In South Africa, youth experience challenges with oral Pre-Exposure Prophylaxis (PrEP) access and uptake. Taking services out of healthcare settings has the potential to increase reach and overcome these challenges. This paper presents young and older people's preferences for decentralized, simplified PrEP service delivery and new long-acting HIV prevention methods, in Ga-Rankuwa, South Africa.Between May and August 2021, both PrEP user and non-user adolescent girls and young women (AGYW), pregnant AGYW, female sex workers, adolescent boys and young men (ABYM), and men who have sex with men (MSM) were recruited to participate in focus group discussions (FDGs) in Ga-Rankuwa, Gauteng. Twenty-two FGDs were conducted. Participants were asked about PrEP uptake, potential acceptability of long-acting HIV prevention products, provision of integrated, simplified, and decentralized services, and digital tools to facilitate access to PrEP and other SRH services. A qualitative approach using inductive thematic analysis was carried out to explore emerging themes on decentralized, simplified delivery and the acceptability of long-acting methods.n = 50) were female, the median age was 23 years ± 5.3. A third (n = 37) were current or previous PrEP users, of which, 59.5% (n = 22) collected PrEP refills from the clinic. Decentralized, simplified service delivery was appealing; health facilities, pharmacies and institutions of learning were preferred as service points for PrEP and SRH services, and recreational spaces preferred for dissemination of health information and engagement. ABYM were more open to having recreational spaces as service points. Long-acting Cabotegravir was preferred over the Dapivirine Vaginal Ring due to concerns around perceived side-effects, efficacy, and comfort.Of the 109 participants included in the study approximately 45% (Providing long-acting PrEP methods through decentralized, simplified service delivery was appealing to this population. They provided practical locations for decentralized service provision to potentially increase their engagement with and uptake of HIV prevention and SRH services. South Africa has the largest HIV epidemic in the world with an estimated 8.3 million people living with HIV and nearly 400,000 new infections per year , 2. AGYWWomen and children have typically been the focus in HIV prevention programs . HoweverThe development of biomedical HIV prevention methods, namely oral PrEP, provides the opportunity for at risk populations to take control of their sexual and reproductive health . Oral PrSome of these challenges could be overcome by providing differentiated services . This inTwo long-acting HIV prevention methods, long-acting cabotegravir (CAB-LA) and the Dapivirine vaginal ring (DVR), have been found to be safe and effective –42. In MWe carried out formative research in Ga-Rankuwa, Gauteng, South Africa with two aims. Firstly, to refine our design of decentralized, simplified service delivery utilizing the hub and spoke concept as the foundation . In the The aims of this formative study are important in preparation for expanding services and access to PrEP products. Findings from this formative research will provide insights into the acceptability of decentralized and simplified health service points for PrEP and SRH delivery and provide data on acceptability of new long-acting HIV prevention methods.We conducted a qualitative study between May and August 2021 in Ga-Rankuwa, Tshwane district, Gauteng Province, South Africa. Ga-Rankuwa, is home to over 90,000 Black South Africans, it is a peri-urban area, where Setswana is the most spoken language . Only 20The population of interest was AGYW 15–24 years), older women up to the age of 29 years, pregnant AGYW and older women (15–29 years), FSW (>18 years), ABYM, older men up to the age of 29 years, and men who have sex with men (MSM) (15–29 years). ABYM were selected because not only are they at risk of HIV infection and transmission, but they also engage less with HIV prevention services compared to their counterparts . MSM and years, oThe study employed purposive sampling to identify the populations of interest. Purposive sampling is the deliberate selection of study participants based on the qualities they possess . To recrParticipants were eligible if they resided in Ga-Rankuwa at the time of the study, were fluent in English, Zulu, and/or Tswana; willing to provide written informed consent, or assent and parental/guardian consent if younger than 18 years. The list included people who were current PrEP users, former PrEP users, repeat PrEP users, as well as those who had never used PrEP. The PrEP user's category enabled us to look at actual experiences with these services. PrEP non-user's participants were considered eligible for PrEP services, therefore may use PrEP, including new long-acting methods, in future, providing information on perceived experiences with these services.All potential participants were contacted telephonically or approached by trained study fieldworkers. The fieldworkers explained the study and assessed their eligibility, interest, and availability to be part of an FGD. If eligible and willing, they were then invited to participate in the study.Two semi-structured FGD guides were developed: one for PrEP non-user participants and one for PrEP users. The aim was to capture differences between PrEP non-users and PrEP users in relation to their experiences, views on long-acting methods and PrEP decision-making.. During the workshop, the participants were given a brief description of the new long-acting HIV prevention methods (DVR and LA-CAB), including the mode of delivery and frequency of administration, and the advantages and disadvantages associated with each method. The long-acting cabotegravir injection can be taken by both males and females, while the DVR can only be used by females and those assigned female at birth. Lastly, both guides sought to examine the potential acceptability of demand creation and digital innovations which could facilitate access to information and services. Fieldworkers, two females and one male, were trained on the use of the FGD guides, study procedures including human research ethics, and qualitative interviewing techniques.The PrEP users' FGD guide assessed their journey and the challenges they may have experienced while using PrEP, whilst the PrEP non-users FGD guide examined their knowledge and theoretical acceptability of oral PrEP. Both guides sought to understand their opinions, experiences, and beliefs around the best ways to receive SRH and HIV prevention services. The guides further sought to assess the preferences for a decentralized, simplified service delivery for PrEP and SRH services. In the hub and spoke concept, one Public Health Centre (PHC) is the hub, providing PrEP and SRH services to potential end users. The PHC is supported by, and its footprint expanded through community services points, such as mobile clinics, schools, places where potential end users congregate , universities and CBOs. In this study, the service points that were presented to the participants were a hospital, two community healthcare centers, a university campus, ten secondary schools, a police station, a CBO, two pharmacies, a pub and grill, a shopping complex, an eatery, and a park. The service points were identified and selected through prior engagements and end user surveys, where end user's reported socializing. Decentralized and simplified service delivery points were presented to the study participants to facilitate a discussion. Secondly, both guides sought to assess the potential acceptability of long-acting HIV-prevention methodsTwenty-two FGDs were facilitated between May and August 2021 . To encoCOVID-19 protocols were adhered to, including a COVID-19 symptom pre-check, social distancing, sanitizing, and masking. Participants completed a short COVID-19 screening form prior to entering the FGD venue . Participants then completed a short, self-administered quantitative survey, collecting demographic information and data on their use and experience of PrEP, social media use and other digital innovations. Following this, FGDs were facilitated by one fieldworker, matched to each group by sex. A second fieldworker took notes during the FGDs. Prior to starting the FGD, participants were reminded that, due to the nature of FDGs, they were not anonymous, but participants were encouraged to keep what was discussed in the group confidential. On average, FGDs were an hour in duration. Using the semi-structured FGD guide, the groups were conducted in English and, where necessary, in participants' preferred language . The FGDs were audio-recorded on a digital recorder. Participants were assigned a unique number, to ensure anonymity when identifying themselves for the audio recording.Demographic data were captured on Microsoft Excel and analyzed using Stata v15 . FGD recDissemination of information’, ‘Decentralized and simplified service delivery to facilitate access to services’, ‘Acceptability of long-acting methods’, ‘Factors influencing PrEP uptake, effective use, disclosure, and support’, and ‘Digital tools.’ However, this paper only focuses on two themes, namely, ‘decentralized and simplified service delivery to facilitate access to services’ and ‘acceptability of long-acting methods’.Two analysis workshops were held where four research team members  discussed the emerging data, coding, and themes. The first round of codes was created through open coding of 2 transcripts during the workshop. Thereafter, using axial coding, these codes were further organized into 18 main codes. The remaining 19 transcripts were divided among and coded by two research team members (PM and NM). Once all the transcripts were coded, the 18 main codes were further grouped into five major themes, namely, ‘Ethics approval for the study was granted by the Human Research Ethics Committee of the University of the Witwatersrand (#M210107). Written informed consent/assent was sought from participants before all FGDs, as well as permission to audio-record the discussions. Minors, interested in participation, provided written assent, and provided their parents/guardians phone numbers to the fieldworkers. Parents/guardians of interested minors were contacted telephonically by fieldworkers and informed about the study. Willing parents/guardians gave verbal consent for the minors’ participation in the study.A total of 109 participants were recruited . With regards to PrEP use, just over a third of all participants (33.9%) had ever used PrEP, higher among females (38.0%) than males (29.6%). PrEP was predominantly collected from a public health clinic (59.5%), followed by mobile outreach services (35.1%), and from private projects/organizations (2.7%).a)Healthcare FacilitiesSome participants liked the idea of having a local hospital and community healthcare facilities as service delivery points stating that it is “easier to get to the clinic” , they offered a sense of privacy and had friendly staff. However, other participants had opposing views stating that these service delivery points were “far, and it (is) always overcrowded” . AGYW highlighted the lack of privacy at health care facilities, opening times, and healthcare provider attitudes as challenges to accessing services:There is no privacy. People enter as they please, so you end up not being able to talk.” “Pharmacy is closed, why do you came at this time? PrEP providers are at the back.” I arrive when I arrive there, “Yoh sister why did you come so late? Come tomorrow at eight!” They do not even want to hear my story that I have a file; I am only late for collection. How about they look at my file and give me pills so that I can leave?” .“Generally, participants were in favor of decentralized and simplified service delivery, noting the benefits and challenges of providing PrEP and SRH services at each of the presented service points. There was no consensus on which service points the participants preferred the most. The views on each service point are presented in turn below:The integration of PrEP services with family planning, HIV testing, and other SRH related services was preferred by all participants as this would encourage participants to access holistic prevention services and would reduce the number of clinic visits and money spent on transportation:Yeah, it should be one stop centre so that when I go for family planning then I collect…. [Currently] you have to go there then you go to another place then come back.” “For instance, I will be going to the clinic, and it's money (meaning that they will use money) …So it's better if you go once to collect PrEP and everything else.” “There were a variety of service delivery characteristics that AGYW thought would encourage them to access healthcare services at clinics. These included friendly staff, privacy, shorter waiting times, separate queues for medication pick-ups, and pre-packaged medication (which would reduce time spent in facilities).I will need…yes, the service…Someone who will help you with love and not in a hurry. You know that you will not get reluctant to go to the clinic because you are worried that you will meet a certain kind of person . I [need to know] know that the person who is assisting me is friendly.” “I cannot always travel to (township name) to collect the pills and I am also not sure what time I will come back, maybe around 13h00, because hai! When you go to the clinic to collect medication you queue with everyone, when you go inside to see sisters, whether you only came to collect pills only or not. You queue just like everybody.” “b)Local police StationParticipants had mixed views about the local police station as a service delivery point. A few noted that they would not mind receiving SRH and PrEP services at the police station and noted safety and accessibility as reasons for this. The police station was also viewed as a place of respect and dignity.Yah, police station is okay you know why?… Police Station is a place that is being respectable. …And dignity” “Some participants stated that using the local police station as a service point removed the element of privacy and discretion they would want when accessing services. They also believed that the police officers would foster and perpetuate PrEP related stigma in the community.Those police will judge you if you go there…they talk too much.” “c)Local pubs and local eateriesAGYW and female sex workers stated that places like pubs and eateries would not work as service points because of lack of privacy. They further stated that they feared being judged by patrons if seen accessing PrEP and SRH services at these service points:However, they were open to considering it if there was a private consultation room. There were no differences between AGYW and ABYM preferences for police stations as service delivery points.Mostly you will find drunkards who talk as they wish. So, with us, they may end up saying hurtful words to you.” .“They were also concerned about safety and confidentiality at a pub, stating that intoxicated pub-goers will be disruptive towards the healthcare providers and clients seeking PrEP and SRH services. Distance was also noted as a reason against pubs as service points, especially among participants who lived far from the pub on the decentralized and simplified service delivery model. Furthermore, a few AGYW and MSM participants described pubs as inappropriate for receiving PrEP services because pub goers are there to have fun and drink alcohol and won’t want to be told about PrEP.We are going to drink  not to take pills” .“I disagree with the pub…Then there you are; “Hey girl come here, PrEP”. When am I going to drink? When am I going to drink? No, I came to drink.” “However, one MSM participant expressed that providing self-care products such as lubricants at pubs may draw their attention and encourage their engagement with PrEP and SRH services.“I feel that if maybe you are at certain, like just do a mini, a mini takeaway thing, it's a PrEP paper [paper bag] maybe you…maybe put in 4 lubes. After putting in 4 lubes I come [to you]. I know that I don’t have lube…Guys also like lube. Which guy doesn’t like lube?… So, you have given us a nice small package friend and we’ll be there.” . Most ABYM participants were more open to the idea of using pubs and eateries as service delivery points compared with AGYW, MSM and female sex workers. One participant believed that there won’t be any judgement or stigma at the pub because everyone will be there to enjoy themselves and mind their own business.Me I feel like at [name of local pub] there would hardly be any stigma, ‘cos like it's a place where it's by drunkards. Everybody is minding their own business so yes…That's why I feel that for me [it's] comfortable to get them there because no one is gonna judge me.” “d)Local parksFemale sex workers, MSM and ABYM were open to the park acting as a service delivery point.Lastly, some participants suggested that pubs and local eateries be used to distribute information on PrEP and SRH services and as PrEP pick-up points.It is at the park why not? Like you will find that they put up a tent, right?…Yeah, we will enter, collect, and leave.” .“It was noted that parks are good places to access young people, especially on weekends:I prefer like public parks your community parks uh parks. Like there are a lot of people especially like during weekends…Like uh this young generation, our age- I can say uh from eighteen to like twenty-five twenty-six.” .“They further stated that having events at the park, targeted at educating the community on PrEP and SRH services would attract potential end users.As soon as you do an event at the park, they will say ‘’at the park, we are going there friend”.” “However, the issue of safety at parks was raised by AGYW participants with some stating that “It is not safe” So, what if we go there and they rob us?” .“In spite of this, AGYW stated that this could be mitigated if a mobile van and security were provided.[T]hat's why I am saying we need mobiles. Because of once we have mobile at  obviously there should be security…So, I think it will only be safe if we have security.” “e)Schools and universitiesParticipants had mixed views about having the local university and secondary schools as service delivery points. The majority of participants felt universities would be acceptable, because they believed that they won’t be judged or stigmatized. They described the university students as understanding and mature, and believed that they too will benefit from the PrEP and SRH services.It would work [be]cause yeah, and a lot of students attending there may consider taking PrEP.” “I think [university name] would also work for me” “Older AGYW and ABYM, pregnant AGYW, female sex workers and MSM were accepting of secondary schools as service delivery points. They felt that secondary schools were safe because:the security at the gate will make sure that you are safe inside the school” .