This article provides the philosophical, scientific, and technical underpinnings of the Network+, the history of the different domains represented in the Network+, and the specific focus of the Network+. The activities, collaborations, and research covered in the first year of the Network+ have highlighted the significant challenges in the chemistry and augmented and artificial intelligence space. These challenges are shaping the future directions of the Network+. The article concludes with a summary of the lessons learned in running this Network+ and introduces our plans for the future in a landscape redrawn by COVID-19, including rebranding into the AI 4 Scientific Discovery Network (www.ai4science.network).The Artificial Intelligence and Augmented Intelligence for Automated Investigation for Scientific Discovery Network  + was created to accelerate scientific discovery using new AAI techniques. Despite useful short-term impacts, this extensive space still has many unsolved challenges. It is vital that the trajectory of this effort continues, encouraging further collaborations, helping funding recipients realize their potential, and creating vital resources for the AAI for scientific discovery community.The AI3SD NetworkA core aspect of our AI3SD philosophy is the importance of the human element in AI, hence why AAI for scientific discovery is our mantra. Humans must remain in the loop for any decision making that requires ethical consideration or the addition of human intelligence. The AI3SD approach combines the best of human and machine intelligence to gain notable acceleration in scientific discovery using transparent, responsible, and explainable AAI.We aim to finish the first term of the AI3SD with a rich collection of resources and useful outputs, enabling members to progress toward the UN sustainability goals in the areas of chemicals and materials discovery. AI3SD will remain a sustainable entity only if members and organizers work together toward AAI. + has had an eventful first year, rapidly establishing a diverse community of different disciplines across academia and industry. We share with you our insights into the potential and challenges of the AI for scientific discovery space, coupled with what we have learned about running a research network.The Artificial Intelligence and Augmented Intelligence for Automated Investigation for Scientific Discovery Network Our bid concentrated on chemical and materials discovery, as these are the areas with which we had familiarity and fields where it was apparent that major developments in industry and academia were already underway, offering huge potential to the community. We are sure that discoveries and techniques arising from our target areas will be transferable to the wider life sciences and beyond.In late 2017, EPSRC announced a call+We were successful, were awarded the grant .We note with some amusement that at the first Advisory Board meeting it was pointed out that we had missed the fact that if we had added a fourth AI then we could have become the AI4Science Network+ is centered on creating community-wide engagement at the cutting edge of both AI and scientific discovery, and we focused our activities not on simply applying known machine learning techniques to data-mining problems in the two problem domains but instead on growing a truly collaborative environment of multi-way interactions. Underlying this emphasis is the recognition that intelligent algorithms should have augmenting human intelligence as the goal . By AAI, we mean the application of mathematical, algorithmic, philosophical, and ethical considerations underpinning computational methods of answering scientific questions.Artificial intelligence refers to computational techniques that complement and augment human intelligence, encompassing the notions of evolution and learning in the context of complex datasets.Augmented intelligence refers to algorithmic techniques that assist in human problem solving, essentially by the extraction of useful information from large and complex datasets, which may be structured.Scientific discovery is the process or product of conducting a scientific inquiry, the results of which add to the scientific body of knowledge. In the context of AI3SD, we have chosen to view scientific discovery as the identification of regular relationships and their underlying causes in a given problem domain by model-based reasoning, and the subsequent verification of them by experimentation, while respecting societal constraints arising from ethics and philosophy.The vision of the Network+ (scientific discovery and AI), then detail the formation and current activities of the Network+ to date, and finish with some reflections on learning so far and considerations on how best to move forward for the rest of the Network+’s time span.This perspectives article will provide a summary of the background of the core elements of the Network+ it is useful to review how the nature of scientific discovery has evolved, at least in the UK, since the enlightenment periodTo set the scene for the Network,Beginning with Bacon, the simple inductivist viewed scientific progress as driven by the collection of data. However, as a description of how scientific progress has actually been made, this does not ring true. As Whewell noted in 1860,Bringing order to the judgements and hypothesis that direct scientific discovery is no easy task. For this reason, philosophers of science have often distinguished between the contexts in which scientific discoveries are made and the context of their justification.Our progress in science owes much to the judgements, intuitions, hunches, and creativity of the scientists involved, as well as to their chance encounters, proclivities, values, and social settings. According to Mendeleev, he literally dreamt up the periodic table. The theory of special relativity supposedly came to Einstein as he stared idly from the window of a moving tram. Intuition seems key. As BenjaminInsights direct investigation. Their genesis offers some explanation of why scientific progress can be so unpredictable.,algorithmic. Empirically, however, expert systems still enjoy at best only a very niche use in the laboratory, and this seems to tally with the skepticism of even the most analytic philosophers of science as to whether we could bring any formal order to the context of scientific discovery.Early attempts to make use of AI not only in the context of justification but also of discovery . In 2009, Hey et al.The UK Government published its own review of the e-science program, also in 2009. References to discovery in this document appear to concentrate on resource discovery . For example, references to drug discovery resolve to the discovery of information in databases rather than to facilitating the process of actual new molecule discovery. There are but three mentions of machine learning. However, the influence of the e-science program cannot be denied, particularly in changing the way a wide range of researchers work; the UK Computing Research Committee (UKCRC) recommended that computer science research could benefit from using some of the e-science technologies to better facilitate collaboration, sharing test datasets and application repositories  techniques have the potential to significantly surpass current industrial applications+ was conceived to accelerate scientific discovery using new AAI techniques and to facilitate the use of scientific ideas to enhance the capabilities of AI. The vision and themes of the Network+ are outlined here, providing a snapshot of our activities for the first year or so and some thoughts on the future .The Network+ is focused on training researchers to develop and deploy AAI for scientific discovery in the chemical and material sciences, in order to truly realize this potential.We are living through a data revolution, which will be as transformative of our society as the industrial revolution. Algorithms, and in particular learning algorithms, are the engines of this revolution. So-called intelligent algorithmic systems affect many areas of our personal and professional lives, making decisions based on prior “learned” knowledge. The use of learning algorithms has the potential to revolutionize the way science develops. The Network+ is highlighted by the fact that the current volume of chemical reaction data is far beyond what humans can effectively use . Murray et al.7, this assessment is small compared with the enumeration of chemical space. Reymond11, this comprises a mere fraction of the estimated 1060 molecules obeying Lipinski's rule-of-five, which was developed to aid the identification of potential drug candidates by their oral bioavailability.180, can found in the table published by Gorse,80.The timeliness of the NetworkFurthermore, we are at the start of an explosion in the availability of detailed reaction data due to the increase in this data being recorded digitally  and the use of robotic reaction systems, which improve data repeatability and increase throughput. Supporting these capabilities are advances in high-throughput analytical methods. Automation has for a long time played a significant role in improving data collection. With our ability now to generate or access huge datasets, machine learning techniques are playing an ever more significant role in data analysis. Finally, with the emergence of sophisticated deep learning systems designed to simulate aspects of human neurological function, we may be on the verge of augmenting or automating some aspects of the creative skills that drive scientific progress.Impressive developments have recently taken place around deep neural network architectures. These are layered networks with trainable parameters forming complex non-linear mappings between input and output data. Learning of such mappings has the property of extracting useful latent patterns in complex high-dimensional spaces. Although, over past decades, it was thought sufficient to work with layered networks that were shallow , and estimating parameters of networks with deep architectures was considered technically difficult, recent advances along several lines of architecture specification and optimization tricks have resulted in such powerful architectures, demonstrating impressive empirical results in diverse domains such as computer vision, automatic speech recognition, machine translation, and computational biology, and playing challenging games such as chess and Go. Learning of latent representations and making accurate predictions endow such models with the power to augment the role of scientists by reducing the space in which one might search for hypotheses or in the ranking of hypotheses in terms of some past experience extractable from data.So, computing techniques, particularly machine learning algorithms, are no longer there solely to increase the number of tasks a scientist can complete; they now stand ready to alter the role of the scientist. The vision of AI3SD is to bring together researchers from both science and technology backgrounds to show how cutting-edge artificial and augmented intelligence technologies can be used to push the boundaries of scientific discovery.•Make use of AAI to drive scientific discovery.•Use the needs of scientific discovery to drive new techniques in AAI.•Provide new and innovative applications to the chemicals and materials sectors.•Address ethical and philosophical issues associated with AAI in an informed manner to ensure adherence to the best possible ethical practices.