This article critically examines engagements of village leaders in an NGO-facilitated participatory conservation program in eastern Indonesia. It explores how the program’s implementation strengthened leadership legitimacy of a dominant customary social group. Customary leaders ensured distribution according to particular norms, and in organizing village governance upheld specific interests and claims over natural resources. Villagers outside of the customary group remained marginalized in village governance, despite being important stakeholders. Findings reveal complex relationships between leaders and villagers that were strongly framed by orders of power and cultural history, which influenced how and to what extent peripheral groups participated. The case study concludes that village leaders can form effective avenues to deliver on conservation outcomes. However, in their preoccupation with maintaining leadership legitimacy, they may inadequately address dynamic intra-community tensions that could jeopardize long-term outcomes. Co-management partners can play significant roles in adapting management and prompting more inclusive governance processes. This leads to the question of whether a dominant group’s authority offers an appropriate starting point for conservation projects  in the village of Tanimbar Kei. This program involves an Indonesian NGO known as the Indonesian Locally Managed Marine Area Network (I-LMMA).n = 55) during the initial data collection period to learn about people’s perception of, and participation in the village LMMA program. In this same period a survey on local leadership and village governance was carried out with 42 households in the village, which were randomly selected after stratifying the data population according to hamlet size. Although the name of the village is used here, the identities of my respondents remain anonymous, and only public positions are named when referring to individual leaders.The study is based on data collected in the community of Tanimbar Kei, during a seven-month residence there between August 2010 and February 2011, followed by five subsequent visits of up to 3 weeks each between 2013 and 2015. My ethnographic engagement with villagers in daily livelihood activities, through participant observations and frequent conversations with key informants provided most of the data used here. Semi-structured interviews were carried out with villagers  from the Kei Archipelago’s main island of Kei Kecil  administration with no administrative hamlet (dusun) subdivisions, despite there being significant historically and physically distinct groupings within the village.Tanimbar Kei Island is located some 4 hours by motorized fishing boat , to become the main source of household income across the village. Many households also still tend coconut plantations to produce and sell copra to middlemen, albeit of lesser importance than before 2005. Fish and other reef-based marine resources are an important part of people’s staple nutritional intake. Given the distance to the larger Kei Islands and lack of cool storage technology, only a small portion of total village catch is traded and only by a few households selling to other households in the village. Aside from marine oriented livelihood activities, households typically maintain small agricultural plots where they plant limited hardy root crops , fruit  and vegetables . The island’s low-lying limestone substratum means soils are infertile and opportunity for extensive agriculture is limited. Basic food staples like rice are bought from markets on Kei Kecil.Livelihoods on the island largely depend on the surrounding marine environment. As indicated in Fig. kios), and bulk transport to Kei Kecil. There are a handful of villagers that work as civil servants, but only one resides permanently in the village .Both men and women take part in most land-based economic activities , albeit with different responsibilities. Marine-based activities beyond the mudflats are exclusively carried out by men , while women share in activities within the intertidal zone  such as seaweed farming and gleaning for mollusks. Other more specialized income sources on the island include boatbuilding, community shops  described in Barraud’s , being all but fished out by 1998. In that year adat leaders reportedly terminated the collaboration and collectively demanded that the company leave. In the years following their exit, little consolidated effort materialized amongst adat leaders to improve marine areas due to what a local leader described as “a lack of technical knowledge in the village” on how to address the acute ecological degradation. Their lack of capacity to address the degradation eventually led to I-LMMA’s invitation by the village head in 2005.Although accounts from villagers showed that Hukum Larvur Ngabal (‘laws of the red blood and lance’)adat institutions under Law No. 32/2004 on regional government  compared to elsewhere on the Kei islands. Not all village matters are necessarily brought to this council, however. Smaller intra-village disputes are for example addressed by particular leadership figures associated with the group where the dispute occurred, as is the case with Mun, where the Muslim leader assumes a primary role in conflict resolution. Religious leaders from all four religious groups play a significant role in local social conflict resolution, although at a village level they function