Historically, the Netherlands has hosted a large number of migrant sex workers. Since sex work is considered a legal profession it might serve as an example of better access to health services, including HIV testing, at least for those working within the legal framework. However, migrant sex workers, especially non-European Union (EU) nationals, might not be eligible to register for official employment and thus face obstacles in obtaining access to health services, becoming essentially invisible. This study examined context-specific vulnerabilities of migrant female sex workers (FSWs) from Belarus, Moldova, Russia and Ukraine, whether and how they have access to HIV testing compared to other EE, non-EU migrant FSWs in Amsterdam in the Netherlands. We conducted a multi-stakeholder perspective study from November 2015 to September 2017 in Amsterdam. The study comprised 1) semi-structured interviews with key stakeholders (N = 19); 2) in-depth interviews with Eastern European, non-EU migrant FSWs (N = 5) and field observations of the escort agency working with them; and 3) in-depth interviews with key stakeholders (N = 12). We found six key barriers to HIV testing: 1) migration and sex-work policies; 2) stigma, including self-stigmatization; 3) lack of trust in healthcare providers or social workers; 4) low levels of Dutch or English languages; 5) negative experience in accessing healthcare services in the home country; and 6) low perceived risk and HIV-related knowledge. Having a family and children, social support and working at the licensed sex-work venues might facilitate HIV testing. However, Internet-based sex workers remain invisible in the sex-work industry. Our findings indicate the importance of addressing women’s diverse experiences, shaped by intrapersonal, interpersonal, community, network and policy-level factors, with stigma being at the core. We call for the scaling up of outreach interventions focusing on FSWs and, in particular, migrant FSWs working online. Current debates on sex work are highly polarized: while opponents portray sex work as exploitative and coercive, and never a free choice, proponents suggest recognizing sex workers’ agency and that denying the opportunity to engage in sex work is a direct violation of civil rights . ConsequThe Netherlands is the only EU country where sex work is considered a legal profession. Even so, since the legalization of sex work in 2000 and introduction of stricter measures to combat human trafficking 2009) there have been debates on the effects of legalizing sex work. In practice, these laws have led to a growing illegal sector, pushing individuals out of the officially recognized and registered sex-work venues within the city councils, multiplying their vulnerabilities and limiting their access to health services , 8. More there haThe prevalence and incidence of HIV in the general population in the Netherlands is relatively low, with an estimated 19,582 people living with HIV (PLHIV), and 749 new cases diagnosed in 2017 . OverallIt appears that sex workers living with HIV are more often unaware of their status than PLHIV in the general population . SpecifiThese studies strongly suggest that migrant sex workers from non-EU countries are a significant HIV-risk group in the Netherlands. The combination of being a sex worker and a migrant together with being unable to work legally is likely to lead to barriers in obtaining access to health services. Those barriers could contribute to a low uptake of HIV-testing services, and therefore to being unaware of HIV status. This could have negative health consequences at an individual level as well as among the population group.EU in 2004 (known as the EU8) and 2007 (the EU2) it’s all just a lie, the advertisement. That's something I really like–the age is a total lie, it's just to attract the customer. (Police officer)For example, one woman described how she had to change her lifestyle in order ‘to look like 20s’ as most clients seek to dominate, and use their power to get extra sexual services for free:I am 37, but I look like 20 years old. I am on a diet, I don’t eat meat, only fish and I work out. No sugar, I eat ice cream only once a year! Clients would never go with me, if they knew that I am 37, never. They all look for young girls, because they can force them to do what they like and not pay for it. Clients ask how old are you? I say 22, they agree, they pick me. They pay money, we go upstairs and when we enter the room, I tell him to do this and that. I am the Boss, not he. I do what I want, and then, they say ‘you are not 22, you are older’. Most of the participants linked youth with a lack of HIV-related knowledge, knowledge of local policies and low self-perceived risk. Moreover, younger women were more likely to work online as escort girls or paid dates, and not perceive themselves as sex workers. Thus, women in the escort services or doing paid dates would not apply for centres using the words ‘prostitution’ or ‘sex workers’, and they would not report their involvement in sex work during health checks:Yes, yes, especially the young women speak that language, like car dates, also from Ukraine or Russia they all speak that way because of this [showing smart phone]. … and most of young people we see, migrants are very surprised that what they do is maybe prostitution, they don’t even know that they are in prostitution, they do not consider this as prostitution as I said they have car dates or paid dates. (City council representative)There is a group who does sex work, but they do not think they do it. They think ‘I am not a sex worker I just receive money for sex’. So, if I am telling them, ‘oh do you want to… to go to… sex workers' centre?’ I am not addressing them. No, because they don’t feel… like there is a place for them there… ‘Slavic languages’, as according to one social nurse ‘Slavic languages look similar’.The majority of stakeholders interviewed identified language as an important mediator which could either facilitate or impede women´s navigation through the local context. While knowledge of English and Dutch played a principal role in finding ‘your way around’, it was poor among EE female sex workers. Moreover, health professionals could not distinguish between different Interviewer:Why have you mentioned language?Respondent:Well, because it's quite bureaucratic here in Holland, they need papers and stamps, […] and to find your way around, it can be quite difficult…if you don't speak the language you can be easily taken advantage of. So, I think especially in sex work, where it is quite difficult to understand tax paying, and the permits…even for me it's not very easy to understand… (Police officer)Moreover, in some cases female sex workers fully relied on a third person (operator) whom they hire for security and language purposes. Thus, operators might fully mediate communication between them and the clients. For example, a client described this situation as follows:Now, what went completely wrong–the communication. E. doesn't speak English well…50% of the time, we could understand each other and the other 50% of the time, we used Google Translate , and so we could communicate: 7 out of 10. The reason for the 0/10 score, is because the agency/operator promised me and told me things that aren't true…According to some stakeholders, key government and non-government organizations providing services for sex workers try to have some part of their information materials translated into Russian, but it was not seen as a key priority as EE, non-EU migrant sex workers are not the largest group in the Netherlands.we hardly have cases of drug addicts among sex workers. It used to be in the 70s…’. Drug use was linked with low perceived risk, illegal employment and working outdoors. One health worker mentioned hearing ‘rumours’ about the high level of drug use among EE sex workers.Drug use was rarely mentioned and participants talked about the past: ‘…to test and to have a pill’.Alcohol consumption was frequent among sex workers, serving as a common strategy to de-stress after work; in some cases, sex workers were supposed to push clients to buy expensive alcohol