•Train researchers to create and use new systems of AAI to push the limits of the synthesis of molecules and the engineering of materials properties, enabling discovery and exploitation of unseen, unexplored, and currently unimagined parts of chemical and material space.Our core aims are to:+’s activities. Molecular compounds underpin just about every aspect of our lives, from sustainable energy, to construction, to healthcare. Society's demands for enhanced performance is far outweighing the capability of the research community to discover materials that deliver it. Furthermore, an inability to then rapidly transform new compound discoveries into usable functional materials exacerbates the shortfall. Such discoveries are critical to meeting the majority of the UN sustainability goals,We chose the design and synthesis of chemicals and materials  as the inter-related areas for the initial cutting-edge exemplars on which to focus the landscape for the NetworkThe complexity of the relationships between chemical/molecular structure, physical properties, and material (and device) performance renders the understanding and prediction of these relationships for the most part intractable by conventional approaches to computation. That the area is ripe for exploitation in the UK is highlighted by the involvement of big and innovative companies, as well as start-ups  for scientific discoveryIn following these general directions, the main themes that have evolved in the first year of the Network+, we were able to draw on our valuable previous experience with the networks and challenge areas described in the Past Experiences box. The lessons learned from the ITaaU Network+ were particularly useful with regard to organizational matters, such as the importance of creating resources derived from workshops, funded projects, and conferences, and how to run different types of meetings in the most effective manner.77In establishing the Network+. Some of the main projects and networks with which we have been involved are listed below:The investigators have had extensive experience in running and working with networks and collaborating on projects across different areas of AI and chemistry, all of which fed into how we formed and run the Network•http://www.itutility.ac.uk/ITaaU: •http://generic.wordpress.soton.ac.uk/dial-a-molecule/Dial-a-Molecule Grand Challenge Network: •https://digitaleconomynetwork.com/Digital Economy Network: •https://www.liverpool.ac.uk/leverhulme-research-centre/Leverhulme Research Centre for Functional Materials Design: •http://www.ncs.ac.uk/UK National Crystallography Service: •http://www.combechem.org/CombeChem - Networks, centers, services, and Projects:We are distilling our main experiences in running networks and will present online resources in the near future (look for How to Train your Network).For the scientific research perspective, we were able to rely on our formative experience with the CombeChem science project,+. In chemistry, this has involved research into the impact of digital technology on area such crystallography, crystal structure prediction, combinatory chemistry, materials discovery, molecular simulations, chemical modeling, and drug discovery.The University of Southampton has maintained a strong focus on digital chemistry,,As our interest in digital chemistry has evolved, we have become increasingly aware of the potential of AI. Research in AI at the University of Southampton spans a range of topics in machine learning, agent-based modeling and mechanism design, Semantic Web technologies,Other aspects of AI have also been studied by Southampton philosophers, who have expertise in the epistemology, logic, and ethics of AI.+ team has proved very valuable, ensuring that we have adequate expertise for the interdisciplinary nature of using AAI to accelerate scientific discovery.This combined experience of the Network+ is defined by our mailing list, and in the first year we have rapidly established a wide-ranging interdisciplinary community that not only brings together researchers from the physical (and life) sciences and computer sciences but also across both academia and industry. As our network is funded by UKRI, it is primarily UK based, although we do have members from outside the UK. As of 22/09/2020 we have over 840 members, with representatives from over 60 different universities and over 80 different companies. The Network+ also has a strong social media presence, with over 470 twitter followers (@AISciNet), and an increasing following on LinkedIn.Membership of the Network+ was to establish a portfolio of activities and support for early-stage research. Since its launch in December 2018, AI3SD has organized or co-organized 12 events. These events comprised five main types: workshops, conferences, training events, hackathons ,and town meetings (for funding). A comprehensive list of the events that have been organized or co-organized by AI3SD can be found on the AI3SD events page.At AI3SD we aim to bring together researchers looking to show how cutting-edge artificial and augmented intelligence can be used to push the boundaries of scientific discovery. As such, an important objective for the Network+, there have been seven workshops, covering the key themes of the Network+ . Each workshop has been formally recorded with a professional report+ Web site and with a formal DOI assigned.Our workshops focus on a particular topic, with the structure typically comprising an introduction to AI3SD aims for the themes of the day, followed by keynote talks from experts in the field, working group discussions, and concluding with summing-up exchanges of views. The time allocation varies according to the specific topic and the aims of the workshop, in some cases emphasizing networking, while others give priority to identifying key issues and emergent themes. Since the launch of the Network+ to learn about and discuss a range of relevant themes. These conferences took similar forms to the workshops in that they comprised presentations with some discussion sessions , and sometimes had short workshops embedded as part of the program. The presentations were on a wider range of topics than for just a workshop, as these conferences were aimed at the Network+ as a whole and looked to cover a wide range of relevant themes to appeal to a much larger audience. AI3SD has held two major conferences so far, the launch event in December 2018 and the big annual conference in November 2019. Both of these have also been formally recorded with a report.These were either single- or multi-day meetings that aimed to bring together all members of the NetworkTwo training events have been run thus far as part of AI3SD. One was a funding workshop that was run as part of the second town meeting. This provided tips on writing funding applications, IP for AI, and writing sustainable research software. The second was a training session on machine learning and data science for chemistry, which comprised training presentations on these different areas, and training on a number of different datasets that were going to be used for a hackathon.+ members to encourage creativity and provide time to try out new methods in a supportive environment with experts on hand to help.These hack sessions were hosted to allow Network+ members to network and potentially find new collaborators. These meetings were not formally recorded in a report, but the questions and answers given were all recorded and put on the Funding FAQ pageThese events were hosted to explain the processes of the AI3SD funding calls, to provide prospective candidates with enough information about how to apply, and also served as a place for Network+ is the inclusion of a special budget to run our own funding calls to support some short £50,000 pilot projects. Two funding calls were run, which led to supporting seven projects overall; details (and available reports) can be found on the AI3SD Funded Projects page.Part of being a Network+ is set to run until June 2021, and, at this halfway point, it is important to evaluate lessons learned so far and identify the main challenges that we have identified during the research that has been undertaken.This iteration of the Network(1)First, the importance of the interdisciplinary approach for accelerating scientific discovery through AAI; it is vital to include experts in the many different areas of AAI, chemistry, philosophy, and ethics to identify the range of challenges from these different disciplines and to provide different approaches and skills to solving problems.(2)Second, the combination of academic and industrial expertise has been an imperative as these bring different techniques, priorities, and access to resources/data that, when combined, present brand new opportunities. Industry is ahead of academia in many areas, and enabling access by academics to the large amounts of data held in industry can prove incredibly effective, as demonstrated by the recent coronavirus disease 2019 (COVID-19) collaborations.(3)Third, from the presentations and discussions that we have engaged with to date, we have identified key challenges in the chemical and AAI spaces that are detailed later.There are three clear lessons that we have learned so far:+ research space (detailed below). Our third main impact has been the collaborations that have formed due to this network: both between AI3SD and other parties and between other academic/industry bodies either due to collaborating for AI3SD funding calls or from seeking out potential collaborators from the AI3SD Network+. Our plans for longer-term impact are detailed later.Thus far, our short-term impacts have been realized in three main areas. Our growing membership; this is defined by our mailing list, which now has over 840 members and is continuing to grow at a steady pace. Second are the outputs of our workshops, conferences, and funded projects  has been the identification of the main discovery challenges in the chemical and AAI spaces. Further, this has highlighted the importance of interdisciplinary training as an important and worthwhile issue, as many of these challenges require significant knowledge in more than one domain.A significant output of the events and funding calls run thus far by the Network•Recognition of the extent of chemical space and other data spaces.•Heterogeneity of data spaces and the ability to link data .•Creating greater quantities of high-quality data, with the emphasis on quality.•How to exploit unseen, unexplored, and currently unimagined parts of chemical and material space.•Understanding the new pathways to discovery opened by the application of AI•How to involve a wider range of the computer science community•Engage the mathematics community•Understanding how to ensure that AAI for scientific discovery is both ethical and explainable+ sustainable for the future.There are several different threads of future plans for AI3SD: running workshops and conferences, creating useful resources for the AAI for scientific discovery community, working with the recipients of the AI3SD Funded Pilot projects to help them realize their impact, and working to make the NetworkAs an interim measure to mitigate the impact of COVID-19, we moved our activities online for the rest of 2020 with the launch of our online summer seminar series, and are continuing to engage regularly with our members through newsletters and our mailing list, which is continuing to grow at a steady pace despite the pandemic. We are currently planning for 2021 with strategies for either continuing online or slowly progressing back to face-to-face meetings depending on how the COVID-19 pandemic progresses.+ themes and identified some key overall challenges, the next steps are to delve further into these spaces. Data and all the aspects characterizing it  have been identified as a key area for AAI for scientific discovery (and indeed any AI/machine learning endeavor). Further interdisciplinary workshops and hackathons will be run in this area, aiming to provide training in understanding and adhering to different data standards and best practices across different disciplines with respect to data governance and data publishing. There will also be training on different techniques for text mining, data linking, and creating or converting data to be AAI ready. In particular, a dual datathon and hackathon will be run, allowing participants to attend either or both, whereby data are cleaned, linked, and analyzed in the first instance, and then used with AAI techniques following this. Further, additional interdisciplinary workshops will also be run in the areas of symbolic AI and machine learning for small deep learning, statistical mechanics and machine learning, AI and molecular dynamics, and AI/machine learning/science and casual reasoning.Having explored the different areas of each of the Network+ members to use. The AI3SD Resources page+ members. Further, the Network+ will be undertaking some horizon/literature scanning exercises in the challenge spaces that have been identified.AI3SD has started to expand its remit to creating and linking to useful resources for the Network+ to make further impact. As noted above, a key assessment criterion for selecting projects to fund was based on the potential for long-term impact as well as short and medium term. The Network+ Team (including our Advisory Board with a wide variety of expertise) will continue to work with the recipients of the funding to see how their work can be taken forward and where further funding can be applied for. Due to the impacts of COVID-19, we have granted each funded project a no-costs extension, and are working with the principal investigators of each project to ensure that they receive the time and help they need to finish their projects before this term of the Network+ ends.Working with the recipients of the AI3SD Funding Awards will enable both them and the Network+ sustainable such that it can continue as a self-sufficient body once the main funding term has finished.Finally, a key area for future planning is to work toward making the Networks.kanza@soton.ac.uk).Further information and requests for resources should be directed to and will be fulfilled by the lead contact, Samantha Kanza (+ can be found on our website (www.ai3sd.org).A wide range of information, including all of our conference and event reports, funding reports, and details about the activities of the NetworkNot available.