“Older participants also suggested that all schools in Ga-Rankuwa be considered as service points because every zone has a school, thus improving accessibility. They believed that this would ensure that everyone has easy access to PrEP and SRH services and will not need to travel to collect PrEP.So that, when you say it's every school then people can go to all of the schools when we’re in Ga-Rankuwa [to access PrEP services] coz some people are far from [school name], they are far from [it] so…So it will be closer for them. Coz every zone has a school in it so there's no they don’t need to take taxis to go and take the pill.” “They felt that they would be less likely to experience judgement or stigma in these environments because secondary school children were too young to understand the services they would be seeking.They [young children] know nothing…yes, my mother came to school, doing what? They do not know.” .“However, younger AGYW and ABYM participants were concerned about lack of privacy, stigma and judgement at the secondary schools. They feared that if seen accessing PrEP and SRH services, teachers, security guards and students would judge them.Teachers will judge you at schools [and say] “you are sleeping around, you are sleeping around””. “I find it's great but at the uh…at schools, eish, mostly we can’t use classrooms because [with] classrooms, anybody is able to come in anytime, it won’t be confidential”. “f)PharmaciesThe majority of participants liked the idea of having local pharmacies as service delivery points. They also suggested using private pharmacies at the local shopping complex as places to collect their medication and get multi-month dosing.If they could come up maybe with an action plan so that we can collect them at Dischem [pharmacy chain] you go with a card [and] collect your meds there… I think it could work .“Participants described pharmacies as convenient, private, and safe service delivery points, with knowledgeable and friendly staff.pharmacies are the safest places, not the pubs.” “… And then also people that work there, they know medication and [how] to treat patients…You arrive, they give you medication, you leave. …No judgements.” “g)Additional service delivery points and suggestionsOverall, most participants suggested that the community service points should be private, easily accessible, and close to main transport routes. Participants suggested additional possible service delivery points, including local libraries, community-based organizations (CBO's), community centers, local churches, and brothels. They suggested that local libraries and churches be used for sharing information on PrEP and SRH services, while CBO's, community centers and brothels (specific to FSW) be used for providing PrEP and SRH services.Participants were excited about the prospect of having multiple PrEP methods to choose from, based on their needs and preferences. Overall, LA-CAB was preferred compared to the DVR. Most of the participants believed that the long-acting methods would reduce time spent at clinics, eliminate overcrowding at clinics, and ensure method continuation, as they would remove the burden of taking a pill daily . The participants emphasized that their potential uptake of the long-acting methods, once available, would be based on their personal preference and perceived effectiveness of the methods. Their preference was largely based on continuation, convenience, product related issues, and availability of information. No distinct gendered differences were observed.a)Dapivirine Ring (DVR)Most AGYW and all the pregnant AGYW and female sex worker participants stated that they would not use the DVR because of the perceived side effects: and false concerns related to misunderstandings of their anatomy “What if it goes to your womb?” . A few ABYM participants were also worried about perceived side effects, particularly pain during sexual intercourse, and low efficacy of the DVR: “Eventually at the end she will say “ah my guy, I’m no longer enjoying sex” then it will become a problem, the relationship will be somehow.” .Specific feedback on preferences, and concerns of the DVR and LA-CAB are detailed below:Some AGYW and female sex worker participants also had concerns about the impact of everyday use of the DVR, using the ring during menstruation and vaginal hygiene. They also expressed concerns around the possibility of the ring being felt during sexual intercourse with one participant stating that; “Coz you know those things right, they can be felt in here (referring to the vagina). And then when you start being intimate with someone, they will feel that thing and it hurts them.” . The participants were also concerned that the ring will be invasive, and that they might feel discomfort or pain while inserting it.Ai, the ring method… I think it will be painful when I insert something inside my vagina and you are saying you also experience pain during sex, you understand me?” . However, few AGYW participants were open to using the DVR once it becomes available highlighting that clear information and no side effects, would allow them to consider using it.“Yeah, for me, as long as it does not cause irritation, like as long as it does not irritate me and remains intact.” “b)Long-acting Cabotegravir (LA-CAB)Most of the participants stated that LA-CAB would be accepted by potential end users and the larger community because of their familiarity with the injectable contraceptive.Uhm (yes), they will accept the injection. It is common, right, for prevention. It is familiar…many people will accept it…they will prefer it.” “Furthermore, the LA-CAB as an injectable was preferred “Injection is better”  to the oral pill because it 1) eliminates burden of daily pill taking, 2) ensures continuation because participants will not forget to take pills, and 3) is convenient and discreet to use.I mean, like, you will not have problem with forgetting the pills and whatnot. As long as you…injected.” “AGYW, 20–29 years, PrEP User)“But you see once they injected you at least you will not have to stress about taking pills” “However, a few AGYW noted that they would not opt for LA-CAB because they feared that they would experience similar side-effects to the injectable contraceptive, such as menstruation cessation and weight gain.Let it be rolled out first because you would inject and gain weight…or it ceases your menstruation I am afraid of [that].” “Some also expressed fear of injections:Injection it's just me, I’m scared of it.” “c)Alternative suggested methods:Despite participants' enthusiasm about the long-acting methods, some participants stated a preference for alternative prevention methods. One PrEP non-user ABYM said he preferred the oral pill instead of LA-CAB because he feared injections and advised that future biomedical inventions should consider developing a once monthly oral PrEP pill, as it would be more convenient and reduce the pill-taking burden.But monthly you can go to the clinic, maybe they can give you a 12 pack for the whole year. So, you only go to the clinic once” “An ABYM participant in a sero-discordant relationship stated that he preferred the daily oral PrEP pills because they did not use condoms. He noted that taking a daily pill is a constant reminder to prevent HIV transmission, and that by taking a pill everyday he could support his partner who was on ART.I’m living that life where I’m exposed to HIV, so I don’t take chances. Oh, uhm, uh I’d prefer, I’d stay with my pill. Why? Because I’m 100% sure of what's happening… Because I’m living this life of [being with] an HIV positive partner and we don’t use protection, but she is on her pills, and I am on PrEP. So, I honestly will stick to the pills so we''ll drink the pills together, … I wouldn’t want to do the injection or any of those things. Because I think the pill, they are 90% [effective] and she's also taking her ARVs, her CD4 is still normal” “A few AGYW participants indicated they would be interested in a multipurpose prevention technology that would prevent HIV and other STI's:Why doesn’t the PrEP project bring substances that protect against STIs and other viruses? …how about maybe they add contents that will prevent STIs, and it becomes one.” .“This study sought to assess the acceptability of decentralized, simplified PrEP and SRH service delivery and to explore the range of additional non-facility service delivery sites and user provider interfaces. This study also sought to examine potential end users' preferences for existing and new long-acting HIV prevention and PrEP methods as a means to simplify PrEP delivery. The integration of PrEP and SRH services was valued by participants as this may reduce transport cost and minimize the number of clinic visits. Overall, all participants were accepting of decentralized and simplified service delivery. They shared the pros and cons of each service point and there was no consensus on which service points sub-groups preferred the most. They welcomed the prospect of having more PrEP methods to choose from in the future, however, LA-CAB was preferred over the DVR among most cis women.Healthcare facilities, pharmacies and schools were generally found to be largely acceptable to the study participants and were seen as suitable for providing full PrEP and SRH services. The police station, pubs, eateries and parks were largely said to be better suited for information dissemination and as PrEP collection points. Taking healthcare out of the hospital or clinic using community-based mobile clinics specialized in HIV services is known to increase access to healthcare and improve health outcomes of patients , 58–61. Preventing HIV infection among ABYM and older men with the goal of reducing HIV transmission to their partners is a key strategy in preventing HIV infection among AGYW . HoweverCommunity based social activities have also been found to be viable in reaching men and promoting engagement with HIV services , 79. ThiParticipants believed that the long-acting methods would reduce the pill-taking burden and allow for the discreet use of an HIV prevention