from a club and then drink it together. Participants believed that alcohol increases risky sexual behaviour while reducing women’s perception of risk. For example, a woman working in a club described one situation when, after drinking with a client, she did not notice that during sexual intercourse he removed his condom. For fear of pregnancy and under pressure of her co-workers, whom she informed about the incident, the woman applied to the Prostitution Information Centre in order ‘Only one female sex worker interviewed reported insisting her clients use a condom; according to the owner of the escort agency, if clients pay more they do not use condoms and it is typical not to use condoms during oral intercourse. Moreover, according to the analysis of the online advertisements, the majority of women provided oral sex without a condom or would allow the client to ejaculate into her face/mouth for an extra 50EUR. During one of the follow-up interviews the respondent reported having a sore throat, which she believed could be a symptom of an STI, yet because of fear of being recognized as a sex worker, who is providing sexual services on a tourist visa and has little knowledge of the local rules, she did not visit any health facility and continued her ‘tour’.I do not go in long tours, I can do it [testing] at home … and I don’t want to draw attention … you know, they [health workers] can ask questions … I am on a tour now… I am ill, I have bad tonsillitis, you know?… and I need antibiotics, but without prescription they do not sell it…I asked…and I even do not know how they go to doctors here and where I need to go, etcs. . . .You know? Those who came as tourists avoided using any medical services even when they had pre-paid tourist medical insurance and even when they were feeling sick as they were afraid to be identified as a sex worker by the police. Self-medication which was brought from their home country was the most common way to deal with symptoms.Moreover, according to the analysis of the clients’ feedback webpage of the escort agency, almost all women were willing to not use condom during vaginal or anal intercourse, if they were paid extra money. Several misconceptions were reported by female sex workers, which they had heard from their peers. So, female sex workers reported taking a shower before sexual intercourse or having sexual intercourse in a Jacuzzi to reduce the risk of STI transmission, and that sexual intercourse with married clients was perceived to be safer than with single clients.Several participants discussed the importance of education. A low educational level was linked to low perceived risk and more risky behaviour. The educational component in Russian was a welcomed improvement to the programme:You should look at the level of education. Do they know what is important when you are doing sex work, and do they know that it is important to get tested, to get treatment, when necessary? ‘my own doctor’ in their home country. Usually, this refers to a doctor, a trusted person, who is paid out of pocket, able to maintain confidentiality and does not put women into the official records. Moreover, this practice was also reported by stakeholders as a common strategy to reduce costs for health insurance among both EU and non-EU sex workers. Negative experience of accessing health services in the home country could also be a barrier when seeking health care in the country of destination. One woman described her experience in a small city in her home country where she could not go to the local AIDS clinic because of the fear that ‘someone will see me entering this building’. The AIDS clinic was seen in the local community as a place ‘for drug addicts and gays’, and thus, she had to find ‘my own doctor’, whom she paid out of pocket and whom she trusted.All women interviewed reported having provoked by girls [sic]…they were too noisy and not careful’.As the police were a source of blackmail, extortion, physical and psychological violence in their home countries, women extended their fear of the police to the country of destination. The interviewed women who travelled as tourists and worked illegally all feared that health professionals would report their illegal work status to the police, which could result in deportation. This fear was also fuelled by the manager of the escort agency, who shared information with women about two cases of ‘deportation, which according to him were ‘Two women who had family back at home reported it to be their ‘biggest motivation’ to stay healthy and to seek regular testing as they had to support them financially.I help my mother; my daughter is in a nice school here [in the Netherlands]. I know why I am doing this job and in order to keep doing it in future, I need to stay healthy. Interviewer:Why do you test?Respondent:Because I take care of myself, I am still working, I am 37. I help my family, I have a daughter she is 19 years old. She is in the University. She is not like me. She still does not have a boyfriend and I started dating when I was 13 years old… back then, no sex. I told her all about men… all they want is to fuck. So she is careful and studies hard. She was studying hard always, reading books, she is clever. My daughter wants me to be happy. My daughter doesn’t know what I do for a living. I told her, that my husband is rich. I also have three sisters whom I support; they all live in Ukraine…and their kids… like if they want an iPhone, I buy. While some stakeholders and the owner of the escort agency believed that the income level facilitated the uptake of health services, female sex workers and healthcare providers did not confirm that. They rather associated income with a type of sex-work venue, which indeed facilitated access to health services. Thus, for women working indoors at a licensed sex-work venue, it was easier to access health services, as social nurses came to them. Local law facilitates access for healthcare providers to all licensed sex-work venues, but this is not possible in case of unlicensed ones, including individual work on the street or at home and online sex-work venues.The majority of stakeholders reported sex workers working online to be the hardest group to reach. There are several organizations in Amsterdam doing online outreach, which implies: 1) weekly monitoring of several online platforms, where sex workers place their advertisements; 2) collecting information into the database ; 3) checking license number; 4) evaluating risks based on a type of services provided, age and opening hours; 5) sending typical messages to all the numbers collected weekly. This approach was reported to be time-consuming while its effectiveness was unknown as there were seldom any responses. Moreover, it was impossible to examine who received the messages as escort agencies might use a third person (an operator) to communicate with clients. This strategy was criticised by one of the respondents because of the lack of individual approach:Respondent:Most people don’t respond to the text messages… […] and they think, ‘hey, this is just a standard text…I don’t respond, just like a newsletter’ or…and the others think ‘well, I don’t know what is this, I don’t trust it’. You don’t see any picture, you don’t see any face, you don’t…any address. Well, if you see pictures of the building, of the faces, it can make a different impression about the atmosphere. How they treat other sex workers. ‘to stay safe’, including a mandatory shower for clients, visual examination . Clients who do not pass muster receive three warnings before being blacklisted. This has been seen as a responsibility of the manager/owner to check clients and to have a special system where they can be checked. Female sex workers also used online communication (online forum) to report cases of abuse or violence. For example, if someone was robbed by a client or an escort agency did not provide the agreed level of support, women would report this situation, including a photo or contact details or screen prints of the online conversations. For example, five women on the online forum reported that the owner of an escort agency did not provide support