The COVID-19 pandemic is one of the worst public health crises in a century, with an expected amount of deaths of several million worldwide and an even bigger number of bereaved people left behind. Although the consequences of this crisis are still unknown, a significant number of bereaved people will arguably develop Complicated Grief (CG) in the aftermath of this emergency. If the current pandemic is unprecedented, the grief following the coronavirus outbreak is likely to share features with grief related to natural disasters and after Intensive Care Unit (ICU) treatment. The aim of this paper is to review the most prominent literature on CG after natural disasters, as well as after diseases requiring ICU treatment. This body of evidence may be useful for helping bereaved people during the acute phase of the COVID-19 pandemic and for drawing clinical attention to people at risk for CG. At the time of writing this paper, over 690,000 people around the world have been infected with COVID-19, which has already caused more than 33,000 deaths. Although pandemic projections must be treated with caution at this early stage, it has been estimated that the global death toll from COVID-19 could reach as high as 15 million even in the best-case scenario  may eventually arise –6.To the best of our knowledge, no studies examined CG in the aftermath of an epidemic or a pandemic. Still, the coronavirus outbreak shares several features with natural disasters that have been previously investigated with regard to CG. Moreover, people dying from COVID-19 usually do so after being admitted to ICU and remaining isolated from their loved ones until the end. This obviously poses an even heavier burden on the loss, but also makes it useful to keep in mind what may happen to bereaved people when the death occurs in such circumstances and what we must expect from their grieving in the aftermath of this global emergency.Based on the above premises, the aim of this paper is to review the most prominent literature on CG after natural disasters, as well as after acute diseases requesting ICU treatment. This body of evidence may be useful for assisting bereaved people during the acute phase of the COVID-19 pandemic and for drawing clinical attention to people at risk for CG.The loss of a loved one during a natural disaster is especially traumatic and distressing, given that the death usually happens suddenly and unexpectedly . SimilarRelatives of patients admitted to the ICU are at risk of psychological morbidity during and after the hospital stay –19. The Hospital and ICU mortality is especially associated with a high incidence of grief reactions, including post-traumatic stress disorder, anxiety, depression, and CG , 21–23. The COVID-19 pandemic represents one of the worst public health crises in a century, with an expected death toll of several millions of people worldwide. The prevalence of CG in the general population ranges from 2 to about 7% (10 to 20% among bereaved people, Together with the loss of loved ones, natural disasters imply multiple losses, the closure of schools and facilities, the stopping of productive activities, and the reduction in services and supplies, which is mirrored in the COVID-19 epidemic. Moreover, people are placed in a traumatic environment, the exposure to which is multiplied by means of news media and social networks . On the Our review underlines that female sex is a risk factor for CG, not only in the general bereaved population but also among bereaved people of ICU decedents or in the context of natural disasters. While grieving a child or a spouse has been indicated as a risk factor for CG after a natural disaster, no differences have been found with regard to the kinship to the deceased among people who lose a relative in the ICU. However, available data have hitherto shown that the vast majority of deaths due to COVID-19 is among older males , which mLastly, it has to be noted that the ongoing COVID-19 pandemic bears the unprecedented circumstance that public funerals have become illegal in many countries due to national restrictions against gatherings and to cemeteries' overloading. Funeral and burial rituals are important for the affective adjustment of people grieving the loss of a loved one and mourners who drew comfort from planning and participating in the funeral were shown to achieve better outcomes in later grief . From thThe COVID-19 crisis has united mental health stressors that have been separately evaluated in other contexts, but which have never been seen combined in one, unprecedented disaster happening on a global scale. This makes it very difficult to infer what is going to happen to people during and in the aftermath of this global event, unless we use previous data as a provisional proxy of such a new and unknown phenomenon.COVID-19 is expected to cause an enormous death toll worldwide. Given that each death leaves up to five people grieving behind , and thaCG, GC, and LD'O conceived the work. IC and BC made the literature search and revision. CG, CC, and LD'O drafted the paper. CC and GC revised the work. All authors provided approval of the version to be published. 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.