below the authority of customary adat leaders. More recently legal matters and inter-village conflicts have increasingly become the domain of the official village administration (desa dinas), but as demonstrated in the following section there is strong influence and representation of adat in the village administration.The customary governance structure around decision making in contemporary Tanimbar Kei is still rooted in the adat systems were superseded by the national Indonesian legal system. In part enabled by its remote location, Tanimbar Kei leaders remained strongly linked to their traditional governing institutions and maintained these substantively intact. For example under Tanimbar Kei’s customary adat structure , the role of village head could only be occupied by individuals from one rahan lineage and was historically inherited along patrilineal lines, rather than through open elective processes. It furthermore represented more of a diplomatic responsibility as the ‘face of the village’ in its engagement with outsiders, and was thus not regarded as a singular point of authority, nor did it involve administrative responsibilities or presuppose extra benefits like a stipend. This contrasts with official village administration under Indonesian law, which is locally understood as a body of externally derived authority backed by central government.The establishment of Suharto’s New Order regime in 1966 saw the implementation of an Indonesian central state bureaucratic system that extended down to village level, consolidated under Law No. 5/1979 on village government. In Tanimbar Kei village, governing structures were instituted whereby local rahan of the adat core. The first appointment of an official (dinas) village head was reportedly around 1975, and saw the head of the rahan associated with the customary role of village representation in external engagements assume this position. Since then the position has been filled by others from the adat core structure following more elective processes, although eligibility for candidature remained implicitly dependent on inherited entitlements under adat, and more recently on being Hindu. In one instance the son of a previous village head made claim to the position of village head, however his challenge was rejected by village elders since he had converted from Hinduism to Christianity (Protestant), and thus was no longer eligible to lead Tanimbar Kei. Similarly, the official village council , as the main village planning and consultative structure under Indonesian law, was at the time of the research dominated five-to-one by elders or representatives from the 23 rahan adat core. As a result customary village leadership norms still strongly shape village governance and steer engagements with external institutions and organizations.Tracing back bureaucratic village leadership in Tanimbar Kei since its implementation in the late 1970s shows that these positions have always been occupied by men from the 23 adat core social order, and the powerful rahan heads that collectively comprise its leadership ‘elite’, maintain the highest level of leadership legitimacy. The hierarchy among rahan heads is determined in part by the specific roles historically bestowed on their rahan, in particular the three leading rahan of the respective la-owan, but appears also to be influenced by personality. One of the heads of the three leading rahan, for example, possesses significant authority through his inherited role as ceremonial master of important adat rituals involved in annual collective millet cultivation. His authority over adat matters in particular is very strong and is embedded not only in his authoritative presence, but also in the respect among villagers of his exclusive knowledge of, and connections to, the spirit world. Another of the three leading rahan heads, claims lesser authority over adat-ritual matters, but is a prominent leading voice in village decision-making, planning and development. He too assumes significant respect from villagers, largely based on his personality and proven leadership track-record over the years.The administrative parameters associated with official village government , have in more recent decades bureaucratized the village head position. Nonetheless, among the local governing centers in Tanimbar Kei, the customary desa dinas), the religious council (tokoh agama) and the traditional council (tokoh adat), do not stand on equal ground in Tanimbar Kei. As schematically presented in Fig. adat leadership in Tanimbar Kei is dominant and strongly embedded in adat identity amongst the 23-rahan adat core group. Primary membership in this group is defined by direct kinship connection and religious affiliation to Hinduism. Where there are examples of adat kin members that have converted to other religions, these individuals may still identify with the adat community, take part in adat ceremonies and make claim to particular land, but they cannot become head of a house or fulfil adat leadership roles. Albeit secondary to adat leadership, religious leaders from all four religions on the island are important figures also and have come to be integrated in one way or another into village governance. For example, the final institutionalizing of various village regulations requires sign-off by the religious council, next to the traditional council and village government. Under I-LMMA’s facilitation the village conservation