to a woman who was caught by the Dutch police and then deported from the Netherlands. It was also mentioned that he blackmailed a woman as she started to work on her own. This opened public debates between the owner and the women on the online forum, with supporters on both sides. Peers also use this channel to provide some information about symptoms of STIs, how to prevent STIs, where to go to a doctor when travelling or how to self-medicate.Pimps, colleagues and peers could be both a source of support and a barrier to accessing health services, including HIV testing. For example, the owner of the escort agency described how he provides health advice to women on tourist visas. He has developed a text message named ‘Operation Moydodyr’ , which contained advice on what sex workers should do before sexual intercourse All in the club knows if you do not do that, no one will work with you’.In addition, a woman who works in a club described how peers influenced her decision to test regularly: ‘Moreover, it was clear that most women who enter sex work for the first time seek help of third parties in arranging travel . For example, two sex workers reported that they were assisted by a female friend, who was already as a sex worker. All other women interviewed reported being engaged through a manager or owner of an escort agency. Also, we saw that with time women became more familiar with the local police and how things work on the ground. Their command of Dutch improves, so they are willing to maximize their independence as well as earnings, and consequently, some decide to work on their own. Female sex workers and a third-party work closely together, but usually the owner of an escort agency would have full information about a woman, including her ID, home address, nude photos and sometimes a video, while a woman would have nothing except a mobile phone, fake name and a bank account. Thus, in most cases, a woman’s greatest fear is that her involvement in sex work will be denounced to her family and friends.‘feeling safe’ or ‘safe place’, which was closely connected with providing health services confidentially and/or anonymously. It was easier to build trusting relationships with female sex workers working at venues than with women working online. One social nurse reported that it takes several visits to a club for women to get used to her.Most stakeholders agreed that trust was important for female sex workers; some mentioned also Language is also an important factor for building relationships of trust with healthcare providers or social workers. All female sex workers interviewed identified the ability to speak in their mother tongue as one of the reasons why they preferred to use health services in their home country.I try to test every six months. I travel to Ukraine every six months and I try to go to my doctor. […] I have melanoma and she knows me so well…and she knows what to do, what I need. I feel comfortable… I don’t want anyone to know. At least, no one else. And in our country they understand our language…it is easier. Moreover, one woman reported that the absence of out-of-pocket payments and ability to choose your doctor reduces her trust in Dutch health care. In Ukraine, paying high out-of -pocket fees made her comfortable as it gave her a feeling of control over the situation as well as the assurance that she has chosen the best doctor (which correlated with high costs). It was also possible to go to another doctor if she was not satisfied with the first one. But in the Netherlands, it was much stricter and doctors all follow the same protocol.You know they [Dutch health workers] will always give you here paracetamol, if you have pain in the knee or something else, they give paracetamol. They act strictly accordingly to the book and I don’t have a trustful contact with them. Issues of the stigma attached to sex workers and migrants were mentioned by most participants. For example, one participant said that nowadays even Dutch sex workers prefer not to go to a family doctor because of the persistent social stigma facing sex workers. Moreover, some participants connected greater stigma with perceptions in Dutch society, partly formed by the dominant media discourse that the majority of sex workers are non-Dutch citizens, and victims of trafficking, who were coerced into sex work, and that their experience is horrific:I spoke to sex workers… In early 90s, like… if they would be at somebody’s birthday party they would tell people: ‘Yes, I am a sex worker in the Red Light district’. And responses would generally be ‘Yes!!??’ Like people would be sort of excited like: ‘How often do you get to meet a sex worker?’ Like: ‘It’s really cool!!!’… People would ask, like: ‘How is it? So, you must have had a lot of adventures and met so many interesting people! You must have had a lot of stories’, and now, since like 2000s the responses have really changed. So, people really become, like: ‘Oh my God! You must have seen a lot of horrible things! It must have been really terrible! How did you end up there?’…It’s a very different attitude. Thus, sex workers prefer to hide their identity or to go to specialized clinics, where they will not be treated as victims. Some participants also connected anti-migration movements, enlargement of the EU, the Dutch referendum on the Ukrainian Association agreement and implications of these ‘attitudes’ on policy change such as raising the age to work in the sex industry from 18 to 21, clients’ responsibility to check the license/registration of sex-work venues, closing of 40% of all the brothels (192 of the previous 482 according to the Project 1012), etc.Topics of the victimization of sex workers and placing all migrant sex workers under suspicion of having been trafficked are major issues for sex workers, as they are not allowed to self-identify. Thus, in most cases even when women do not recognize themselves as victims, they would be seen as such according to the law and the way this law is interpreted and applied in practice:As I said before, even if they [migrant sex workers] don’t feel as victims, they are victims to me. If they tell me stories like ok, somebody paid half-price for the ticket, somebody arranged this room, or hotel or half-price of it. ‘I am sharing that [costs] with them [third parties], so I need to pay them. And how do they get the money from your sexual services? So, somebody is profiting from your work and do you know what the debt is? No, I don’t know, but I am sure that, if I pay, etc…’ So, for them [migrant sex workers] it is like a strategy to live and to survive and they don’t even think that they are victims. (Police officer)‘our people’:Self-stigmatization of sex work along with a fear being recognized as a sex worker in her home country made women ashamed of who they are and to pretend to be of another nationality and avoid I’m ashamed when I hear Russian language; I pretend that I don’t understand it. Luckily, I don’t look like a Russian girl…All of them are stinkers; …dirty smelly stinkers. Who will pay extra money for such dirty stinkers? I am not a dirty stinker, I am not like them, and they are infected and ill. All women interviewed as well as some stakeholders talked about the time and transport costs as a potential barrier to accessing HIV testing:If you do not have an appointment you will not get medical services … And if you have your appointment at 14.10 and you are late. Once I was in a traffic jam, I was eight minutes late and they did not let me have my appointment. And when you are waiting for them it’s ok. For example, some stakeholders mentioned how opening a new STI clinic outside Amsterdam’s city centre or a mobile testing facility could facilitate HIV testing. Moreover, one stakeholder described a pilot project where a self-testing approach was used. Although there were some concerns regarding the link to treatment and HIV care, the ability to pay for self-testing kits, and possible misuse or misinterpretation of test results, some individuals appreciated this approach as it was fast, easy to perform and could be done without involving anyone else.Opponents of the Dutch prostitution