The Netherlands is well known for its early adoption of harm reduction (HR) programs at the height of its heroin crisis in the 1970s/1980s, including the implementation of the first needle and syringe program worldwide. In this manuscript, we describe how the Amsterdam Cohort Studies (ACS) among people who use drugs (PWUD) was conceived within the context of the Dutch HR approach, including the challenges scientists faced while establishing this cohort.This required striking a balance between public health and individual benefit, solving research dilemmas in the face of uncertainty, developing controversial innovative and cutting-edge interventions, which changed the prevention landscape for PWUD, and using longitudinal cohort data to provide unique insights. Studies from the ACS covering follow-up between 1985 and 2016 revealed that participation in both opioid agonist therapy and needle and syringe programs led to a major decrease in the risk of HIV and hepatitis B and C infection acquisition. ACS data have shown that the observed decrease in incidence also likely included shifts in drug markets and drug culture over time, selective mortality among those with the highest levels of risk behaviour, demographic changes of the PWUD population, and progression of the HIV and HCV epidemics. Moreover, HR programs in the Netherlands provided services beyond care for drug use, such as social support and welfare services, likely contributing to its success in curbing the HIV and viral hepatitis epidemics, increasing access and retention to HIV and HCV care and ultimately decreases in overdose mortality over time. Given the low coverage of HR programs in certain regions, it is unsurprising that continued HIV and HCV outbreaks occur and that transmission is ongoing in many countries worldwide. If we aim to reach the World Health Organization viral hepatitis and HIV elimination targets in 2030, as well as to improve the life of PWUD beyond infection risk, comprehensive HR programs need to be integrated as a part of prevention services, as in the Netherlands. We should use the evidence generated by longstanding cohorts, including the ACS, as a basis for which implementation and improved coverage of integrated HR services can be achieved for PWUD worldwide. The Netherlands is well known for its early adoption of harm reduction (HR) programs at the height of its heroin crisis. Both early implementation and broad access to these programs for people who use drugs (PWUD) have been linked to limited transmission of HIV and hepatitis B and C infections in Amsterdam . These fIn this manuscript, we describe how the ACS among PWUD at the Public Health Service of Amsterdam (PHSA) was conceived within the context of the Dutch harm reduction approach. To this end, we dive into the lessons learned from over 500 published manuscripts and opinion pieces based on the ACS among PWUD and its value to the current epidemiological situation in the Netherlands and other countries. Moreover, given the length of follow-up to date, we take the opportunity to reflect on some of the developments over time to which the cohort was able to provide evidence.The origin of the PWUD population in Amsterdam, The Netherlands, can be traced back to the introduction of heroin to the Amsterdam hippie scene in 1972 . In the In conjunction with the heroin crisis, incidence of sexually transmitted infections (STIs) increased in the Netherlands during this time and was especially high in Amsterdam . Sex witThe growing heroin crisis in the 1970s was perceived negatively by most residents of Amsterdam due, in part, to more PWUD in the streets and increasing crime. To manage the crisis, a harm reduction approach, which included the provision of methadone, was adopted and focused on minimizing harm from drug use to PWUD and more broadly to society. While methadone was being prescribed by a few general practitioners and in addiction clinics, not all PWUD were being reached, especially Surinamese PWUD . To faciIn the 1980s, it was estimated that around 7000–8000 of the 20,000 heroin-dependent individuals in the Netherlands resided in Amsterdam . Accordi‘Junkiebond’ Medical Social Service for Heroin Users (i.e. Junky Union/MDHG), a Dutch organization for PWUD, then promoted the idea to distribute free needles and syringes in Amsterdam [In 1983, the main pharmacy located in the city-centre stopped selling low-cost injecting equipment to people who inject drugs (PWID) due to customer complaints. The decreased availability of clean needles and syringes raised concerns about a potential hepatitis B virus (HBV) outbreak among PWID. The Amsterdam’s msterdam . Since tmsterdam , and thumsterdam . FollowiIn 1981, the first case of acquired immunodeficiency syndrome (AIDS) in Amsterdam was diagnosed in a man who has sex with men (MSM) and a burgeoning HIV epidemic then followed . As HIV One of the biggest critics of the cohort was the Amsterdam PWUD organization (i.e. MDHG) . They arAs soon as there was sufficient support from the PHSA’s drug department, it was decided that because of concerns of a looming HIV epidemic in this group, the prospective ACS among PWUD had to be initiated and in 1985 recruitment of the cohort commenced. The overarching original aim of the cohort was to study the prevalence, incidence and risk factors for HIV infection among PWUD. An advisory committee including PWUD organizations was formed to ensure that the MDHG’s criticism was taken into account. HIV testing was performed at each study visit, yet as there was no available treatment, HIV status was only relayed to participants on an opt-in basis. The majority of PWUD participating in the ACS opted to receive their test results .Engagement with the PWUD community at the PWUD/sex-worker outpatient STI clinic and at the mobile methadone clinic facilitated the first wave of recruitment of PWUD to the cohort. Recruitment started at the STI sex-worker clinic and was then extended to methadone outpatient clinics and by word of mouth. As it was hypothesized that sexual networks of injecting and non-injecting PWUD could be mixed and thus an important risk factor for sexual HIV transmission, non-injecting PWUD were also included in the cohort. Inclusion of former, current and non-PWID in the cohort facilitated the study of the incidence of IDU initiation along with the impact of NSP on increases in IDU , 18.Despite the belief that HR programs in Amsterdam would be sufficient in preventing the spread of HIV, the first results of 308 PWUD enrolled in the ACS in 1986 showed that 28% of participants without AIDS-related symptoms had HIV antibodies [The cohort continued recruiting at the same locations throughout follow-up except for recruitment at the STI sex worker clinic which stopped in 1997. Then, in 2000 stronger efforts were made to direct recruitment at young PWUD (30 years old or less) because young and recent-onset PWID were found to be at higher risk of HIV . Over tiIn 2014, HIV incidence had remained nearly zero for a decade in PWUD. HIV transmission was concentrated in mostly MSM, and pressure was mounting to relocate the total ACS budget to the MSM cohort and expand recruitment in this cohort. Furthermore, the proportion of PWID participating in the ACS who actively injected drugs decreased from 82% in 1985 to 16% in 2015, the uptake of NSP and opioid agonist therapy (OAT) decreased in parallel : 3.7–16.6) and the median number of visits was 18 IQR 7–32). Between 1985 and 2016, 476 participants died and 72 were known to have emigrated outside of the Netherlands. The number of PWUD presenting for a cohort visits fluctuated over the years  was launched in Maastricht and as of 2018, 24 DRCs—where mainly heroin and freebase cocaine are used—were operating nationwide . Other uDecreased risk behaviour and HR programs likely contributed to a decline in IDU and HIV, HCV and HBV incidence over time , 25–27. The introduction of NSP among PWUD was more controversial than the provision of methadone, particularly in countries other than the Netherlands. Two Dutch scientists presented the novel NSP approach in 1986 at a conference in the USA at the invitation of American researchers established in this field. At the time, there was still no evidence that NSP could affect risk behaviour or infection transmission. Their presentation sparked heated discussion among participants, including representatives of the African American community who were disproportionally affected by the heroin crisis and were worried that the Dutch approach could bring greater risk of drug use . More spEarly findings from the ACS (1989–1990) demonstrated that HIV-negative PWID who regularly participated in NSP (≥ 90% of needles/syringes coverage by NSP) more frequently engaged in IDU and had a longer history of regular IDU than non-regular NSP participants (< 90% NSP coverage) . This suDuring the initial planning for methadone distribution around Amsterdam, health professionals were aiming to connect with harder to reach PWUD and these individuals feared that higher dosages of methadone would make them addicted to methadone and heroin would have less of an effect. Consequently, the PHSA provided low doses of methadone to PWUD as part of their low-threshold program. Based on the work by Peter Selwyn in New York, reporting that 60 mg/day was the adequate dose of methadone to promote retention in OAT programs and thus reduce the spread of HIV, the methadone dosing policy changed in the Netherlands in 1991 . In lineTo prevent PWUD from receiving multiple doses of methadone via various program levels and prescribers, the central methadone register (CMR) was initiated in 1981 and recorded all methadone prescriptions until 2012. Linking data from this registry with the ACS data, we showed that between 1985 and 1994, the majority of newly enrolled ACS participants (86%) were receiving methadone from low-threshold programs, compared to 10% and 4% from medium- and high-threshold programs, respectively. Importantly, methadone dosages reported from ACS participants were shown to be highly concordant with data from the CMR (weighted kappa = 0.97) , while uFindings from the ACS demonstrated that higher doses of methadone were associated with lower HIV risk behaviours, including frequency of inconsistent condom use with clients among female sex workers and borrowing of syringe/needles, and an additional methadone dose increase of 5 mg or more per day per year was a predictor of IDU cessation for at least one year , 35. AnoHeroin, methadone and injecting use patterns are not only highly variable between cohort participants, but also within participants . An ACS By the beginning of this millennium, there was individual-level evidence that ACS participants receiving methadone decreased their HIV risk behaviours. Moreover, participants engaging in NSP reported a higher frequency of IDU and a slightly lower frequency of borrowing needles and syringes compared to those who did not . From daNevertheless, there were speculations that the declining trends in HIV and HCV incidence observed among ACS participants were due to alternative explanations, and hence a modelling study using ACS data was initiated to assess several scenarios with and without HR programs. It was hypothesized that, in addition to the effect of HR, PWID with higher levels of IDU risk behaviour may have succumbed to HIV-related disease in the 1980s–1990s  became widely available) and resulted in a smaller pool of PWID living with HIV and/or HCV. The so-called survivors could have engaged less frequently in risk behaviours and therefore were less likely to transmit these viruses. This study demonstrated that while a decrease in the incidence of these infections was certainly plausible in the absence of HR, the model best performed under the assumption that HR programs gave way to strong decreases in risk behaviour . BuildinSeveral reviews of the available evidence on the effect of HR programs and infection risk have been conducted and have found that most studies did not adequately adjust their results for time-varying confounding or the effect of biased selection into HR programs participation (i.e. people engaging in risk behaviours were more likely to participate in HR programs) , 22. As Each year, information