program was first to apply these requirements, however since then these have been independently applied to legitimize agreements made in village-wide government development initiatives.The three leadership bodies often associated with official village governance in Indonesian villages, namely the village government (desa dinas) is a more recent institution, yet increasingly gains currency as an avenue to access resources and infrastructure through national development programs. The vast majority of its staff belongs to the adat core group. However several well-respected figures, as for example the Catholic Church leader, are also involved. Originally from a village on the mainland of Kei Kecil, he married into an adat family and has ever since lived in the adat core section of Tanimbar Kei. Being well educated and from a high ranking social order on Kei KecilThe administrative village government (imam) and several elders . Without administrative hamlet status there is no separate body representing interests for Mun residents specifically. As a result most involvement in village government matters by these elders is primarily through the village administration’s consultative meetings rather than by an integrated process that recognizes a formal role for Mun in decision-making. This is evident also in their low participation in the village LMMA program.Integration of the smaller Muslim hamlet of Mun in village-level leadership does not extend beyond involvement in village government of the Muslim leader . Being a relatively small NGO, I-LMMA regards its assets as largely embedded in the community programs it mentors. Although focus remains small scale, I-LMMA’s larger vision is “to create and share a community-based, sustainable, and fair marine resource management model for coastal areas and small islands in Eastern Indonesia” I-LMMA : 1. TaniThe national I-LMMA program is coordinated by a small team of four fulltime employees. Additionally four focal area coordinators (FAC) are employed to oversee and coordinate program activities in each of I-LMMA’s focal areas.2) marine zone around the island as an LMMA, with one small four hectare permanently closed no-take area designated as a nursery for trochus shell (Trochus niloticus) population regeneration. Annual trochus shell harvest outside of this no-take area moreover has been reduced from the previous six-month opening to a five-day opening period. Annual population monitoring activities carried out in the first 4 years after the implementation of the harvest restriction in 2006 showed a significant annual increase in average trochus size (from 7 cm in 2006 to 13 cm in 2010), and a consistent rise in the total annual trochus harvest (from 814 kg in 2006 to 2334 kg in 2010). Similarly, 5-yearly coral monitoring activities that mapped coral cover around the island between in 2006 and 2011, indicated significant growth of hard corals in areas that had previously been damaged.The program has designated a 40,000 ha . This mandates Tanimbar Kei, through village government, to sanction anyone in violation of the regulations. Using these, the community manages outsider fishers who harvest marine resources without permission from adat leaders or who use destructive fishing techniques defined as illegal in state regulations, which are reiterated in the village regulations.The total LMMA area corresponds with the traditionally owned marine territory of the Tanimbar Kei people, all of which falls within the four nautical miles under official district jurisdiction. The community has gained legal recognition for the ownership and management rights over the area from subdistrict government, through facilitation provided by I-LMMA. In a similar vein, the program has facilitated the formulation of a set of official resource use regulations  management plan. Since 2013 the LMMA has become subject to a rotating system along four equal quadrants that dictates fishing access annually, so that in any given year one quarter of the LMMA is closed for fishing. Implementation of this rotational closure has been agreed upon but has yet to be enforced.adat leaders. At a meeting involving adat leaders, I-LMMA staff and the LMMA village program team members , it was agreed that the income would firstly contribute to financing ongoing activities of the LMMA village program and secondly be set aside as collective savings. These savings could be drawn upon in several instances, but only with consent of adat leaders and the LMMA village program team. It was agreed at the meeting that the funds could be used to support communal events or activities like the annual new year festivities (commonly celebrated village-wide across Kei); to support poor households in crisis ; and to support students who are in their final year of tertiary education (as the high expenses in the last year was a main reason students in the past did not complete their studies). Conditions were moreover established that only residents of Tanimbar Kei were eligible to appeal for these funds . In the first year, these funds were primarily channeled back into LMMA program activities to cover operational costs. However in the second year, next to covering operational program costs, the funds supported one tertiary student in his final year, helped another family overcome a family crisis and provided households village-wide with rice after government food relief provisions did not eventuate. Although