assess whether it is possible to implicitly reduce the attentional bias toward trauma-related stimuli through a single session of ABMT in individuals who experienced a traumatic occupational accident. Nineteen individuals who had experienced a traumatic work-related accident and 11 workers who never experienced a work accident (control group) underwent a preliminary assessment of cognitive performance (executive functions and sustained attention) and an evaluation of the attentional bias toward accident-related pictures by means of a dot-probe task. The results showed that injured workers performed more poorly than controls in tasks of executive functions and concentration abilities. Also, injured workers showed an attentional bias toward trauma reminders . Injured workers were then randomly allocated to a single-session of ABMT ( European statistics have shown that in 2015 there have been close to 3.1 million non-fatal occupational accidents , 2017. WIndeed, two components of the early attentional bias toward threat-related stimuli have been highlighted, specifically, facilitated attentional engagement and impaired disengagement. Following initial automatic orienting to threat cues, directing attention away from threat (avoidance) would represent a strategic attempt to alleviate the anxiety elicited by threat-related stimuli .It has been proposed that the ability to reallocate attention in a flexible way after a stressful or traumatic event may be crucial in supporting a gradual decrease in intrusive re-experiencing and, consequently, a reduction of the attentional bias toward trauma-related cues . In thisThe ABMT has been shown to be effective in reducing anxiety symptoms in individuals with high trait anxiety see , with obHowever, in the past few years the effectiveness of the ABMT has been questioned in some reviews and meta-analyses e.g., . InconsiThe aims of the present study were twofold: first, to assess the presence of an attentional bias in workers who experienced a traumatic work-related accident; second, to evaluate the effectiveness of a single session of ABMT in modulating the attentional bias in injured workers.Table 1.Nineteen members of the Associazione Nazionale Mutilati e Invalidi del Lavoro (ANMIL)  who had experienced work-related accidents were recruited. Inclusion criteria were the following: age-range between 18 and 50 years, time lapsed from the accident between 6 months and 5 years, degree of physical impairment between 19 and 70% . Mean age, mean time lapsed from the accident, and mean degree of physical impairment are reported in The gender ratio in our sample of injured workers  fairly matched the gender distribution of work-related injuries in the European and Italian populations  and a description of the type of accident. The type of accident could be classified as follows (number of participants in parenthesis): driving a car while on the job (6), being hit (6), being caught in, under or between something (2), fall at the same level or from an elevation (2), cut (2), lifting weights (1).Eleven healthy individuals  were recruited as control group. Inclusion criteria were the same as for the injured worker’s group, except for the absence of work-related accidents.For both groups, exclusion criteria were: the presence of physical and psychological disorders unrelated to the accident; substance abuse; use of drugs or medications that could affect the individual’s ability to perform cognitive tasks; incapacity to give informed consent, traumatic brain injury, sensory  loss. Specific questions of the semi-structured interview were aimed at collecting information relevant to the above exclusion criteria.Table 1).Injured workers and Controls did not differ for age, gender, and educational level (see N = 19) were randomly assigned to a single session of ABMT (N = 10) or Attention Control Condition (ACC) (N = 9). Injured workers undergoing ABMT showed no difference from injured workers undergoing ACC training in terms of sociodemographic , psychological , cognitive  variables and Attentional Bias Score .After the administration of the semi-structured interview and the questionnaires, the cognitive tests and the pre-training dot-probe, injured workers .The State-Trait Anxiety Inventory  was usedThe Beck Depression Inventory-II BDI-II;  was usedThe PTSD Symptom Scale PSS;  was usedWorry was assessed by the Worry Domains Questionnaire WDQ , a self-The following instruments were used:Trail making test TMT; : it assed2 test : it provA modified dot-probe task was used to measure the attentional bias both before and after the training. Thirty digitized picture stimuli depicting neutral stimuli (household objects) and 30 trauma-related pictures collected and validated from our group in previous studies see , depictiN = 200) started with the presentation of a fixation point in the center of a gray background for 500 ms. Then, a pair of picture stimuli, one trauma-related and one neutral, or both neutral, were presented above and below the center of the screen for 500 ms, followed by a target probe that appeared at the location of one of the two pictures. Target stimuli consisted of a “+” or a “×” symbol and remained on the screen until a response was given. Participants were instructed to discriminate the two arithmetic operators by a vocal response  were those where the target was presented at the location of the trauma-related picture. Instead, Incongruent trials (N = 80) were those where the target appeared at the location of the neutral picture. On Neutral trials (N = 40) both pictures were neutral, and the target could follow on either location. Picture category , location (above or below the center of the screen) and target type (“+” or “×”) were counterbalanced; each trial was repeated twice.When the picture pair consisted of one trauma-related and one neutral picture, Congruent trials  processor, with a 14.1′′ monitor and 1280 × 800 resolution, running “E-prime 1.1” software  for picture presentation.Vocal reaction times (RTs) were recorded using a microphone, connected to a Response Box . Not naming the correct target, and unrecognizable or missing responses were computed as errors.The ABMT was developed to train the participants’ attention toward neutral pictures using a modified dot-probe procedure. The training consisted of 400 trials divided into four blocks. The procedure was identical to that of the pre-training dot-probe task, except that pictures were taken from a different set than that used in the pre- and post-training dot-probe task. Also, the target always appeared at the location of the neutral picture. Specifically, 320 trials were Incongruent and 80 were Neutral. Picture category , location (above or below the center of the screen) and target type (“+” or “×”) were counterbalanced; each trial was repeated four times.The ACC consisted in a dot-probe task where the target could appear with equal