about vital status of ACS participants was obtained by matching the ACS data to the municipal and national population registries in the Netherlands. Causes of death were systematically obtained from hospital records, general practitioners, the national HIV Monitoring Foundation, or coroners. Between 1985 and 1993, nearly 44% of HIV-positive PWID and 12% of their HIV-negative counterparts had died . Early fAnother ACS study among 1,254 PWUD with at least two cohort visits reported that of the 406 deaths that had been observed between 1985 and 2012, the highest number of deaths (n = 130) occurred during the period 1990–1996. Of these 130 deaths, 40% were HIV-related, 32% due to non-natural deaths , 21% due to natural causes and 5% due to liver-related disease . Crude aDutch HR programs encompass more than simply the provision of injecting equipment and OAT. These programs form a point of contact with healthcare providers from which PWUD are able to receive services beyond direct care related to drug use. Social workers at HR sites refer individuals to other organizations that can provide stable housing or sheltering and daytime activities. Integrated service centres providing different types of care to PWUD at a single location was officially introduced in 2004 . These sIn 2004, HR programs across Amsterdam facilitated the recruitment of PWUD who actively used drugs, including ACS participants, for an HCV testing and treatment project outside of hospital settings. At the time, HCV treatment duration lasted up to 48 months and could lead to serious psychiatric side effects. Data from this project showed that cohort participants using methadone were more likely to accept HCV testing than those not on methadone and cure rates in this population were comparable to those previously reported among the general, non-drug using HCV-infected population . This waHR programs do provide advantages not only for the individual, but also for the society as a whole. In a randomized study among heroin-dependent PWUD in the USA, immediate methadone use was shown to lead to decreased number of arrests compared to remaining on a methadone waiting list . The lowWritten by the pioneers of HR in Amsterdam, those who initiated the ACS and those who witnessed and decided to close the cohort, we recount the story of striking a balance between public health and individual benefit, solving research dilemmas in the face of uncertainty and developing controversial innovative and cutting-edge interventions, which changed the prevention landscape for PWUD. It is evident that since its inception in 1985, the ACS has produced an impressive body of research spanning more than 30 years. Of course, evaluating the causal effectiveness of HR on infection incidence, IDU, morbidity and mortality would be more appropriately assessed through randomized trials. However, the public health urgency of the HIV/HCV epidemic in PWUD made such a trial, with limited follow-up, unethical, impractical and expensive. Longstanding cohort studies, such as the ACS, were needed to provide the necessary evidence of the effectiveness of these programs in addition to unique insights into trends and trajectories in exposures and outcomes over time.This cohort was initiated in the face of criticisms, teaching us the importance of working together with the community. Over the years, new challenges emerged such as a potential lack of funds to keep running both cohorts, pressure to reallocate the budget and the constant search for funds to continue research using ACS data. One of the most difficult decisions was whether and when to terminate the ACS among PWUD. A decade before the cohort officially ended, there had already been pressure for its closure given that incidence of HIV and HCV was very low. However, the threat of new infection outbreaks and new groups of PWID emerging still persisted and if closed, there would be no possibility to restart the cohort. After ten years of almost zero incident infections, supported by national HIV and HCV notification data, it was then confirmed that this group was at very low risk of transmission. Nevertheless, continued follow-up of cohort participants could have resulted in insights into the ageing PWUD population, trends in direct-acting antiviral uptake and liver-related mortality. However, these research questions substantially deviated from the original aims concerning HIV infection.Studies from the ACS have taught us that while there is clearly a strong protective effect of HR programs on infection risk and to some degree on mortality risk, it is important to recognize and understand the range of factors contributing to the changing patterns and natural progression of the epidemic. For example, the ageing PWUD population, combined with shifts in drug markets and decreased injecting behaviour, were likely important drivers of declining infection incidence and overdose mortality in Amsterdam. On the contrary, in some countries other than the Netherlands, there has been an increased demand in opioids and new injecting initiates. This, in conjunction with outbreaks of HIV and HCV infection, as has been observed in rural counties in the USA , stresseWhile problematic heroin use is currently no longer a major public health concern in the Netherlands, the number of prescription opioid users nearly doubled between 2008 and 2017 as well as the number of opioid-related hospital admissions and individuals treated for opioid use disorder . The locNowadays, the Netherlands has one of the highest prevalence of MDMA consumers and number of producers in Europe , while  observed between 1985 and 2012 among ACS participants, which could be explained by changes in demographic structure, the drug market, selective mortality and broad access to HR programs—but the contribution of each of these factors remains largely unknown. Based on our knowledge of how HR programs reduce the risk of infection, it is important that future studies consider the effect of combination OAT and NSP on mortality alongside each of these two components separately. Moreover, given the rising rates of fentanyl use in some countries—which bears a higher risk of overdose compared to heroin—HR programs might not have the same, previously observed effect on mortality attributed to overdoses. However, to date, it is unknown whether the effect of HR programs on mortality and infection risk differs by the type of opioid used. Regardless, given the degree of bias due to self-selection and time-varying confounding, causal inference methodology should be utilized to the fullest extent possible.HR programs in the Netherlands offer additional services beyond infection prevention, such as opportunities for stable housing, sexual counselling and access to general and mental healthcare. Therefore, the direct and indirect causal pathways between HR program participation and infection risk lack empirical evidence. For example, lack of stable housing is well known to be associated with increased HIV and HCV acquisition  and is aGiven the low coverage of HR programs in most countries, it is unsurprising that HIV and HCV outbreaks continue to be observed in high-income countries, such as the UK and USA, and that transmission is ongoing in many countries worldwide , 63, 64.


Patients with schizophrenia spectrum disorders experience severe difficulties in interpersonal communication, as described by traditional psychopathology and current research on social cognition. From a linguistic perspective, pragmatic abilities are crucial for successful communication. Empirical studies have shown that these abilities are significantly impaired in this group of patients. Prosody, the tone of voice with which words and sentences are pronounced, is one of the most important carriers of pragmatic meaning and can serve a range of functions from linguistic to emotional ones. Most of the existing literature on prosody of patients with schizophrenia spectrum disorders focuses on the expression of emotion, generally showing significant impairments. By contrast, the use of non-emotional prosody in these patients is scarcely investigated. In this paper, we first present a linguistic model to classify prosodic functions. Second, we discuss existing studies on the use of non-emotional prosody in these patients, providing an overview of the state of the art. Third, we delineate possible future lines of research in this field, also taking into account some classical psychopathological assumptions, for both diagnostic and therapeutic purposes. Patients with schizophrenia spectrum disorders typically present with significant difficulties in social functioning that can occur in various areas, including in interpersonal communication . Schizopvia their verbal or nonverbal messages. Pragmatics, the branch of linguistics that takes into account the relationship between language and its context, including the correct interpretation of non-literal contents, plays a major role . A follow-up utterance “Do you want to see the car[GIVEN]?” refers to the car for a second time and it is therefore given. Referents can also be in focus or in the background  . Prosodyckground . For exa speaker . Note thMost of the literature on prosody in patients with schizophrenia spectrum disorders has focused on recognition of emotional functions. There is a general consensus on significant impairments in this capacity, despite the heterogeneity of the tasks used , 24. HowThe present paper summarizes the main existing studies on the topic. It provides an overview of the state of the art, with papers selected from a search on PubMed and Google Scholar of those published in the period between 1990 and November 2019 . From the initial 217 papers, we finally selected 11 studies reporting on patients with any of the following diagnoses: schizophrenia, schizoaffective disorder, first episode psychosis, persons at risk of psychosis, schizotypal personality disorder. We considered all the articles referring to schizophrenia spectrum, together with first episode psychosis and conditions at risk of psychosis, in order to include the whole continuum of different stages of schizophrenia psychopathology (from vulnerability and trait conditions to full-blown disorder). Therefore, the diagnoses of affective psychosis or other psychotic, non-schizophrenia disorders were excluded. We only selected studies in which these groups were compared with healthy controls in their ability to perceive and/or produce non-emotional prosody. Finally, studies had to be written in English. In addition, we manually searched for papers from reference lists of the main articles and reviews, finding one additional study. While focusing mainly on findings regarding pragmatic prosody, we also included results on grammatical prosody, as these are not always clearly distinguishable. Building on this review, the aim of the paper is to identify controversies and limitations of this important, though relatively thin, strand of literature and to delineate possible future lines of research in this field, guided by classical psychopathological notions.Although some studies found an intact performance, there is evidence of a deficit in the perception of non-emotional prosody in patients with schizophrenia spectrum disorders. Below we present the empirical evidence following the continuum of prosodic functions   , 36 and The production of non-emotional prosody in patients with schizophrenia spectrum disorders has been investigated mainly in terms of acoustic parameters of patients’ speech. Generally, the experiments used to analyze participants’ discourse consisted of clinical interviews , free spFor the productive use of linguistic prosody, the previously reported study by Murphy and Cutting  also tesAltogether, there is evidence that in patients with schizophrenia spectrum disorders the capacity for processing grammatical prosody is intact, both with respect to the ability to use phrasing to resolve syntactic ambiguities  and withThe use of non-emotional prosody in patients with schizophrenia spectrum disorders has seldom been compared with other clinical groups. Edwards and colleagues  did not Finally, the capacity to use pragmatic prosody was associated with Theory of Mind scores  and a siIn sum, results