rice provisions were handed out across the whole village, including Mun, the two cases involving family-specific support both involved families from the 23 rahan structure. Other ‘non-adat’ families were technically eligible for such support and several were arguably in need of it, however none of these families applied for such support nor were they put forward by a third party.Since 2012 the village LMMA program has implemented a concession system, whereby seasonal fishing ‘licenses’ are sold to outside fishers. This has created a significant source of collective income, which is managed by the coordinators in conjunction with We [Tanimbar Kei people] had several NGOs come to us to start projects […], we always agreed, but they [local NGOs] always only worked closely with members of the [administrative] village government because they thought those were the most important people in the village. That is not so in Tanimbar Kei.rahan elder, Tanimbar Kei, November 2010). on the basis that they possessed necessary authority and leadership qualities. With exception of one individual (the Catholic community leader), all individuals on this list were bound through kin ties to the adat core. The selection procedure for the community conservation team that was also formed during this meeting involved more specific selection criteria specified by I-LMMA. As a requirement from I-LMMA to ensure ‘broad capture’, the community conservation team had to be made up of seven core youth members from all parts of the village, while maintaining an open structure to allow free participation in activities by all (adat and non-adat) villagers. I-LMMA furthermore insisted on the inclusion of two women and a representative from Mun as core members. However those present at the meeting appeared to have steered the selection process towards an adat preference, since all chosen core members of the community conservation team, including the two women, were part of Tanimbar Kei’s adat core kin structure . The selected representative of Mun was also from an adat rahan; having married a woman from Java, he had chosen to settle in the Muslim community of Mun at the wish of his wife. Local leaders justified it on the grounds that this individual came to the main village frequently to see his family as opposed to other Mun inhabitants, thus allowing him to participate in meetings when called. Given that only the Imam attended the meeting, Mun representation in the community conservation team following this meeting was predictably low. While their absence at the meeting was interpreted by many adat leaders as disinterest, the Imam attributed this to reluctance among many Mun residents to confront adat leadership.At communal meetings that were initiated by senior members of the adat leadership, responsibility for decision-making in the program remained strongly aligned with the perspectives and interests of customary leaders. This gave the program a strong local adat identity. The program secured further support once the first formal recognition by subdistrict government of tenure rights over the marine territory was realized, allowing Tanimbar Kei leadership to take tangible measures to control outsider access.I-LMMA’s focus on developing local autonomy and leadership capacity formed its main strategy to gain community interest, an approach that appealed to many in Tanimbar Kei. Support for this approach was unsurprising, considering that villagers frequently made reference to their collective identity as being distinct from the wider Kei culture. In that vein, I-LMMA sought to develop in-village social and environmental project assets through proven collaboration and commitment of enthusiastic villagers, rather than initiating intervention with an injection of capital and physical assets. Given that the project initiation stages ran primarily through adat leaders from the 23 rahan; rather than through other potential links which might have included Mun’s fishing-oriented minority Muslim community.adat leaders referred to the program as their own local initiative, downplaying I-LMMA’s facilitating support, and the program was frequently used in narratives of the communities’ distinctiveness from neighboring communities,We [Tanimbar Kei people] are not like them [villages on neighboring islands] […] you can see we are the only village that have maps and fishing rules which we made ourselves […] we take care of ourselves.rahan elder, Tanimbar Kei, November 2010). Mun households did not engage in trochus shell collection or trade as part of their livelihood strategy, therefore restrictions on trochus shell harvest triggered neither interest nor resistance among Mun residents. When asked, Mun households did however express concern regarding the rotational fishing closure system, for two main reasons. First and foremost the access restriction to regular fishing grounds they visited would possibly mean a loss in income, and secondly these restrictions meant that they could no longer offer fishing access to visiting Bugis fishers. These reservations, however did not lead to collective efforts by Mun residents to raise this issue with village leadership or with the community conservation team, likely because the rotational closure system was yet to be enforced implying that their fishing had yet to be impinged upon.adat leaders’ dominant role in the LMMA village program, it is important to take note of the program’s