policy and law perceived it to be permitting growing demands to use HIV/STI testing services for non-legal female sex workers from EE and non-EU countries in the Netherlands. This is often associated with a trend in which policy and law in relation to prostitution become increasingly strict and therefore have increasingly repressive effects on non-legal migrant female sex workers from EE, non-EU countries. For example, one of the social nurses experienced the separation between legal and non-legal prostitution as a barrier to doing her work:I feel that the non-legal sector is much less easy to access than the legal sector. So, if the non-legal sector becomes legal, it would be much easier to access them [sex workers]. Prostitution will always exist, no matter if it is legal or non-legal, but the accessibility for healthcare providers becomes less if it is non-legal. One participant questioned a definition of the voluntary nature of sex work and thought that many legal sex workers do not voluntarily choose this work, while the government pretends that they have freely chosen to be a sex worker:It is suggested that exploitation of women [who are SWs] can be eradicated if you only allow sex workers to work when they have self-chosen for prostitution. However, these measures are not solving anything…I believe that if a person wants to sell his or her own body, some kind of damage has probably occurred in the past. So, what is being meant with self-chosen prostitution? Most of the participants perceived the combination of providing health care and the government measures that aim to reduce non-legal prostitution as a barrier to sex workers’ trust in government organizations in the Netherlands. For example, the programme manager prostitution stated that this combination is not always easy to apply:In a situation where a healthcare provider, who has a confidential relationship with a sex worker, is confronted with human trafficking of that sex worker, the connection with the police needs to be made. However, this would damage the confidential relationship with that sex worker; we do not want that. (Programme manager prostitution)The physician pointed to the discouraging effects of the municipal prostitution policy to focus on non-legal migrant female sex workers from EE, non-EU countries:If you are not being supported by your own municipality, it feels like a barrier to focus our efforts more on non-legal sex workers…that is actually really weird from a public health perspective. (Physician)The programme manager prostitution mentioned that every sex worker should have similar access to take an HIV/STI test, but not to other things, such as Dutch language classes. However, the allocation of financial resources also determined the focus of the municipal health services:Our core business is the legal sector because that is being financed. […] Time–we do not have enough time to reach out to escort ladies. (Programme manager prostitution)Although human rights aspects, such as universal access to comprehensive prevention programmes, treatment, care and support, constitute a fundamental principle and were introduced in the Netherlands long ago, some stakeholders as well as all female sex workers interviewed had fragmented knowledge about whether and how ART treatment would be covered for non-EU female sex workers. To address this issue, one NGO has developed various educational materials and training aimed at health professionals. One NGO representative described a specific case of a Ukrainian woman who was pregnant and was diagnosed HIV-positive, and all the difficulties they faced in helping her with beginning ART, as she also had other health problems, which involved additional costs . Even though the NGO managed to provide some support, which took several months of hard work, at some point the woman returned to Ukraine:She could access [treatment] as an exceptional case, we did it, we found a specialist, because she needed more than just ART. […] She needed different specialists… Okay, finally we were able to find the supporting organization, that did more or less what we asked to do, but at some point we lost contact with her. We heard from her mother […] the grandmother of the child, that she moved to Israel for work. This paper sought to examine the context-specific vulnerabilities of non-EU migrant female sex workers and to describe their experiences and perceptions of existing HIV testing services in Amsterdam. In summary, the analysis highlights six barriers to HIV testing most commonly reported by research participants: 1) migration and sex-work policies; 2) stigma, including self-stigmatization; 3) lack of trust in healthcare providers or social workers; 4) low levels of Dutch or English languages; 5) negative experience in accessing healthcare services in the home country; and 6) low perceived risk and HIV-related knowledge. Having a family and children, social support and working at the licensed sex-work venues could facilitate HIV testing among migrant female sex workers in Amsterdam. Moreover, this research adds the voices of EE, non-EU women involved in escort services, which often remain inaudible to research, health providers and the public  to publish the content specifically under the CC BY 4.0 license.http://journals.plos.org/plosone/s/file?id=7c09/content-permission-form.pdf) and the following text:We recommend that you contact the original copyright holder with the Content Permission Form (http://creativecommons.org/licenses/by/4.0/). Please be aware that this license allows unrestricted use and distribution, even commercially, by third parties. Please reply and provide explicit written permission to publish XXX under a CC BY license and complete the attached form.”“I request permission for the open-access journal PLOS ONE to publish XXX under the Creative Commons Attribution License (CCAL) CC BY 4.0  remove the figure or ii) supply a replacement figure that complies with the CC BY 4.0 license. 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Please see We will update your Data Availability statement on your behalf to reflect the information you provide.[Note: HTML markup is below. Please do not edit.]Reviewers' comments:Reviewer's Responses to QuestionsComments to the Author1. Is the manuscript technically sound, and do the data support the conclusions?The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented. Reviewer #1: Yes**********2. Has the statistical analysis been performed appropriately and rigorously? Reviewer #1: Yes**********3. Have the authors made all data underlying the findings in their manuscript fully available?PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.The Reviewer #1: Yes**********4. Is the manuscript presented in an intelligible fashion and written in standard English?PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.Reviewer #1: Yes**********5. Review Comments to the AuthorPlease use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. Reviewer #1: This is an original publication of qualitative data exploring barriers and facilitators to HIV testing (as a proxy for a wider range of HIV services) available to migrant sex workers in the Netherlands. The motivation for the study is policy-oriented rather than an acute crisis of rising HIV infections or a high HIV mortality among the population of interest, although evidence of a high lack of awareness of HIV infection among sex workers is probably the biggest "signal" presented by authors. The contradictory policies of legalized sex work versus restrictive employment policies for immigrants have created a "loophole" of sorts - services can't be accessed by those who may need them the most.The introduction is long and reads more like a policy or social science paper in some ways. However, because the observations and conclusions are unique to an often forgotten, marginalized group, with little opportunity to voice their experiences (as evidenced by the very limited number of sex workers that could be interviewed), we must recognize the value of these data as a baseline, a platform to grow the body of research on this subject. It would have been interesting to include