about the relationship between the use of non-emotional prosody and vulnerability to psychosis , 33, 37 The main limitation of the present review is that it is not a systematic one. Nevertheless, to our knowledge this is the first attempt to date to sum up the existing literature about the use of non-emotional prosodic cues by patients with schizophrenia spectrum disorders.The existing literature focusing on the use of non-emotional prosody in patients with schizophrenia spectrum disorders is still very limited. Further research is needed to shed light on the existing results. We suggest that these lines of research should be extended, for a deeper understanding of the specific communicative impairments underlying the disorders. This in turn could contribute to a better diagnosis and possibly help discriminating between schizophrenia and other psychiatric conditions in the future. Moreover, there is evidence of the efficacy of training targeting both pragmatic skills and the use of prosody , 51. ThiWe have identified some possible points to be addressed by the future research agenda regarding the use of non-emotional prosody by patients with schizophrenia spectrum disorders. The following require investigation:A number of prosodic functions that have not been investigated so far. These include (a) The capacity to understand other speakers’ communicative purposes conveyed through prosody, beyond those already tested (sarcasm and commands), especially the ability to correctly detect a threatening disposition. As previously mentioned, the core feature of schizophrenia spectrum is an impairment in the tacit understanding of social situations  are to be considered specific to schizophrenia spectrum disorders. Interestingly, schizophrenia has also been described primarily as a linguistic disorder, . From this perspective, the study of prosody in this clinical population warrants even more interest.A deeper understanding of possible links between the use of non-emotional prosody and clinical variables, in line with the Research Domain Criteria (RDoC) strategy. This approach aims at combining several data types, e.g., neurobiological or clinical data, to investigate basic domains of functioning underlying human behavior  for the study of psychiatric conditions  as part of the SFB 1252 “Prominence in Language” in project A02 “Individual behavior in encoding and decoding prosodic prominence” at the University of Cologne.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.


Process evaluation addresses the implementation, mechanisms of impact, and context of participants in complex interventions. The STADPLAN study assesses the effects of conversations on advance care planning (ACP) led by trained nurse facilitators. The complex intervention consists of several components that may lead to various changes in attitude and behavior regarding personal ACP activities. With the process evaluation, we aim to assess how changes were achieved in the STADPLAN intervention.The planned process evaluation study will be conducted alongside a cluster-randomized controlled trial on ACP in home care services (HCS). Trained nurse facilitators will deliver the ACP intervention consisting of an information brochure and two ACP conversations. A logic model depicts the assumed change processes of the intervention: the educational program enables nurses to conduct ACP conversations with patients and their caregivers. Patients gain knowledge and reflect upon and engage in their own ACP. Caregivers better understand patients’ wishes and feel reassured in their role as surrogates. Designation of a surrogate and communication on ACP are facilitated. We will assess the effects of the educational program with questionnaires and a focus group including all participating nurses. We will measure ACP engagement, and prevalence of advance directives in patients, and ask for their experiences with the intervention. We will conduct semi-structured interviews with caregivers about their expectations and experiences regarding ACP in general and the intervention. We will address context factors, e.g., basic characteristics of the HCS . Analysis will be based upon the logic model, integrating qualitative and quantitative data.The comprehensive process evaluation will provide essential information on the feasibility of implementation strategies and the clinical relevance of a nurse-led ACP intervention in home care recipients and its generalizability and transferability to other settings.DRKS00016886. Registered retrospectively on June 4, 2019, first participant included on May 29, 2019.German Clinical Trials Register:  The STADPLAN study is a large cluster-randomized controlled trial and one of the first trials on ACP in community dwellers. It will provide evidence on the effectiveness of an ACP intervention provided by nurses in home careThe process evaluation as outlined in this paper will indicate how the ACP intervention is related to patient activation, ACP engagement, and surrogate designation and evaluate its feasibility in the home care settingThe mixed methods approach based on the MRC framework for the development and evaluation of complex interventions will ensure high methodological rigorResults will support the implementation of ACP in the community setting“Advance care planning is a process that supports adults at any age or stage of health in understanding and sharing their personal values, life goals, and preferences regarding future medical care. The goal of advance care planning is to help ensure that people receive medical care that is consistent with their values, goals, and preferences during serious and chronic illness” .ACP can be documented in written form and relatives can be involved in the communication –4. The nIn this study, we will adapt an ACP program to the German home care setting, which has been successfully implemented in other countries and settings , 13, amoWe will measure secondary endpoints, such as proportion of persons with advance directives, hospitalization, and quality of life as well as depression and anxiety.The study protocol of the cluster-randomized trial has been published . This paThe complexity of interventions is determined by several dimensions, e.g., the number and interaction of components, the number and difficulty of behaviors required for delivering or receiving the intervention, or the number of groups or organizational levels targeted , 17. ThiAccording to the UK Medical Research Council’s framework for the development and evaluation of complex interventions, the first question to be answered is as follows: what is the theory behind the intervention? Why is the intervention supposed to work, in which participants and by which mechanisms ?On this theoretical basis, intervention components, participants that are involved and context factors, as well as expected effects, can be depicted in a logic model , 19.A logic model allows to allocate outcomes to participants and processes and thus forms the foundation for the development of the research design and the instruments of the process evaluation. Furthermore, contextual factors inherent to participants and organizations are considered, as they influence the procedural and overall outcomes.The process evaluation aims to depict how the STADPLAN ACP intervention is embedded in the context of participating HCS, patients, and caregivers, how it was received and accepted, and whether it is feasible in the home care setting.We developed and piloted the STADPLAN logic model. Taking necessary adaptations of the intervention to the German home care setting into account, we created and discussed the logic model within the collaborating group  to ensure that relevant actors and procedural outcomes were incorporated. In the pilot study, we tested the evaluation instruments for feasibility.The focus of the process evaluation lies on all participants involved and their context, namely the HCS, nurses, patients (or clients) of the HCS and their caregivers .The logic model for the STADPLAN trial describes 1) the intervention, (2) the implementation, (3) the participants and their mutual relationship, (4) their context, and (5) the anticipated procedural outcomes on the individual level , including an information brochure with workbook.During the first conversation, the BEVAs collect information on patients’ ACP activities to date and hand out the information brochure. BEVAs assess patients’ knowledge about ACP and provide additional information accordingly. They motivate patients to read the brochure and use the questions and commentary fields to reflect upon their thoughts regarding ACP. They invite patients to include one or more persons of trust, such as family members or designated surrogates (referred to as “caregivers”), to take part in the second conversation.In this second conversation, BEVAs talk with the patients about their views on life, quality of life, life expectancy, situations of decisional incapability, and wishes regarding life-prolonging treatment.The focus of the conversation is to support patients in reflecting about their wishes and values, to guide the involved persons of trust in listening to patients’ views and in their role as proxy decision maker, and to facilitate further conversation within the family. The aim of the intervention is thus to enable patients to act in their own ACP. The conversations follow structured topic guides, containing commentary fields which the BEVAs use during the conversations to document the discussed topics.The information brochure with workbook contains information on ACP in plain language and contact details of regional advisory services. The workbook section contains questions facilitating reflection on ACP and room to write them down.Trained nurses of the participating HCS will conduct the intervention. Their training  encompasses two 1-day workshops, course material, the information brochure, and topic guides with commentary fields for ACP conversations.The first workshop provides knowledge on ACP, types of AD (advance directives), surrogate decision-making, and training on the use of the topic guides, which support BEVAs in leading the conversation and ensure that all relevant issues are discussed. Furthermore, the topic guides serve as documentation for adherence, as BEVAs are instructed to use all commentary fields to document what was discussed.The second workshop is designed to refresh content of the first workshop and to address BEVAs’ experiences with ACP conversations. It is therefore tailored to the BEVAs’ needs, based on structured modules. Before we finally determine which modules to address during the workshop, we will question BEVAs via phone about their experiences with the ACP conversations and suggestions to identify workshop topics. Based on experiences of the pilot study, these could be repetition of informational content; simulation of difficult conversations; peer discussion of experiences regarding recruitment, organization, or challenging interview situations; or other topics requested by the BEVAs. At the end of the workshop day, we will reflect on BEVAs experiences and discuss their overall assessment of the study in a focus group.Participants of the complex intervention are patients, BEVAs, and caregivers. Patients are clients of the participating HCS, 60 years or older, and care dependent (based on assessment by the long-term care insurance). Caregivers are family members who are defined by patients as their main carers. BEVAs are registered nurses of the participating HCS.Context of the HCS: basic characteristics, resources, organizational norms regarding ACPContext of nurses and BEVAs: experiences, attitudes, expectations that are relevant for the interventionContext of patients and caregivers: experiences, attitudes, expectations, relationship within the dyad and with the HCSContext of the implementation and the intervention: organization and conduct of the educational program and ACP conversationsContext macro-level: actual and perceived norms regarding ACP in the home care setting in general, new developments regarding ACP (like legislation or changes in funding), other incidents affecting the daily practice of HCS with potential influence on the study proceduresTo describe contextual