probability at the location of the trauma-related or the neutral picture . Picture category , location (above or below the center of the screen) and target type (“+” or “×”) were counterbalanced; each trial was repeated twice.N = 19) were randomly assigned to receive either the ABMT (N = 10) or the ACC (N = 9) (duration about 20 min), followed by the post-training dot-probe task (duration about 10 min). At the end of the session, participants were thanked and debriefed. Specifically, all injured workers were provided with information on pre- and post-training assessments and about the ABMT and the ACC. Injured workers in the ACC group were given the possibility to undergo an ABMT protocol.Before participation in the study, all subjects read and signed an informed consent form. After the semi-structured interview and the questionnaires, the cognitive tests  were administered, and the pre-training dot-probe task was run (duration about 10 min). Then, only injured workers  and unrecognizable or missing responses, were removed (average 0.67%). Following the procedure reported by Attentional Bias (AB) scores were calculated for both the pre-training and the post-training task as mean RTs on Incongruent trials minus mean RTs on Congruent trials. Positive AB scores indicate vigilance toward trauma-related stimuli (faster RTs when the probe appeared on the location of trauma-related stimuli), whereas negative AB scores indicate attentional avoidance (slower RTs when the probe appeared on the location of trauma-related stimuli).U-tests and χ2s for independent groups were performed to compare Injured workers to healthy Controls in terms of age, gender, educational level, scores on questionnaires , performance measures on the cognitive tasks  and AB score.Mann–Whitney Moreover, Pearson’s correlation coefficients were calculated to test whether pre-training AB scores could be related to age and to questionnaire scores  in the Injured workers group. Univariate analysis of variances (ANOVAs) were also used to evaluate AB scores as a function of gender  and educational level .p < 0.05) were followed by Fisher post hoc comparisons to identify specific differences.As a second step, mixed ANOVA was conducted to compare AB scores in injured workers who underwent the ABMT and the ACC. Specifically, an ANOVA with Group (ABMT vs. ACC) as a between-subject factor, and Time (pre- vs. post-training) as within-subject variable was performed. Partial eta-squared .Table 1).The analyses performed on questionnaire scores showed no significant differences between Injured workers and Controls in self-reported state and trait anxiety and depressive symptoms. Injured workers scored significantly higher than Controls in self-reported symptoms of PTSD and worry .Injured workers performed significantly worse than Controls in the TMT-A [sec], TMT-B , and d2 [concentration performance]. No significant differences emerged in the other performance parameters .Injured workers showed significantly higher AB scores than Controls in the pre-training dot-probe task (see p’s > 0.08). No differences emerged between males and females  . Post hoc analysis revealed that there was a significant reduction in AB scores from pre- to post-training in the ABMT group (p < 0.01), while no difference in AB scores from pre- to post-training emerged in the ACC group (p = 0.80). No significant effect of group emerged , as well as to age and questionnaires scores. In our group of injured workers no one showed clinical symptoms of PTSD, and this could be explained by the fact that the questionnaire could not evidence subtle cognitive-emotional changes such as those that emerged in the dot-probe task. These results fit with previous findings showing a lack of correlation between PTSD symptoms severity and RTs in an emotional interference task .Our findings are in line with previous studies that have found an attentional bias characterized by faster RTs to trauma-related pictures in individuals who underwent a traumatic event e.g., . AccordiInjured workers scored higher on questionnaires measuring post-traumatic symptoms and worry compared to controls, while no differences between groups emerged for anxiety and depressive symptoms. These results, although consistent with those of previous studies in which injured workers were found to report the presence of PTSD symptoms, fail to replicate the evidence that individuals who underwent work-related accidents also report more anxiety and depressive symptoms than controls . As a poA single-session training aimed at directing attention away from trauma-related stimuli was effective in reducing the attentional bias in our sample of injured workers. A substantial reduction of attentional bias scores was observed from pre- to post-training, as measured with the dot-probe task, only in injured workers who underwent the ABMT, while no differences emerged in injured workers who underwent the ACC. These results are in line with previous studies where the ABMT was found to be effective in reducing/modifying the attentional bias in healthy  and subcThe findings of the presence of an attentional bias in injured workers and of the effectiveness of a single session of ABMT in reducing such bias is of great importance, given that the presence of an attentional bias has been found to be associated with worse performance in cognitive tasks. It is particularly relevant to note that an occupational accident in the previous 3 months has been associated with a higher risk of experiencing a new accident . ReducedThe obtained findings should be considered as preliminary in light of the fact that the sample was relatively small, thus limiting statistical power. However, and importantly, our study provided evidence that a single session of ABMT was effective in reducing the attentional bias in injured workers who do show an attentional bias toward trauma-related stimuli. In order to increase the potential use of the procedure in work and clinical settings, multiple follow-ups would be crucial to evaluate long term cognitive-affective changes after a single session ABMT. In addition, future studies should address the issue of the generalizability of the effect of the training on other cognitive functions. Indeed, previous studies found mixed results, with some reporting improvement in tasks which are similar to the one used for the training see , and othThe preliminary findings of the present study support the presence of an attentional bias toward trauma-related stimuli in injured workers and suggest the possibility of reducing this bias through a short behavioral intervention.GB, EP, and DP contributed conception and design of the study. EP gathered the data and organized the dataset. GB, EP, and SMB performed the statistical analysis. All authors contributed to manuscript revision, read and approved the submitted version.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.