method. They also believed that long-acting methods would increase PrEP continuation. These views are supported by findings from LA-CAB and DVR clinical trials , 85. ForOne strength of this study was that it included perspectives from a wide range of potential end users. The study also contributes to formative evidence that may inform the design of decentralized delivery. There are also some limitations. The service delivery points were specific to the study area, so challenges to certain delivery points, like distance and transport costs may be specific to this area, therefore, the findings are not generalizable to other areas. While the techniques for data saturation  were notThere remain gaps in access, uptake, and effective use of HIV prevention and SRH services among target populations. Decentralizing and simplifying PrEP and SRH services by providing services outside the traditional healthcare setting will bring services closer to clients and has the potential to increase access to and engagement with end users, especially men. Furthermore, service orientation and delivery cannot be considered homogenous. Different population groups have different needs and preferences; therefore, they need service delivery options that provide integrated services and fit their preferences and lifestyle.Addressing concerns of the DVR through counselling and sex positive messaging could improve its potential acceptability among cis women. A variety of engagement and education strategies with potential users, partners and key gate keepers are also critical to the uptake and effective use of any HIV prevention methods. Nonetheless, increased choice in HIV prevention methods allows the end user to choose a method that meets their needs and suits their lifestyle. Providing a variety of long-acting PrEP methods, has the potential to increase access to prevention services, subsequently leading to increased uptake, improved continuation, and a decrease in new HIV infections.


Ovarian hormone fluctuations over the rodent estrous cycle and the human menstrual cycle are known to significantly impact brain physiology and disease risk, yet this variable is largely ignored in preclinical neuroscience research, clinical studies, and psychiatric practice.To assess the importance of the estrous cycle information for the analysis of sex differences in neuroscience research, we re-analyzed our previously published data with or without the estrous cycle information, giving a side-by-side comparison of the analyses of behavior, brain structure, gene expression, and 3D genome organization in female and male mice. We also examined and compared the variance of female and male groups across all neurobehavioral measures.We show that accounting for the estrous cycle significantly increases the resolution of the neuroscience studies and allows for: (a) identification of masked sex differences; (b) mechanistic insight(s) into the identified sex differences, across different neurobehavioral outcomes, from behavior to molecular phenotypes. We confirm previous findings that female data from either mixed- or staged-female groups are, on average, not more variable than that of males. However, we show that female variability is not, at all, predictive of whether the estrous cycle plays an important role in regulating the outcome of interest.We argue that “bringing back” the estrous cycle variable to the main stage is important in order to enhance the resolution and quality of the data, to advance the health of women and other menstruators, and to make research more gender-inclusive. We strongly encourage the neuroscience community to incorporate the estrous cycle information in their study design and data analysis, whenever possible, and we debunk some myths that tend to de-emphasize the importance and discourage the inclusion of this critically important biological variable.HighlightsOvarian hormone fluctuation impacts brain physiology and is a major psychiatric risk factor, yet this variable has been overlooked in neuroscience research and psychiatric practice.From rodent behavior to gene regulation, accounting for the estrous cycle increases the resolution of the neuroscience data, allowing identification and mechanistic insight(s) into sex differences.Female variability does not equal (and is not predictive of) the estrous cycle effect and should not be used as a proxy for the effects of ovarian hormones on the outcome of interest.Neuroscience researchers are advised to incorporate the estrous cycle information in their studies to foster more equitable, female- and gender-inclusive research.Studies of the ovarian cycle are especially important for improving women’s mental health. Ovarian hormone fluctuation shapes brain physiology –7 and reThe answer goes back to decades of preclinical neuroscience research that focused on the male brain. Approximately, for every 5.5 studied male animals, only one female animal was examined in neurosciences, as reported in 2011 . The maiMore recently, there have been important calls for including females in biomedical research as a necessary step for a more equitable research practice and to enable an understanding of sex-specific brain physiology and disease risk –23. UnfoResponding to calls for female inclusion, in 2016, the NIH mandated the use of both sexes in all experiments, under the policy known as Sex as a Biological Variable (SABV) . PrelimiFast-forward to the past year or so, another acute problem in sex difference research has been called out. Voices have been raised that sex is a non-binary, multilayered, and context-dependent biological variable ; that seOur paper addresses all above-mentioned points of view. We take a practical approach, and by re-analyzing our previously published data , 34 withData To assess the importance of the estrous cycle information for the analysis of sex differences in neuroscience research, we reanalyzed our previously published data , with post hoc test showing diestrus females spending less time in the center compared to both proestrus females (P = 0.006) and males  = 21.63, P < 0.001], which was driven by diestrus females spending less time in the light than both proestrus females (P < 0.001) and males  = 5.33, P = 0.009], with diestrus females spending less time in the open arms compared to proestrus females (P = 0.008) and there was a similar trend in the diestrus–male comparison  = 1.05, P = 0.303], the light–dark box , and the elevated plus maze .Notably, when the two female groups are merged and compared to males Fig. A, none oTaking the light–dark box test further as an example, we visualized the normal distributions of the data, comparing mixed female and male group distributions, as well as distributions of separate diestrus, proestrus, and male groups Fig. B. We fouF = 0.80, P = 0.456; Levene’s test]; we also found equal variance  and equal distribution shapes  between merged females and males. We then looked into the time spent in the light compartment of the light–dark box test and found equal variance between proestrus, diestrus, and males ; we also found equal variance  and equal distribution shapes  between merged females and males. Finally, we examined the time spent in the open arms of the elevated plus maze and found equal variance between proestrus, diestrus, and males ; we also found equal variance  and equal distribution shapes  between merged females and males.We then addressed data variability between both males and merged females, as well as between proestrus, diestrus, and males for all three anxiety tests. For the time spent in the center of the open field, we found equal variance between proestrus females, diestrus females, and males , with proestrus females having a higher density than both diestrus females (P < 0.001) and males  = 16.04, P < 0.001; Fig. To extend our study to other neurobehavioral outcomes, we performed similar analyses of dendritic spine density in the ventral hippocampus Fig. . We prevF2, 97 = 1907When we analyzed this data using normal distributions Fig. B, we fouF = 5.65, P = 0.004; Levene’s test], as well as between males and merged female groups . We also found that distribution shapes were unequal between merged females and males .We also tested data variability for dendritic spine density in the ventral hippocampus. We found unequal variance between males, proestrus females, and diestrus females , with proestrus females having higher expression than both diestrus females (P < 0.001) and males (P < 0.001), and with males having higher expression than diestrus females  = 2.72, P = 0.015; Fig. Ptprt expression.For ata Fig. . CompariHtr2b, we found a significant difference between diestrus females, proestrus females, and males , with diestrus females having higher expression than both proestrus (P < 0.001) and male (P = 0.013) groups  = 0.19, P = 0.829; Levene’s test]; however, variance was unequal between merged females and males , while distribution shape between these two groups were equal . For expression of Htr2b in the ventral hippocampus, we found equal variance between proestrus, diestrus, and male groups ; we also found equal variance  and equal distribution shape  between merged females and males.We then looked into data variability, both among proestrus, diestrus, and male groups, as well as between the merged female and male groups. For expression of Ptprt expression to follow the same pattern that we see with the structural dendritic spine phenotype; we found more variability in females than in males and that the sex difference, detectable when females are merged, is actually driven by the estrous cycle stage. With Htr2b expression, we see the pattern that we observed with anxiety-related