impacts in terms of conservation outcomes and benefit distribution  indicate that customary leaders did acknowledge the needs of other groups. So although arguably limited, these other groups did receive some form of benefit. Lastly, in the context of adat-dominated leadership, I-LMMA’s criteria for participation of peripheral groups, although steered by adat leaders, did urge those leaders to incorporate measures for wider participation.With the exception of outside Bugis and Butonese fishers, Table adat core group certainly benefited significantly from the LMMA village program. With legal rights and village regulations crafted around adat norms and adat members taking up program positions (implying higher exposure to opportunity for skills development), suggests an active appropriation of opportunities by adat leaders. This sway in the balance of authority and potential benefit distribution in favor of the adat core group, and the consequent points of tensions with minority groups that may emerge, suggests minority groups may increasingly find themselves disadvantaged. Indication of this tension already appeared during the community conservation team’s catch monitoring activities, which involved gathering catch landing data from outsider seasonal fishing groups. Many Mun residents have Bugis ancestry, which means that they maintain significant ties across extensive Bugis diaspora networks. In their seasonal fishing activities around Tanimbar Kei outside Bugis fishers use Mun as a base of operation. Whereas outside Butonese fishers were seen by the community conservation team to cooperate willingly, significant antagonism existed towards Bugis fishers. LMMA conservation team members noted that cooperation with Bugis fishers was difficult and complicated by their links to Mun.Getting information from them [Bugis fishers] is always more difficult [than from the Butonese fishers], they do not like to work with us and are unreliable […], they always stay in Mun for a long time especially during the flying fish season, but they do not want to follow our [LMMA village program] rules..In examining who ‘won’, the Restrictive measures on where and what can be fished, and imposition of payments for seasonal fishing concessions to all outside fisher groups, undermines Mun residents’ particular relationship with outside Bugis fishers and so too their connection to those networks. Without active participation and opportunity for skills development for Mun residents, and without extra efforts to inform Mun residents of the importance of conservation measures for their livelihood security, they appear unlikely to compromise the existing safety nets they maintain through links to extensive Bugis diaspora networks.adat group. The primary function of the administrative village government was locally understood to facilitate the flow of resources from state development projects to the village and to facilitate official engagements with external organizations, first and foremost with government authorities. On the other hand, internal village governance matters, especially social matters, still fell to the responsibility of the local adat leaders who used their norm-rooted authority to mold conservation and development programs to those customs and values.Following community-wide recognition of the need to manage marine resources more sustainably, distinct new leadership roles and functions have formed out of encounters between community leaders and I-LMMA. The collaborations were used in different ways to promote not only collective interests but also the particular political interests of the adat norms and with village government positions predominantly filled by adat core members, adat structures have been reinforced through I-LMMA’s intervention. Individuals from the adat group were unsurprisingly appointed to program coordinating positions following consultation with I-LMMA. The village secretary, for example, was a head of one of the 23 rahan, but alongside his official role in village government he also was the financial coordinator in the LMMA program. Similarly, the second program coordinator, who doubled as the focal area coordinator, is in line to inherit the position as head of his rahan, and also functioned as the village facilitator in the national community development program (PNPM). Only the third coordinator, being the Catholic leader, was not a kin-member of a rahan. However his position was also close to the adat core by marriage into one of the 23 rahan to which he had aligned himself over the years. All three of these individuals may not have had the same local authority as adat elders, however their alignment with adat means they enacted those norms in engaging with outside actors while drawing from technical skills that adat elders often lacked.With village leadership embedded in local dominant adat leaders made certain concessions regarding recruitment for the village LMMA program, which followed particular criteria that I-LMMA required to ensure broad participation. I-LMMA urged the inclusion of at least two women and a representative from Mun to be part of the core community conservation team. These criteria were met, however the selection of these individuals was strategic in that both women and the Mun representative who were eventually involved were each from adat lineages. I-LMMA’s recruitment criteria were also implicated in the selection of the three coordinators, by