questions to the stakeholders on how best to access migrant sex workers operating "under the radar."I commend the authors on a well-written, well-reasoned manuscript on a fairly novel, under-explored area of research, especially given the evidence that incidence is declining in most parts of the world, except for Eastern Europe where may of the migrant sex workers originate.Minor revisions requested:1. Recommend "sex workers who use drugs" rather than "drug-using sex workers."2. Check wording please: "...problems of being [able] to work legally..." - consider more direct wording. Rather than problems of being able to, consider "...together with being unable to work legally..."3. Thank you for highlighting the limited numbers in phase 2 - migrant sex workers, particularly those working without legal status, are absent from data collection. Could this be expanded? I think it's a methodological note worth explaining - so that future research on this area/this population can learn from the authors' experiences. What would they have done differently if they could re-design their strategy to access this population?4. Should phase 3, interviewee number 6 be re-categorized to phase 2?5. Is there a reason that only one interview tools was included in the submission? "Interview guide for key stakeholders" - is this from phase 1 or phase 3?6. Were the selected criteria for "key stakeholders" in phases 1 and 3 different? It seems like the same pool of stakeholders?7. To readers less familiar with qualitative methods, please ensure the difference between semi-structured interview and in-depth interview and the reasons to select one method or the other are clear.8. Wording check: "...and use their power [to] get extra sexual services for free.**********what does this mean?). If published, this will include your full peer review and any attached files.6. PLOS authors have the option to publish the peer review history of their article  digital diagnostic tool,  27 Apr 2020February 24, 2020Academic EditorPLOS ONEDear Prof. Joan A.CaylàOn behalf of my co-authors  I am re- submitting our manuscript entitled “I don’t want anyone to know’: experiences of obtaining access to HIV testing by Eastern European non-European Union sex workers in Amsterdam” (Manuscript ID: PONE-D-19-24622). Below, we provide a response to each point raised by the academic editor and reviewer(s).Comments ResponsesJournal Requirements:1.Please ensure that your manuscript meets PLOS ONE's style requirements, including those for file naming. We have corrected the file naming to meet PLOS ONE's style requirements.2.Please revise your ethics statement in the submission form to reflect the information in sec. 2.4. We have corrected ethics statement in the submission form.3.Please can you update the corresponding authors contact details to provide an institutional email address. We have updated the corresponding authors contact details and provided an institutional email address.(Page 1)4.We noticed you have some minor occurrence of overlapping text with the following previous publication, which needs to be addressed: Tokar, Anna, et al. "HIV testing and counseling among female sex workers: a systematic literature review." AIDS and Behavior 22.8 (2018): 2435-2457. In your revision ensure you cite all your sources (including your own works), and quote or rephrase any duplicated text outside the methods section. Further consideration is dependent on these concerns being addressed. Thank you very much for the comment.We have added this reference.5.We note that Figures 1 and 2 in your submission contain copyrighted images. All PLOS content is published under the Creative Commons Attribution License (CC BY 4.0), which means that the manuscript, images, and Supporting Information files will be freely available online, and any third party is permitted to access, download, copy, distribute, and use these materials in any way, even commercially, with proper attribution. Both figures were developed by the authors. Figure 1 represents the project phases of the current studies and was exclusively developed for this publication by the authors. (Page 8)https://doi.org/10.1007/s10461-018-2043-3).Figure 2 was developed as a result of the systematic review, which was published in the AIDS and Behavior . AIDS and Behaviour. Vol.13:(0123456789), [Original research].We have added reference under Figure 2.6.Please do not include funding sources in the Acknowledgments or anywhere else in the manuscript file. Funding information should only be entered in the financial disclosure section of the submission system. We have deleted funding information from Acknowledgments. It is only included in the financial disclosure section of the submission system and funding section of the manuscript.(Funding -Page 30)7.We note that you have indicated that data from this study are available upon request. PLOS only allows data to be available upon request if there are legal or ethical restrictions on sharing data publicly. a) If there are ethical or legal restrictions on sharing a de-identified data set, please explain them in detail  and who has imposed them . Please also provide contact information for a data access committee, ethics committee, or other institutional body to which data requests may be sent.b) If there are no restrictions, please upload the minimal anonymized data set necessary to replicate your study findings as either Supporting Information files or to a stable, public repository and provide us with the relevant URLs, DOIs, or accession numbers. We would like to keep the data available upon request because of several reasons:a) de-identified transcripts of interviews with stakeholders might still allow to identify who those persons were as they describe their work routine. Moreover, there are a limited number of organizations focusing on sex workers or migrant sex workers in Amsterdam , which makes it easier to identify people. b) The interviews with migrant sex workers contain sensitive information, including information about women’s health and family status, as well as detailed descriptions of how they violated some work and migration policies either in past or in present.c) Collected advertisements, contain personal information , and even after deleting all personal information it might be possible to use some parts of the text in order tofind these advertisements online as they are still available at the website of the escort agency.Review Comments to the Author1. Recommend "sex workers who use drugs" rather than "drug-using sex workers." Thank you very much for the comment. We have changed"drug-using sex workers" to"sex workers who use drugs".(Introduction Section- Page 3)2. Check wording please: "...problems of being [able] to work legally..." - consider more direct wording. Rather than problems of being able to, consider "...together with being unable to work legally..." We have changed "...problems of being [able] to work legally... " to "...together with being unable to work legally..."(Introduction Section-Page 4)3. Thank you for highlighting the limited numbers in phase 2 - migrant sex workers, particularly those working without legal status, are absent from data collection. Could this be expanded? I think it's a methodological note worth explaining - so that future research on this area/this population can learn from the authors' experiences. What would they have done differently if they could re-design their strategy to access this population? Thank you very much for the comment.We have written a separate methodological paper focusing on different methodological issues, challenges as well as presenting some reflections. This paper is now under review. We have added: “A more detailed descriptions and reflections on methodological aspects of this study, including sampling, data collection and ethical issues, could be found in another article, which we have written.”(Methods Section- Page13)4. Should phase 3, interviewee number 6 be re-categorized to phase 2? Interviewee number six, was not a migrant from Eastern Europe. This was a Dutch resident, who was born in the Netherlands and at the moment of our interview, worked as a street-based sex worker. Also, this person was an activist and a member of one sex worker-led organization in the Netherlands. 