behavior; males and females show similar variability and sex difference can only be detected when there is information about the estrous cycle stage.In summary, we found Finally, we explore our previously published data derived from the unbiased chromosome conformation (Hi-C) assay Fig.  34]. Th. Th34]. Adcyap1  = 0.514, P = 0.608, Fig. t(9.94) = 1.87, P = 0.092; Fig. Finally, we decided to test our data variability across all neurobehavioral measures—behavior, hippocampal dendritic spine density, and gene expression—using the coefficient of variation (CV = standard deviation/mean), as a measure of relative variability, previously described in the meta-analyses performed by Prendergast et al.  and BeckIn sum, our data are consistent with the data previously reported in mice and rats that females are, on average, not more variable than males , 22, 26.In this manuscript, we show that accounting for the estrous cycle significantly increases the resolution of the neuroscience studies and allows for: (a) identification of masked sex differences; (b) mechanistic insight(s) into the identified sex differences, across different neurobehavioral outcomes, from behavior to molecular phenotypes. We strongly encourage the neuroscience community to incorporate the estrous cycle information in their study design and data analysis, whenever possible, and we debunk some myths that tend to de-emphasize the importance and discourage the inclusion of this critically important biological variable Table .Table 1MSince the NIH and other funding agencies mandated the use of both sexes in grant proposals, there are an increasing number of studies that include both males and females, as opposed to the past preclinical neuroscience research that largely focused on males . The SABWhile we acknowledge that some researchers do not have sex difference as a focus of their research, the moment males and females are being included, the effect of sex should be assessed by designing a well-powered study to incorporate sex as a variable in data analysis. First, considering the sex differences already identified across diverse neurobehavioral outcomes, one cannot reasonably suggest that sex will not affect a particular measure without testing this assumption. Identification of such sex differences is particularly important for understanding the understudied female brain, since it contextualizes previous male-specific findings. Second, the focus of preclinical neuroscience research should reflect the need to understand the near-ubiquitous sex bias in prevalence and symptomatology of brain disorders. For instance, each study of depression- and anxiety disorder-related phenomena should address the important question of why women are at twice the risk for these disorders than men are. In this case, finding female-specific mechanisms and treatments could be transformative for two thirds of the patient population. Third, running small, underpowered cohorts of mixed male and female animals risks missing an existing sex difference which can lead to exclusion of females in future experiments, as some researchers will continue with only males if no sex difference is found initially Table . This caConsidering the importance of sex difference research for women’s health, and the challenges faced by this field, then, one might wonder whether emphasizing the need to study the estrous cycle represents just another roadblock to equitable research. In fact, this variable was the major reason why females were excluded from neuroscience studies for decades . In respHtr2b, a gene implicated in these behaviors, we can find sex differences only if we account for the estrous cycle stage. This is important because it was suggested that the old tests that were developed for males, such as the elevated plus maze, may not be applicable to females as they cannot re-create increased female risk for anxiety disorders reported in humans [In fact, here we want to show why “bringing back” the estrous cycle variable to the main stage is important and can help us improve the health of women and make research more gender-inclusive, while also enhancing the ability to detect and interpret sex differences. First, we show that in our anxiety-related behavioral data and gene expression results for n humans , 41. Whan humans , 9 or otn humans , postparn humans , 12, andn humans , 14. At n humans . Thus, wThis important effect of the estrous cycle is not only applicable to behavioral, structural, and candidate gene expression data, but we also observe it in cutting-edge epigenomics data. The neuroepigenomics field  has beenWe want to emphasize that the increased resolution that we are seeing in our studies is because the hormonal status is a sex-specific factor that is more precise than sex. Multiple researchers have indicated that sex is a complex, multi-layered variable that should be used as a proxy rather than a variable that explains sex-based variation , 44. We deserve to be studied and that (b) ovarian cycles are not important experimental considerations [Our results also debunk the myth that female variability is predictive of the importance of the estrous cycle for the regulation of the outcome of interest. This frequently touted misconception states that it is now proven that the estrous and menstrual cycles do not make females more variable than males, and that this means that (a) females erations , 46, 47.deserve to be studied. The time is now to improve our understanding of the female brain and the health of women and other menstruators, and for this, we need to acknowledge the ovarian cycle as a critical biological variable that shapes the brain and behavior.As mentioned previously, sex hormone fluctuation is one of the most important indices that determines women’s health outcomes and, in particular, there is no other factor, except for possibly trauma, that may acutely increase the risk for mental disorders as can a drastic shift in systemic ovarian hormone concentration. We see this postpartum, premenstrually, and at perimenopause. Yet, stress or trauma is one of the most studied factors in mainstream neuroscience and psychiatric research, while we are far behind with studying the effects of ovarian hormone changes. And, it is difficult not to assume that the main reason for this is that we are talking about a female-specific factor. We hope that our colleagues will recognize that “women’s health” should not be a niche field but that, rather, it is the health of half of the population, 50% of whom are in the reproductive period and dealing with the ovarian cycle. As such, no further information is needed to justify why females Here we provide evidence that incorporating the estrous cycle information makes the data across neuroscience studies more interpretable and increases our ability to discover and explain sex differences. Thus, we recommend that neuroscience researchers utilizing reproductive-aged female animals incorporate the estrous cycle information whenever possible. This recommendation certainly raises concerns regarding the practicality and feasibility of this approach, particularly for the studies that incorporate multiple treatment groups and large numbers of animals. So, we would like to address this issue here.Ideally, the estrous cycle should be tracked systematically, by daily vaginal smearing for three consecutive cycles, approximately for 2 weeks, so that the experiments can be performed with properly staged female animals , 34. TheHowever, we acknowledge that this approach is more difficult to implement in the studies that incorporate multiple treatment groups and large numbers of animals. In that case, we suggest an approach that is less labor-intensive and more typically used in practice, which is taking vaginal smears at time of data collection, either after the test was performed  or postmortem . Even if these studies are underpowered to find differences between females at specific estrous cycle stages, merging stages with similar hormonal profiles can still give insights into whether the outcome of interest is affected by ovarian hormone fluctuations. As an example, in our study of the combined effect of early life stress and adolescent stress, we had four treatment groups with females and males in each group and, thus, systematic tracking of the cycle was not possible . HoweverHowever, we would like to warn the researchers that some manipulations  may disrupt the regularity of the rodent cycle and that careful examination of the estrous cycle patterns across the experimental groups is always advised in order to spot possible biases. As an example, animals may appear to be overwhelmingly in a single cycle stage, such as estrus or diestrus, in which case the estrous cycle and its effects need to be re-examined with a more comprehensive approach.Further, for transcriptomics and epigenomics analyses with budgets limited to one male and one female group, the researchers may decide to control for the effect of the cycle by selecting females equally distributed across the cycle or in one stage only , based on information acquired using vaginal smears post-mortem. In general, we believe that the information of the estrous cycle stage of the animals should be provided in each study, together with other major animal information such as strain, age, sex, light–dark cycle, housing conditions, time of testing, etc. Even if this information is not directly analyzed by the researchers, it represents valuable information for the field that can inform future analyses.Finally, as we consider the estrous cycle tracking, we would like to highlight the two biggest misconceptions related to this procedure that make researchers reluctant to include it in their studies: 1) that estrous cycle determination requires expertise in reproductive endocrinology; (2) that this procedure is a major stressor to the animals (see Table  that estAs the field embraces the importance of this variable, we hope that we may see development of the approaches that will allow for even easier estrous cycle tracking, with minimal manual labor, perhaps by devices that will allow continuous tracking of the variables that can accurately predict the estrous cycle stage such as temperature, sleep pattern, food intake, and activity levels. We believe that there is no reason for a sophisticated field such as neuroscience, which regularly uses light-driven genetic tools and mini-scopes, to reject the inclusion of the estrous cycle tracking out of inconvenience.Here we provided experimental evidence that the estrous cycle information increases the resolution of the preclinical neuroscience studies while critically informing women’s health research and allowing for more gender-inclusive research practices. We encourage all researchers to consider implementing the estrous cycle tracking in their study design, provide some practical considerations and recommendations, but also envision future technological innovations that will facilitate this process, as long as there is desire and need to study this important variable.