factors is essential in complex interventions, as these can affect the implementation and mechanisms of impact of the intervention, thus potentially influencing the targeted outcomes. Contextual factors differ, depending on the setting of an intervention, and have to be addressed specifically tailored to the intervention and setting to be evaluated . DiffereWe will assess procedural outcomes primarily on the individual level, addressing, e.g., knowledge, attitudes, and self-perceived competencies. The educational program enables and motivates nurses to conduct meaningful ACP conversations with patients and their caregivers. Patients learn about ACP and reflect upon what matters to them in life and what this implies for end-of-life care. They feel prepared to actively engage in their own ACP. Caregivers gain knowledge on ACP and a better understanding of patients’ wishes and attitudes. Thus, they feel reassured in their role as surrogates. The intervention facilitates the designation of a surrogate and the communication on ACP within the patient/caregiver dyad.The process evaluation follows the course of the main study as depicted in Fig. We will use a variety of instruments to capture intervention processes. The process evaluation is based on the MRC framework on process evaluations for complex interventions  as shownTo describe the context of the participating HCS, we will use qualitative interviews with the heads of the HCS and nursing staff and assess basic characteristics such as ownership, number of clients, and number and qualification of staff quantitatively .To gauge overall prerequisites for the conduct of our study in the home care setting, we will transparently describe the recruitment process. Time constraints, staff shortage, and scarce funding might hinder HCS to participate in the study and influence the study’s progress. We will therefore document non-participation of all invited HCS during the recruitment process in a standardized template at each study site. The HCS will anonymously document the recruitment of participants with standardized forms and question non-participants on patients’ level for their reasons to decline. We will categorize reasons for non-participation on HCS and patient level and report them descriptively. Furthermore, we will discuss recruitment obstacles within a focus group on day 2 of the educational program with the present BEVAs.We will conduct face-to-face interviews with closed and open-ended questions with patients, concerning their knowledge and expectations regarding ACP , 22, then = 16) asking patients and caregivers present in the main data collection for participation in a separate telephone interview.We will conduct semi-structured interviews with caregivers about their experiences and expectations regarding ACP , their sWe will focus on four elements of the intervention: the educational program; the recruitment of participants; the ACP conversations; and the information brochure with workbook. We will document the conduct of the educational program by observations focusing on adherence and involvement/interaction of participants. We will base the observations on a template listing each activity of the educational program. The observers (research assistants) will document length and method of the activity, involvement of participants, and questions/unexpected events. The outcome on BEVAs’ level will be assessed with questionnaires at the end of the respective program day, testing knowledge on ACP and self-reported confidence in communication abilities, and expected feasibility of the upcoming ACP conversations in all participating BEVAs. At the second workshop day of the program, we will conduct a focus group discussion on the experiences of the nurse facilitators, as this will take place after completion of most of the ACP conversations. We aim to include all BEVAs present at the workshop, yet participation is voluntary. We will audiotape the focus group discussion and transcribe verbatim using transcription rules adjusted to the aim of content analysis.HCS will document recruitment of participants as described above.We will evaluate the ACP conversations on the level of BEVAs (in the focus group discussion), on the level of patients at t1 using face-to-face questionnaires with open-ended questions, and on the level of caregivers using qualitative telephone interviews. This multi-dimensional approach allows for gaining a comprehensive picture of all involved parties’ experiences. The same approach will serve to evaluate the information brochure with workbook.We will use the documentation of the BEVAs’ ACP conversations to estimate adherence to the planned procedure. The topic guide forms provide commentary fields and BEVAs are instructed to document whether the questions were discussed and concerning which content or result. BEVAs’ experiences with the topic guides, feasibility, and reasons for non-adherence will also be discussed in the focus groups.n = 64, intervention group). We will interview caregivers by phone at t1, focusing on individual experiences, perception of BEVAs’ performance, and perceived benefits or pitfalls of the intervention . We will assess impact on the communication about ACP in the family and ACP engagement in all patients as part of the main data collection at t0–t2. In the semi-structured interviews, we will ask caregivers about habits of decision-making within the dyad at t0 and t1.Mechanisms of impact describe reciprocal influence and interaction of participants and intervention. In this case, this means the influence of the ACP conversations on patients, caregivers, and BEVAs and how this shapes the conduction of the intervention. We will evaluate these mechanisms at t1 in patients with open-ended questions regarding their experiences and fulfillment of expectations as well as their perception of BEVAs’ performance , patients (n = 5), heads of HCS (n = 4), and staff (n = 3). Only minor revisions were necessary where we deemed questions redundant.We will conduct semi-structured interviews face-to-face or by phone and audiotape and transcribe interviews verbatim, anonymizing data in the transcription process. We will store all data for the process evaluation in an anonymized manner, and document only study site and date/measurement point on data sheets, as we decided against linking the process data and the main outcome on an individual level and opted for a cumulated comparison between the points of assessment at baseline/enrolment and t1, and between control group and intervention group. We will use data necessary to contact patients and family caregivers at home only to access them for scheduling and conducting data collection. During our pilot study, we tested the interviews with caregivers . We will conduct a content analysis and use a deductive–inductive approach . Based oACP requires reflecting on personal values, end-of-life care, and death. These topics must be treated in a sensitive and respectful manner, as they may cause distress in participants. Data collection, especially semi-structured interviews, will be conducted by experienced research assistants, who are not involved in patients’ care and have no professional or personal relationship with the patient. Interviews with patients will be conducted at their own homes in familiar environment. Patients will receive written information about the study and will have the possibility to ask questions before giving written consent. They will be informed about the possibility to end participation at any time without negative consequences regarding their care or relationship towards the HCS. Heads and BEVAs of the collaborating HCS and caregivers will receive oral information on the aim of the data collection, anonymization, data storage, dissemination, and voluntary consent. The have the possibility to ask questions and give oral consent or decline without negative consequences.Protocol version: Version 3 – 29.12.2019.The STADPLAN Trial is currently being implemented and will be completed in January 2021. Recruitment started on May 29, 2019, and will be completed by January 31, 2020.The STADPLAN study is a large cluster-randomized controlled trial and one of the first trials in ACP in community dwellers. It will provide evidence on the effectiveness of an ACP intervention provided by trained nurses in home care. The comprehensive process evaluation will indicate how the ACP intervention is related to patient activation, ACP engagement, and surrogate designation and evaluate its feasibility in the home care setting. We will follow current internationally acknowledged guidelines ; the proProcess evaluation is of utmost importance, but still it must be feasible. The MRC framework recommends to rather reduce the amount of data collected in favor of collecting the right data. For this reason, we developed the logic model within the project group, which provides guidance and commitment on the relevant questions.Looking at the key recommendations for process evaluation by the MRC framework , the strFor this phase, the key recommendations focus on the relationship, the expertise, and the synchronization of the process and outcome evaluation teams.Researchers of four universities with experiences in successful earlier study collaborations conduct the STADPLAN study. We developed the intervention and the process evaluation in close cooperation but with different responsibility among partners. All partners discussed the logic model intensively, to make sure that it represents the linking key.Thus, the close relationship, yet distinct responsibility for intervention development and process evaluation as required according to the MRC framework, as well as the necessary expertise, is fulfilled in this study.Key recommendations regarding this phase are as follows: describing the intervention and clarifying causal assumptions, defining the most important research questions, and selecting a combination of methods. In the STADPLAN study, we use a logic model to show the main elements of the intervention and the procedural outcomes we focus on. To define the relevant outcomes, we considered previous research in this domain. Furthermore, we approached important stakeholders in advance, both on local and national levels, for example, the association of legal guardians and the federal nursing council. The advisory board incorporates members representing research in ACP, geriatrics, and primary care as well as a patients’ organization. Thus, we were able to collect expertise and receive support on relevant contextual factors and current considerations in the research field.The instruments are based on theoretical foundation and the recommendations of stakeholders and target each step of the MRC evaluation framework see Fig. . We willKey recommendations of this phase are considering mixed methods data, analyzing these in an iterative process, building qualitative and quantitative analyses on each other, and publishing process data early in advance to main outcome measures. In our pilot study, we already developed the analysis scheme for the qualitative data, building a deductive analysis process upon the concepts incorporated in our logic model.This allows us to analyze the process data alongside the running trial. We decided to set data collection points for process evaluation in BEVAs, patients, and caregivers around t1 (6 months after baseline), after implementation of the intervention. This will facilitate the timely completion of the process evaluation. At the end of the study, we will conduct interviews with the heads of the HCS for a full account of their experiences.We will disseminate results via conferences, scientific forums, and publications as well as via reports and workshops targeted towards stakeholders. In reporting this protocol and the results of the process evaluation, we followed the MRC framework and previous study protocols and process evaluations with comparable approaches , 35. In After completion of the study, we will invite all stakeholders for a presentation of first results by the universities on a local level, promoting discussion and networking. Thus, we aim to enhance impact of research on the local level of nursing practice.Additional file 1. CReDICI 2 checklist STADPLAN project.