5. Is there a reason that only one interview tools was included in the submission? "Interview guide for key stakeholders" - is this from phase 1 or phase 3? The initially included guide was from Phase 1.We have included now all the guides as annexes.(Annex 2-4 - Pages 35-44)6. Were the selected criteria for "key stakeholders" in phases 1 and 3 different? It seems like the same pool of stakeholders? The pool of respondent for Phase 3 was defined based on the results of Phases 1 and 2. It included some of the NGOs, which we have contacted in the Phase 1 (three of them), yet we have never talked twice to the same person. Moreover, as you may see from the list of participants (Table 1), in Phase 1 a broad range of stakeholders was included , while in Phase 2 we were able to focus exclusively on those stakeholders working with EE non-EU migrant FSWs.7. To readers less familiar with qualitative methods, please ensure the difference between semi-structured interview and in-depth interview and the reasons to select one method or the other are clear Thank you very much for the comment. We have added a description of both methods as well as reasons why these methods have been applied. Terms “semi-structured interviews” and “in-depth, narrative interviews” were used in accordance with definitions given by Judith Green and Nicki Thorogood, “Qualitative methods for Health Research”, SAGE Ltd, 2004. “Since we aimed to collect information on predefined topics in this first phase of the project, we conducted semi-structured interviews, in which a researcher set the agenda in terms of topics covered, but the respondent determined the kinds of information obtained as well as the relative importance of this information.” (Methods Section – Pages 8-9)“In Phase 2 we used in-depth, narrative interviews as this method allowed respondents to have enough time to develop their own accounts of the issues important to them, while interviewer served rather as a facilitator of this process. Respondents determined the conversation flow.”(Methods Section – Pages 9)8.Wording check: "...and use their power [to] get extra sexual services for free Thank you very much for the comment.We have changed “and use their power to get extra sexual services for free.”(Results Section– Page 15)http://www.transglobalhealth.org).ISGlobal, University of Barcelona, Barcelona, Spain is her host institute. Ms. Tokar’s living allowances and cost of her PhD research (as bench fees) are funded by the European Commission (EC). Under the PhD scheme, Ms. Tokar received a limited amount of money as bench fees  and there is no fund dedicated to cover publishing costs. In the Erasmus Mundus Program Guide on page 43-45 you can find all the information about the grant award. Moreover, currently Ms. Anna Tokar does not receive a salary, as she has finished her PhD and now is about to defend her thesis.We also would like to mention that we have initially applied to receive a publication fee waiver. Ms. Tokar, a first author, a Ukrainian, is a Trans Global Health PhD student  from the PLOS ONE.Thank you very much for your consideration of this manuscript.Sincerely, Anna TokarBarcelona Institute for Global Health ,Hospital Clínic – University of BarcelonaRosselló, 132, 4thES-08036, Barcelona, SpainAttachmentResponse to reviewer_Tokar.docxSubmitted filename: Click here for additional data file. 29 May 2020I don’t want anyone to know’: experiences of obtaining access toHIV testing by Eastern European,non-European Union sex workers in Amsterdam, the Netherlands.PONE-D-19-24622R1Dear Dr. Tokar,We are pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it complies with all outstanding technical requirements.Within one week, you will receive an e-mail containing information on the amendments required prior to publication. 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If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.The Reviewer #1: Yes**********5. Is the manuscript presented in an intelligible fashion and written in standard English?PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.Reviewer #1: Yes**********6. Review Comments to the AuthorPlease use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. Reviewer #1: (No Response)**********what does this mean?). If published, this will include your full peer review and any attached files.7. 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The ultimate goal of all medical activity is to restore patients to a state of complete physical, mental, and social wellbeing. In cancer, it is assumed that this can only be obtained through the complete eradication of the tumor burden. So far, this strategy has led to a substantial improvement in cancer survival rates. Despite this, more than 9 million people die from cancer every year. Therefore, we need to accept that our current cancer treatment paradigm is obsolete and must be changed. The new paradigm should reflect that cancer is a systemic disease, which affects an individual patient living in a particular social reality, rather than an invading organism or a mere cluster of mutated cells that need to be eradicated. This Hippocratic holistic view will ultimately lead to an improvement in health and wellbeing in cancer patients. They deserve nothing less. Our current therapeutic strategy is based on the fact that a cancer cure can only be achieved through the complete eradication of the tumor burden. Based on this and following the concept of the “poisoned arrow” described by Ehrlich, finding the “Achilles heel” of tumors that may be exploited as a specific target while sparing healthy tissues becomes essential . At presTherefore, the factual question remains unanswered: how can we truly cure cancer? We can only find the answer to that question if we first accept that our current cancer treatment paradigm is obsolete. The evaluation of the present paradigm shows many triumphs in basic and clinical research but, unfortunately, continues to fail in our goal of restoring a state of complete physical, mental, and social wellbeing in most cancer patients. To cure the approximately 18 million people with cancer worldwide, we must shift from this paradigm . It is t“Physician must convert or insert wisdom to medicine and medicine to wisdom” (Hippocrates) .Modern medicine is based on the works of Hippocrates (460-370 BC) and his disciples , 10. In The aim of cancer treatment should be to restore a state of complete physical, mental, and social wellbeing in cancer patients, and not only to eradicate the tumor burden. Then, we need to move from the paradigm that claims “for extreme diseases, extreme methods of cure” to a new paradigm that may be reformulated as “for systemic diseases, systemic methods of cure”. This new paradigm should be based in new axioms that will lead to novel treatment strategies .“The exacerbations and remissions will be indicated by the diseases, the seasons of the year, the reciprocation of the periods, whether they occur every day, every alternate day, or after a longer period, and by the supervening symptoms” (Hippocrates) .An important breakthrough in cancer biology was the recognition of tumors as abnormal organs acting in the context of an entire organism –17. Tumoα, IFNγ, IL6, and lactate) can disrupt the metabolic functions of the liver and lead to cachexia, which accounts for nearly one-third of cancer deaths [A clear effect of the tumor-derived macroenvironment is the severe suppression of the immune system, resulting in an increased risk of infections and patient mortality , 22. Tumr deaths , 26. Furr deaths . Given tr deaths , 28. Allr deaths . These f“What remains in diseases after the crisis is apt to produce relapses” (Hippocrates).foci, where a main or “leading” metastasis inhibits the growth of the other metastatic colonies. Nowadays, we know that there are four main mechanisms of concomitant resistance: (i) the growth of a tumor might generate a specific antitumor immune response, which even though not strong enough to inhibit its growth, it is capable of preventing the development