A crucial component of value-based health care concerns the redesign of organizational structures. In theory, hospital structures should follow value creation: addressing medical conditions for specific groups of patients over full cycles of care. In practice, however, it remains unclear how hospitals can reorganize themselves into value-based structures. The purpose of this study is to explore the ways in which Dutch hospitals are currently implementing and pursuing value-based redesign.This qualitative exploratory study used semi-structured interviews and a focus group for data collection. Transcripts were analyzed through deductive coding, for which we used Mintzberg’s theory on organizational structures, particularly his work on design parameters.In their efforts to create more value-based structures, Dutch hospitals often employ a variety of liaison devices, such as project teams and committees. By contrast, the actual formation of units around medical conditions is much rarer. Outcome data are widely used within planning and control systems, and some hospitals partake in external benchmarking. Not all hospitals use cost indicators for monitoring performance.Value-based redesign is not necessarily a matter of radical changes or binary choices. Instead, as Dutch hospitals show, it can be an incremental process, with a variety of potential knobs to turn to various degrees. Health care executives, managers, and professionals thus have a wide range of options when they aim for more value-based structures. Our conceptualization of “value-based design parameters” can help guide the selection and implementation of strategies and mechanisms for further coordination around medical conditions over full cycles of care.The online version contains supplementary material available at 10.1186/s12913-022-08564-4. The organizational structures of hospitals have repeatedly been criticized for impeding coordination, hampering efficiency, and delivering suboptimal patient care –3. Moreoto optimize value by continuously striving to achieve the best outcomes as efficiently as possible r, you let it arise organically from practice, bottom up, because the demand for a new organizational structure comes up. And that is the choice [our hospital] made (2).The concept of “value-based grouping” refers to the establishment of hospital units around medical conditions. Within Dutch hospitals, the considerations concerning the formation of units were relatively comparable. For instance, most interviewees expressed the belief that value-based units could indeed enable closer collaboration among everyone involved in treating patients with a particular medical condition. However, hospitals had acted upon this recognition in different ways.Multidisciplinary, around a medical condition, we have now four [teams]. [E]ach of those [multidisciplinary teams] has a daily leadership board. [A]s the daily management of the team, the leadership board is responsible for the quality of care within such a team. [N]ow, we are mainly concerned with really working from within those multidisciplinary teams, that people know each other, know the process that a patient goes through, and know what the most important objectives are and shape that into a whole. [W]hat we are working toward is that these teams will be incorporated into the organizational structure (3).But in small parts, of course. You could first start with those three integrated units with which we have started. So, a gradual transition (1).Most hospitals opted for a more bottom-up approach in regard to value-based grouping. Accordingly, several hospitals had started “pilots”  in which they established multidisciplinary teams around a relatively small number of medical conditions. Respondents stated that the idea was to eventually create more of these teams and to incrementally carve these teams into the formal organizational structure.We discussed that this was going to be the new reality, and that means that people have just switched from A to B. [T]hen, that also means that everyone around [those medical conditions], that those people are just added to another flow. So, we have discussed it and said: listen, we are going to organize it differently. [W]e made various patient flows, what we call [value-based units]. So, for example, the breast cancer flow contains the doctors, nurses, the breast cancer department. They are all added to this patient flow, and together they are responsible for finances and quality (7).Not all hospitals applied such an incremental approach. One, in particular, consciously made a different choice regarding the grouping into units around medical conditions:In sum, the respondents widely recognized that grouping into units around medical conditions could enable hospitals to better address the interdependencies of various activities that are needed to care for patients. Yet, most hospitals were hesitant to radically transform their traditionally functional unit structure into multidisciplinary value-based units around medical conditions.between their functional units through various types of liaison devices.Rather than switching to units around conditions, most hospitals were trying to increase coordination I work as a program manager VBHC. [S]o yes, in essence, I am responsible for setting up and continuing the VBHC program within our organization. So, the roll-out of care around medical conditions. And adding value, for the patient (1).To start, hospitals were making use of liaison positions. In fact, most hospitals had appointed a VBHC manager precisely to foster interunit coordination around medical conditions.I go to the highest manager below the executive board and ask “hey, on which medical conditions do you want to work in light of VBHC?” Because I need to know what is interesting for the hospital. Then, I go to that physician […] and we discuss the matter one-on-one. Afterward, we see who else we need to include, but it usually starts with me and a specialist. From there, I’ll work things out and discuss with the physician how to get things off the ground (8).More specifically, these managers were assigned the task to coordinate the work conducted in several distinct units; they should have a “primarily supporting role” and “help teams organize themselves around a clinical pathway as best as possible” (11). Some respondents stated that in their hospitals, these managers are usually approached by a group of medical specialists, who then ask for support related to VBHC. In other organizations, it was usually the other way around, and managers had to actively search for potential cooperation.At the time of the interviews, some hospitals had a single VBHC manager who was operating relatively autonomously, but it was not uncommon for hospitals to have several managers with complementary roles in a VBHC management team. The exact composition of these VBHC management teams varied considerably among hospitals. In some organizations, the program manager was accompanied by a single medical specialist . Others had appointed a few more members, each focusing on a specific aspect of VBHC  (10). Overall, the primary role of these VBHC managers was to foster communication between separate units that are involved in the full cycle of care for a medical condition. In practice, they were often doing this by utilizing another type of liaison device.they are liaisons, overlaying the formal  structure.Within the project, we did not just look at the organizational structure but also at the meetings and consultation structure that goes with it, and we have set that up so that you can exchange and switch faster […] so, more of different levels, putting different disciplines together (6).To facilitate mutual adjustment, hospitals had commonly established what Mintzberg  lmuch more common and widespread than the actual formation of units around a medical condition. In a common pattern, these committees started with a kickoff meeting, in which a large multidisciplinary group partook in determining the overarching mission and goal of the multidisciplinary interunit teamwork. After the kickoff, hospitals moved on to regular meetings—monthly was a common timeframe—to discuss their performance with a select group of delegates from the various specialties involved.It is a periodic meeting in which basically the team gets together, [those] who are