Functional near-infrared spectroscopy (fNIRS) is a neuroimaging technique that has undergone tremendous growth over the last decade due to methodological advantages over other measures of brain activation. The action-observation network (AON), a system of brain structures proposed to have “mirroring” abilities , has been studied in humans through neural measures such as fMRI and electroencephalogram (EEG); however, limitations of these methods are problematic for AON paradigms. For this reason, fNIRS is proposed as a solution to investigating the AON in humans. The present review article briefly summarizes previous neural findings in the AON and examines the state of AON research using fNIRS in adults. A total of 14 fNIRS articles are discussed, paying particular attention to methodological choices and considerations while summarizing the general findings to aid in developing better protocols to study the AON through fNIRS. Additionally, future directions of this work are discussed, specifically in relation to researching AON development and potential multimodal imaging applications. Interactions in everyday life require us to continuously encode the actions and intentions of others. It has been suggested this ability to interpret the actions of others requires the involvement of our own motor system and is mediated by a distinct class of neuronal cells historically referred to as mirror neurons  in humans has been associated with processes as social cognition, namely empathy  and electroencephalogram (EEG) have largely been used to study the human mirroring system. This literature has limitations and is criticized for frequent lack of appropriate experimental designs, often due to the restrictions of the chosen neural measurements (which will be discussed further in the context of this review article). These limitations have led to criticism of the “mirror neuron” nomenclature in humans, as there is not yet convincing evidence that: (1) mirror properties are present at the neuronal level in humans  as a neuroimaging technique to study the AON in humans. We start by providing a brief overview of the current state of the EEG and fMRI literature on the AON, as well as a discussion of the advantages and disadvantages of each modality. We then conduct a review of 14 fNIRS studies that have examined the AON in adults, detailing their methods and findings, as well as a discussion of their limitations and suggestions for optimizing fNIRS data collection in AON studies. Finally, we discuss the potential utility of using fNIRS in combination with other techniques and how a multi-modal imaging approach can provide a better understanding of the AON.mu desynchronization  in the 8–12 Hz frequency band at central scalp sites, which is referred to as Kuhlman, . Mu desyKuhlman, , though Kuhlman, . FurtherKuhlman, , action Kuhlman, , and modKuhlman, ; e.g., lAdditionally, there is an ongoing debate regarding whether mu desynchronization reflects AON activity, or specifically “mirroring” activity in the brain, or whether this can be attributed to confounding signals. Mu rhythm shares topography with the beta rhythm during motor paradigms  and deoxygenated hemoglobin  AND (mirror neuron OR action observation OR action-observation OR action/observation OR execution observation OR execution-observation OR execution/observation)]. These searches yielded 137 results, with 64 of these being novel articles. Articles were then individually reviewed using the following inclusion criteria: (1) published in a peer-reviewed journal; (2) an empirical article; (3) used fNIRS to measure hemodynamic activity in the brain; and (4) contained and analyzed both an execute and observe condition in the AON paradigm. After these criteria were applied, 14 articles remained and were included in the present review article, which offers a critical literature review article. A flowchart outlining the search and inclusion process is presented in A summary of details regarding the methodology and findings from the articles that were included in the present review article is provided in median = 24) channels across various regions of the cortex. In terms of hemispheric coverage placement, there were fewer studies that utilized a bilateral probe : , Hitachi systems , Shimadzu systems , and a custom-built system (1/14). The fNIRS systems used across these studies employed between 8 and 54 . These were studies that were interested in probing the AON based on our initial search criteria but did not adequately do so due to missing key conditions in their experimental paradigms, even though fNIRS is perhaps the technology best suited to assessing motor conditions . Future studies should be mindfully designed to ensure that at minimum a clear observe and execute condition are included in the paradigm to properly probe the AON.The types of paradigms used across the studies varied widely, including whether objects were used  and what type of stimuli were presented. Notably, most of the articles  used pre-recorded video stimuli during the observation condition instead of live-action observation of an experimenter. While this approach allows greater control of stimulus presentation during the observation condition, it has the potential to minimize AON activation elicited. Previous studies have shown that mu suppression is attenuated in adults in response to video stimuli compared to live-action stimuli during AON paradigms , though the most common number of trials was eight per condition with a range of 1–54 trials administered. Most of these studies used an event-related design, as opposed to a block design to evaluate the activity of the AON. The use of an event-related design allows the entire hemodynamic response function to be modeled, which allows for multiple features of the hemodynamic response to be quantified  and for event-related coupling of brain activity  between an execution, observation, and imagery condition; however, they did not identify which of these regions drove the main effect to determine how the conditions may have differed in activation patterns , and stimulus administration . While findings across these studies were generally consistent, this amount of variation introduces noise and calls the generalizability of these results into question. Furthermore, a standardized approach would allow more specific hypotheses to be generated in future studies aiming to further detail the functionality of the AON. Additionally, many of the studies in the initial search did not end up fitting the AON criteria to be included in the present review article, largely due to a lack of both an execute and observe the condition. The lack of either of these conditions makes them inconsequential to studying the AON. Optimizing the utility of these protocols in studying the AON can be achieved through careful study planning and consideration of the literature, as this is an issue that is also seen in other neuroimaging modalities targeting the AON. Future studies should ensure that both action execution and observation conditions are included and that the paradigms that are used are consistent with standards from the fNIRS and AON literature.Additionally, the analytic design across papers was disparate and makes their comparability suspect. While this is an issue within the field of fNIRS generally  relative to fMRI . Wireless fNIRS devices have several advantages over wired fNIRS devices and fMRI. Not only are they less stressful for subjects due to freedom of movement and reduced sensitivity to motion artifacts . While ASD is well characterized behaviorally, the underlying neurocognitive mechanisms of the disorder are still not understood. Oberman et al.’s  seminal The current review article focused on the suitability of fNIRS in the study of the AON, emphasizing the potential of this neuroimaging technique in the context of the study of action-observation and action-execution. Although it has been over two decades since the AON  was first described in humans (Iacoboni et al., The manuscript was conceived by EC and HM. The literature search, article selection, and article review were conducted by EC, HM, JM, DH, and KK. The manuscript was drafted and edited by EC, HM, JM, DH, KK, NF, and AG. All authors contributed to the article 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.