of small secondary tumors [The “societal” organization of cancer may be compared to the behavior of certain species of ants, which form complex organizations known as supercolonies, with the ability to expand their nests over large areas allowing them to achieve ecosystem dominance , 31. Indy tumors , 36;  ty tumors ; (iv) thy tumors , 38, 39.The concomitant resistance model explains the patterns observed in the clinical evolution of some types of cancers. For example, disease recurrence in patients with early breast cancer shows a bimodal pattern, with a broad dominant early peak of relapse at about 1.5-2 years after surgery, followed by a second peak at about 5 years, and then a tapered pattern of relapse extending up to 20 years , 41. Accβ) [One of the first researchers to link cancer and inflammation was Virchow, who suggested that irritation of the stroma caused sites of “chronic inflammation” with tumorigenic potential . Years lβ) , 59. ROSβ) , 60. Theβ) . Over tiβ) . Therefoα, IL1β, IL6, and IL17) and infiltrated immune cells  without exhibiting structural alterations or loss in their primary functions [Alternatively, recent evidence suggests that cancer may also be the result of systemic, low-grade chronic inflammation (SLGCI). In SLGCI, peripheral tissues chronically exhibit high levels of inflammatory factors .Treatment decisions are often based on data obtained from a small percentage of patients, i.e., those who take part in clinical trials. This means that clinical information from the majority of patients, who do not take part in clinical trials, is not being used . This isOne of the most interesting areas of research in AI is virtual medicine. The human body is the biggest data platform. A variety of fields have used computational models as virtual surrogates of human physiology. These models can be considered as virtual representations of a subset or the whole of the patient's physiological identity . PatientIt is clear that a cancer cure will not be achieved only by the eradication of the tumor. Indeed, a tumor-centric treatment can never be a solution to a systemic, medical problem. With this in mind, how can we treat cancer patients to truly cure them? We can start by following the example of other therapeutic areas. The clearest is the paradigm shift produced in the treatment of the metabolic syndrome, a cluster of conditions comprising increased blood pressure, high blood sugar, excess body fat around the waist, and increased cholesterol or triglyceride levels. In the past, all these conditions were diagnosed and treated separately, without a global approach. Today, we know that all these markers are related to chronic inflammation, tend to occur together, and increase the risk of heart disease, stroke, and diabetes. Indeed, once established, SLGCI promotes and perpetuates metabolic alterations, establishing a deleterious cycle that promotes pathological processes such as insulin resistance, arteriosclerosis, and endothelial dysfunction. In order to break this cycle, it is necessary to control both the metabolic and inflammatory components simultaneously. These new concepts led to a shift to therapeutic strategies with a more holistic, multidisciplinary approach . FirstlyAs an old medical adage goes, it is better to prevent a disease than to treat it. This is why the first important step is to educate people so that they can take care of their own health. Simultaneously, primary care should not only include a global clinical analysis and routine imaging/laboratory tests but also include the assessment of SLGCI markers on a regular basis and the characterization of the patient's microbiota whenever possible. The routine analysis of these variables by clinical, imaging, and laboratory tests will allow to determine the levels of chronic inflammation. Therefore, those identified as having a high risk of cancer (among other diseases) based on their level of chronic inflammation can receive early intervention strategies.As with other chronic diseases, cancer is linked to unhealthy lifestyles such as smoking, poor diet, lack of physical activity, obesity, sleep deprivation, and alcohol abuse, along with the daily chronic stress imposed by modern life. Thus, current global cancer prevention and treatment strategies should firstly focus on drastically modifying people's lifestyles. Indeed, individuals with a healthy lifestyle appear to have a remarkably lower risk of cancer , 114. ThPhysical activity induces a series of adaptive processes that affect tissue metabolism, angiogenesis, and immune regulation . For exaDifferent studies have consistently shown a correlation between increased body weight and cancer, with increased mortality rates for all cancers and for cancers at multiple specific sites in obese patients –129. Impβ) and cortisol levels [Sleep has an impact on a vast array of physiological functions, such as immune function, cognitive ability, and glucose metabolism . When sll levels –138. Thel levels –141. Sleβ secretion, so as to prevent obesity-promoted tumor growth and desmoplasia. In preclinical models, this strategy is proved to be successful [Once a primary tumor is diagnosed, the therapeutic strategy must be adapted to each patient: this is the only true personalization of medicine. Firstly, we must have new diagnostic tests to evaluate, besides tumor genetics and TME, the degree of interrelation of the tumor with its host organism , its micro- or macrometastases (concomitant resistance), and the degree of SLGCI. Then, a global approach taking into consideration all these variables must be adopted. For example, we have previously discussed how obesity stimulates pancreatic tumor initiation, growth, and metastasis –144. Thuccessful .m-Tyr. This metabolite was recently shown to exert its antimetastatic effect at low concentrations with no detectable toxic side effects [Novel therapeutic strategies should modulate specific tumor microenvironments to maintain them in a dormant state. Current adjuvant chemotherapy should be administered with different schedules that could be more effective than standard regimens. For example, in surgically treated breast cancer patients, first recurrences tend to occur after 1.5-2 years. Thus, it may be worth to reintroduce specific systemic treatments during that time period in order to eradicate the growing micrometastatic foci; in this sense, the use of oral metronomic chemotherapy appears to be the most interesting schedule as, besides showing antitumor activity, it modulates tumor angiogenesis and immune responses with a moderate toxicity , 145. Or effects . Surgica effects , 148. Ex effects . Thus, a effects , 151. MiTherapeutic modulation of chronic inflammation is likely to transform a protumorigenic microenvironment into a healthy microenvironment. For this reason, several commonly used medications, including nonsteroidal anti-inflammatory drugs (NSAIDs), metformin, and statins, represent an additional tool in cancer treatment. For example, COX2 inhibitors are effective cancer chemopreventive agents and have also demonstrated to control cancer-associated chronic inflammation , 153. EfC. difficile infection, or graft-versus-host disease.Manipulation of the gut microbiome to restore a protective microbiota (eubiosis) is a goal in patients that show disturbances in microbial composition and functionality (Raman 2013). Diet is the easiest way to restore eubiosis. For example, the consumption of fruits and vegetables promotes the growth of bacterial species that produce butyrate and lactate, which helps to preserve the colonic epithelium through inducing a relatively low pH. This might reduce amino acid fermentation and the growth of cancer-related pathogens , 154. InThere is no doubt that throughout history, the current paradigm has significantly improved cancer care. In addition, nowadays, thanks to recent medical discoveries, patients with cancer live longer and with better quality of life than in the past. But the goal of curing all cancers has not been accomplished yet. We believe that the current paradigm regarding cancer treatment needs significant changes and considerable efforts. Currently, cancer