involved in the care of the medical condition. [A]nd in such a meeting, based on KPIs, they look at which outcomes can be improved. A nurse will also join, so basically everyone who should be involved, so someone from business intelligence also joins. And, yes, then you will basically determine “which KPI now requires the most attention, and which actions are we going to [undertake] to improve it?” (1).At the time of our data collection, developing these liaison “committees” had been Now, although these value-based committees are not actual units, in some hospitals, these committees did form the basis for the “pilots” in which the value-based units around a medical condition were being experimented with .As we have seen, at the time of our interviews, several Dutch hospitals were forming multidisciplinary units around a medical condition. However, this does not imply they were intending to sacrifice their functional units. Instead, they were conceiving of a transition toward a matrix structure—an organizational design that combines functional and value-based units.A disadvantage of a matrix organization is that it will generate a lot of coordination at the intersections between vertical and horizontal management. If that is going to cause a lot of hassle, this can be a reason to eventually switch completely, in one direction or the other (3).Not everyone appeared to be convinced, though, of the desirability of such a matrix structure. A recurring theme—regarding the matrix structure but also regarding value-based redesign in general—was that the end goal, the ideal structure, should be determined along the way.In sum, what applies to the (possible) transitions toward a matrix structure, in many cases applies to the use of all liaison devices: hospitals were utilizing them with caution, incrementally tweaking and experimenting with various types of connections between units.Value-based planning and control systems refer to the utilization of outcome and cost measurements as performance indicators. Whether concerning project teams or official units, all hospitals were engaged in some type of value-based performance measurement.The approach of [hospital name] is that you benchmark the scorecard, and when you see differences, these will be discussed. And when you think one of the hospitals is doing something which leads to better results, then the others will adopt that—free of obligation, for the time being (3).All hospitals we spoke to were actively involved in outcome measurements, thus trying to optimally standardize the outputs of their services—in this case, referring to the effects of these services on patients’ health. The way in which these measurements were used, however, differed from one hospital to the next. Most notably, there were differences regarding the issue of benchmarking and comparison with other providers. Some hospitals had formed collaborations in which they benchmarked their outcome data:internal reflection.We are building quality dashboards, some of which are already implemented. [A]nd we use those to continuously improve the care paths, for the [multidisciplinary] teams, but we also use them for reporting to the board of directors (2).Several hospitals had been able to establish such benchmark partnerships, and those that had not seemed to recognize the potential benefits of these collaborations; some explicitly expressed the desire to form such partnerships in the future (7). Although not all hospitals were, at the time of the interviews, involved in external benchmarking, all of them were either developing or already making use of dashboards for They really start to cooperate better, being aware of each other’s problems and also solving those better with each other. [B]etween different specialties, nurses but doctors too, they will really look much better at that dashboard together: this is what we find important, this is what patients find important in terms of treatment and outcomes, and we actually think this is important too. They make dashboards that much more belong to them, which also makes them put much more effort into improvement. (7).Next to standardizing work output, value-based performance measurements seemed to have generated a boosting effect on the collaboration among team members by creating a sense of shared responsibility for particular goals:No, not yet actually. On the cost side we are struggling quite a bit to make that insightful. That is also not our focus. Our focus is: we want to improve the outcomes of care, from the philosophy that the costs will then lower automatically (9).With regard to value-based performance measurement, costs seemed to have received relatively little attention compared to outcomes. While all Dutch hospitals were involved in outcome measurement, several hospitals had not (yet) utilized cost measurements in their efforts to create more value-based coordination. This was exemplified by one respondent when s/he was asked whether their multidisciplinary teams were accounting for costs:Among those that were measuring costs, approaches differed. Some were making use of “cost drivers”—with proxy indicators such as length of stay, without immediately connecting these indicators to hard currency (5). Several hospitals, however, had been using cost price calculations, and some had hired an external agency to make this work (11). Moreover, these cost measurements were increasingly becoming part of the dashboards that enable multidisciplinary teams to evaluate their performance.In sum, at the time of our data collection, multiple hospitals had been struggling to gain insight into the costs of their services, yet others seemed to have made steps by incorporating cost price indicators into their performance dashboards. These differences among hospitals though, may have been related—at least partly—to the degree of official commitment from the highest levels of the organizations and the recourse allocation that comes with it.Tell the story. Explain why you do this and repeat it. Repeat it. Repeat it. Repeat it. And explain, each time, this is the reason why we do this, we think changing this will work better. So, don’t begin by telling them what you are going to change, but first just start by creating the setting in which it makes sense to change (5).For organizational redesign to be successful, whether sweepingly or incrementally, it was widely recognized that a solid support base among all levels of the organization is crucial.We are actively involved in training within those [multidisciplinary teams]. Both specifically for the daily leadership and also more broadly. [N]ext tot that, we have set up a general training program in which within the [multidisciplinary teams] they can use this training. On the one hand, that is really about clear knowledge, so “what is value-based health care, what are those [multidisciplinary teams], why do we do this, how does this match the developments in the Dutch health sector?” On the other hand, knowledge and education for a specific [multidisciplinary team] (3).To generate a deep and widespread support base within the organization, Dutch hospitals utilized particular tactics. Some applied a focused but unofficial approach, in which the executives first “look for the right informal leaders and convince them,” and then, through these informal leaders, they tried to get everyone else on board (7). But while several hospitals were handling their “indoctrination” ( p97-99) Really including the leadership of the hospital in that vision, that’s still missing for us. I think that this is also essential for success in the long term. [T]hat somewhere there will be a turning point from bottom-up to also top-down management. [T]hat element is still missing for us to make that switch, because that does seem like a very nice one, when you can combine that with the bottom-up enthusiasm (12).So, with regard to the provision of training and value-based “indoctrination,” some hospitals had relatively formalized frameworks in place. Others, however, found themselves making “baby steps” in developing a more coherent program (11). Additionally, there were cases in which the leadership was not actively propagating VBHC theory—even when VBHC was part of the official hospital strategy.To conclude, regarding value-based indoctrination, an important distinction we noted among the approaches of various hospitals relates to the degree of official commitment to value-based redesign, particularly from the higher levels of the organization.with whom people collaborated on a day-to-day basis (7).Value-based job specialization concerns the division of labor that is explicitly related to VBHC. Ideally, job specialization enables organizations to effectively match individual workers to their specific tasks ( p70-79).For me, a big lesson is the importance of a good leader above those [multidisciplinary] teams. And this is also a challenge we’re facing. Currently, the leaders are the ones that took initiative, but they are not always the best leaders. That is something we definitely have to deal with (9).One of the lessons is that appointing a daily leadership [group]—formally, through an application procedure—has been very beneficial (3).When it comes to appointing the leadership roles within the multidisciplinary teams—the daily management referred to in the section on In sum, some Dutch hospitals had come to develop official application procedures for the daily management of multidisciplinary teams, while others were—thus far—favoring a more organic approach.In 2016, we started with internal VBHC clinical paths, kind of a combination of Lean and VBHC. So, really trying to streamline the processes, measuring the right outcome indicators, assessing those, and steering on that basis (8).In general, as a design parameter, “formalization of behavior” refers to the predetermined standardization of work processes ( p81-83).All of the hospitals we spoke to were involved in the development and implementation of clinical pathways around medical conditions. In many cases, however, this continued to be a work-in-progress.In my opinion, you should first have results, in a small setting, and then see “what have we learned from this? What works and what doesn’t?” In terms of ICT [information and communications technology], dashboards, indoctrination, all those variables you take into consideration. And those, you scale up, before you start looking at structures, systems, architectures (12).For the purpose of this study, value-based decentralization refers to the process by which value-based units acquire greater organizational autonomy. As with other design parameters, most Dutch hospitals had been hesitant to turn this knob. For some, it remained questionable why and to what extent such autonomy is even desirable:[T]he current integrated [value-based] units, they will start next year with sort of their own budget. You could call it a “shadow budget.” [A]nd for new integrated units we’ve set aside a kind of mandate to give them some financial leeway so that they control their own development. So, there is already something like a budget. But we are also seriously considering, thinking about, “can we really autonomize them entirely?” That’s a question we’ll be taking about (1).Some hospitals were starting to experiment, on small scales, with more autonomy for their value-based pilot units. In particular, this concerned financial autonomy: value-based units with their own budget control.A recurring theme regarding decentralization but also more generally regarding value-based redesign, was the notion of a gradual transition toward more value-based structures. Interestingly, in many cases, the final stage of this transition was not clearly envisioned but rather seen as something that would be determined later on, based on the experiences and lessons learned during that incremental process.This research combines theory on value-based health care with theory on organizational structures, and explores how Dutch hospitals currently work toward value-based redesign: structural coordination around medical conditions over full cycles of care. Our study demonstrates that Mintzberg’s  organizaInterestingly, while the core literature on VBHC depicts value-based redesign as a fundamental change, with radical and sweeping implications , 7, 8, obasis for grouping in health care organizations [The design parameter that best illustrates this contrast is unit grouping. Although one hospital did establish value-based units (through a top-down approach), most hospitals we spoke to are hesitant, at least for the time being, to (re)group into units around medical conditions. Rather, these organizations aim to spur coordination through various liaison devices, such as intermediary managers and regular multidisciplinary team meetings, leaving the original functional units intact. This contrasts with the authentic notion of integrated practice units (IPUs)—which concerns, above all, a izations .Whereas our current study describes the use of liaison devices (rather than unit grouping) to enhance coordination between functional units in terms of applying VBHC principles, this can also be seen as the manifestation of a broader trend in which hospitals worldwide are trying to overlay their functional designs with multidisciplinary teams . This trthe chain of activities that generates value for patients. Within this framework, it is first and foremost the creation of value that should determine organizational structures [When it comes to organizational structures, VBHC coincides with the idea of process orientation, although there are some defining characteristics. Similar among both, though, is the belief that the traditional functional structures of hospitals are flawed organizational designs that can and should be overcome , 3, 8. TWhatever the phrase, the point would be that health care organizations should structurally coordinate their work activities such that value for patients is optimized. And hard-line adherents of VBHC are convinced that this requires a radical transformation toward IPUs for medical conditions, rather than just overlaying a (dys)functional structure , 8.However, an important finding of our study, one that mirrors accounts on process orientation , is thatincremental redesign. These organizations employ a variety of design parameters to various degrees. They generally envision a transition toward more value-based structures, but this is usually described as a “slow process,” starting with “experiments” and “pilots,” characterized by “baby steps.” Moreover, the envisioned end point of this transition—the quintessential design—remains unclear; the idea is that this will be determined along the way. So, even when the core principles of VBHC are widely embraced, many of our interviewees do not acknowledge IPUs as the pinnacle of structure in health care.Overall, Dutch hospitals aim for units in hospitals by itself is not enough to overcome the extensive reliance on disciplinary boundaries in everyday health care delivery practices [For several reasons, an incremental approach to value-based redesign may well be more viable than the radical transformations professed by Porter , 8. To sractices . Breakinractices . Thereforactices , 7, 8.effects of utilizing these design parameters on performance. We strongly encourage future research regarding the results of value-based redesign.This study has at least four important limitations. First, it should be noted that while Mintzberg’s design parameters have proven to be highly useful for analyzing value-based redesign, our use of this framework has undoubtedly shaped our findings. Second, our study focuses on Dutch hospitals; the existing policies, regulations and financial arrangements in the Dutch health sector have likely molded how these organizations may or may not pursue a more value-based design. Third, we interviewed only one representative per hospital, most of whom did not have a clinical role. Interviewing only one  representative per hospital may have generated biased pictures of what is happening within the individual hospitals, which could potentially have spilled over to our aggregate findings. Fourth, while our conceptualization of “value-based design parameters” may be useful for analyzing and implementing VBHC, it was beyond the scope of this study to examine the Hospital executives, managers and leading physicians who want to upgrade coordination around medical conditions have a variety of organizational knobs to turn to various degrees. Our study indicates that many providers will likely favor incremental redesign over radical transformation. Considering hospital units, rather than radically regrouping the entire organization into units around medical conditions, a more incremental approach could be one in which a hospital first experiments with one or a few condition-based pilot units . Depending on how the pilot proceeds, modifications can be made, such as granting more financial autonomy to the respective unit.If, at least for the time being, (most) traditional specialty units are left intact, coordination around medical conditions can still be enhanced in various ways. For instance, hospitals could appoint one or more  managers, whose roles are first and foremost to foster interunit communication and coordination. A common way to do this is by forming multidisciplinary teams around a medical condition, with members from various specialty units meeting on a regular basis. One point of discussion during these meetings can be how to improve value for patients with a similar medical condition—based on value-based performance measurements (e.g. outcomes and costs).It is widely recognized that structural changes, whether sweepingly or incrementally, benefit from a solid support base across all levels of the organization. Concerning value-based redesign in Dutch hospitals, systematically propagating information  has been regarded as a useful way to generate awareness and support throughout the organization.Multiple Dutch hospitals initially struggled with the composition of the leadership of their multidisciplinary teams. Their experiences indicate that the characteristics of these leaders matter: it is probably good to have multiple leaders, each representing a particular organizational component , and several hospitals have come to favor official application procedures over automatically granting leadership to the most enthusiastic physicians.Ideally, hospitals would not have to repeatedly develop all of these approaches by themselves. Instead, the path toward more value-based structures could be built on the efforts and lessons of others. Therefore, we encourage providers to gather information, evaluate proceedings and report on their experiences; this can give rise to a knowledge base on which value-based redesign may be founded.incrementally exploring various ways to improve coordination around medical conditions over full care cycles. Our study demonstrates that Mintzberg’s [Value-based redesign is not necessarily a matter of radical changes or binary choices between traditional structures on one side and value-based designs on the other. Instead, inspired by the idea to achieve the best outcomes as efficiently as possible, hospitals are tzberg’s  organizaAdditional file 1. Theory on design parameters.Additional file 2. Interview guide and topic list.Additional file 3. Coding scheme.