therapy is still based on the millenary paradigm that establishes that in order to achieve a cure, the complete eradication of cancer cells must be achieved. The old philosophical concept of “magister dixit”  has encouraged the faithful fulfillment of the current paradigm despite the fact that, for a long time, no significant improvements have been observed in actual cure (not just remissions) rates, and despite recent scientific and technological advances. Consequently, should we be surprised by this despite the efforts invested in drug discovery and development, pharmacology, and technical devices? Probably not. What should be surprising is the insistence in maintaining a paradigm and axioms that do not work. Nowadays, what seems to matter is not what the medical community knows or does not know regarding a certain fact but rather what it believes or does not believe about it. The real individualization of cancer treatment consists in treating each individual patient following the good general practices of oncology and taking into consideration his/her own particular needs.Our past reductionist approaches have led us to miss the bigger picture, look in the wrong places, or worse still, not even question if we have the right starting point . AccordiBig data and AI are redefining cancer research and management , 164. ThIn conclusion, cancer should not be seen as an invading organism or a mere cluster of cancer cells that needs to be eradicated. Instead, a tumor may be better understood as an organ-like structure, acting in the context of a whole organism (a systemic disease) of an individual patient living in a particular social reality. Such a view is more appropriate for understanding complex systems, where some properties of the whole system cannot be inferred from the separate properties of its individual components. Indeed, if one regards the tumor as an organ-like structure within an organism that is a human being (the patient), it seems less outlandish that cancer may be related to homeostatic imbalance, inflammation, or concomitant resistance. These new concepts highlight the notion that even “transient” phenomena can have an impact with lifelong consequences, or in the words of chaos theory, “the ultimate outcome is exquisitely sensitive to the initial conditions.” In summary, the understanding of cancer disease based on holistic clinical and pathophysiological concepts will finally lead to an improvement in the health and wellbeing of cancer patients. They deserve nothing less.


Why would a computational biologist with 40 years of research experience say bioinformatics is dead? The short answer is, in being the Founding Dean of a new School of Data Science, what we do suddenly looks different. Now that I have your attention, clearly, bioinformatics as a field is very much alive. The name, however, no longer applies to what we actually do in the field. It is not what forward-thinking scientists should be calling themselves in this era of the fourth paradigm of data science , where dBut first, let me acknowledge Florian Markowetz, who started the discussion . As NIH Still, its promise could not be denied. A new generation of practitioners emerged who were as adept in silico as they were in vivo and/or in vitro. Bioinformatics spread its wings as computational biology and then systems biology, which is roughly where we are today. In 2014, I predicted that by 2020, computation would be steering the biomedical ship, experiment would increasingly be used to confirm predictive models, and causation would increasingly be determined from digital data previously collected by others or by bioinformatically guided laboratory robotics that maximized experimental insights.My predictions about timing were off, but not about outcome. The role of what I’ll call digitally based causation and predictive analytics is assured. Thus, how we describe our field, to truly express what we do, is off. What’s driven the changes? The same thing that spawned bioinformatics: digital data. But now there is much more of it, and it’s not just DNA sequences but data at all scales, from molecules to populations, and it’s being collected (high-throughput methods) and generated (via simulations and modeling) at unprecedented rates. Add to that hardware and software architectures that support a variety of increasingly robust machine learning techniques and you see where we are headed.Data, or as we now refer to it, “big data,” drive change. It’s embodied in the field of data science. If you call yourself a “bioinformatician,” you may be thinking, “what’s the big deal, I’ve been doing data science all along.” But I would argue that something fundamentally different is going on.My career spans a large part of the third paradigm of computation , and the—the “school” gives us autonomy in an academic institution, and the “without walls” means we don’t own anything but contribute to everything (or at least aim to).Bioinformatics researchers may think we have a unique “in” to the fourth paradigm, derived from a sense of being first as well as limited exposure to other domains that’s reinforced by the siloed walls of academia. Data science in academic institutions across the world is changing that view. Wherever a data science initiative lives within an academic institution, it is breaking down those silos, simply by being interdisciplinary. Data science—part computer science, part statistics, part information science, and part applied math—with its unique blend of methodologies and scientific cultures—doesn’t acquire meaning until put to practical use. Add to that the influence of the private sector, think DeepMind , and youThis arrangement creates an institutional nexus to exchange best practices between disciplines in a way that did not exist previously. It recognizes that new developments relevant to biomedical research will happen far beyond the walls of biomedicine, and the most successful biomedical researchers will embrace these opportunities first. There is nothing fundamentally new here. Recall that hidden Markov models developed in the 1960s for signal processing found their way into bioinformatics in the 1980s, and ontological research with roots in artificial intelligence (AI) influenced the development of the gene ontology. What is fundamentally new is the speed of adoption and the locus of new opportunities.How data science can be a catalyst of change depends on how you define data science see . But itsThat name better reflects what we do, or certainly what the students we are training today will do. It really doesn’t matter what you call it. Just do it.Within our School of Data Science, we have given a great deal of thought to this question , focusinThe “4” refers to systems, design, analysis, and value, and the “1” to all the disciplines/domains to which these fundamentals are applied. Bioinformatics is only one of the many disciplines/domains.Each of the “4” brings forth the influence of the “1,” through the data, methods, protocols, culture, etc. of those fields. Synergistically, the “4” then influences the “1.” Three examples of this synergy include the influence of available environmental data on epigenetics, the influence of social media networks on our understanding of biological networks, and advances in the use of natural language processing in the digital humanities influencing developments in biocuration from the literature.Systems implies high performance computing, cloud environments, high-throughput systems, workflow systems, benchmarking analyses, cybersecurity, and the like, all tuned to the needs of big data.Design concerns the relationship between data and computers and humans at all stages of the data life cycle, from ingestion through to visualization and other forms of dissemination.Analysis, mistakenly considered as all of data science, is only one important part and comprises techniques seeking both causality and prediction such as deep learning, data mining, and natural language processing.Value implies, at its extremes, the tension between the value an analysis brings versus the unintended negative consequences that can result and how to strike the right balance.