inclusion of a younger person among the three coordinating positions. This was in part to ensure sustainability of the program, to transcend generational divides and to involve individuals with the skills and learning potential of the younger generation. This led to the recruitment of the second coordinator, who later would also come to function as the focal area coordinator. Although it was likely that this person would come to play an important role in future adat leadership, being the first son of one of the rahan heads, his rapid rise into the coordinator position resulted from his selection by adat leaders following I-LMMA’s criteria. This initial exposure as a coordinator in the village LMMA program has led to similar coordinating roles being assigned to him in other unrelated projects, as for example the village facilitator under government sponsored rural development projects. As important as his adat association, was the fact that he exhibited exceptional skills in both communicating with authorities and mobilizing local resources and people to ‘get things done’ in village projects. The elevation of individuals to leadership positions appears then to be based on more than simply adat association, but also on personality, perceived skills and a proven track record. Although the initial opportunity to show these skills was through an I-LMMA intervention, adat leaders’ decision to build upon this has elevated his position into one of broader village planning and leadership.In collaborating with I-LMMA adat leadership recognized the need to make important concessions in their recruitment of program leaders. Their adherence to I-LMMA’s recruitment criteria was somewhat consolidated by measures in the recruitment process that would prevent loss of adat representation. As a result in negotiating criteria and identifying individuals matching those, the candidates’ adat ties appeared to be of prominent, but not determinate, importance.To maintain collaboration with I-LMMA the adat engagement. Beyond the primary gains of improved management of the island’s marine resources and the collective income generated from it, the collaboration over time proved beneficial to the position of adat leadership. First and foremost I-LMMA’s primary alignment with the adat social institutions meant resources and personnel were allocated largely through adat engagement. This strengthened the existing dominance of the adat core’s leadership in internal decision-making and patterns of participation within the village. It further reinforced the norms and values by which the community was internally governed. Recognizing that I-LMMA’s inception strategy involved a deliberate alignment with customary institutions, it is important also to note the relative weakness of the village government (dinas) structures in Tanimbar Kei, and indeed throughout Indonesia  and arguably more democratic one that would in the short term undoubtedly have been less effective.From its inception, the village LMMA program provided opportunities for prominent adat among institutions beyond the community. Under district level legislation, subdistrict authorities accepted Tanimbar Kei’s ownership and management rights over the community’s marine territory based on adat claims to those areas. This provided for the first time a mechanism whereby Tanimbar Kei’s adat rules could be applied legitimately to outsiders, in, for example, its capacity under district law to sanction the intrusion of outside illegal fishers who were fishing without permission or using illegal fishing methods. The institutional channel through which these regulations were carried out was the administrative village government; however, the principles of local autonomy and ownership on which these regulations are founded reflected strong interests in the recognition of local adat norms. This was also evident in that all village government staff were also adat affiliated.Secondly, the collaboration yielded official recognition of local adat institutions in times of rapid socio-economic and political change on the island, arising from dramatic changes through democratization and decentralization policies that recognized previously deprived customary community property rights and enhanced village autonomy. The close community engagement of I-LMMA’s grassroots approach, provided opportunity for the dominant rahan groups at the time to strengthen particular leadership constellations over other potential arrangements, in particular, the potential for more prominent leadership roles among minority migrant and Muslim household groups.Within the village, the engagement with I-LMMA fortified local leadership and maintained legitimacy of rahan had little input in the decision-making processes. Although Mun households had a stronger seaward livelihood orientation, in part because as in-migrants they had no legitimate claim to land, their inclusion in decision-making about access to and use of marine areas remained low. Their participation was limited to consultation meetings that involved primarily informing Mun residents of plans to establish no-take zones for input around the implementation, rather than participation, at earlier planning and design stages. Mun residents’ reluctance to attend open meetings indicates that this exclusion was not apparently contested, and may have been chosen by Mun residents themselves. Their fishing and seaweed based livelihoods meant they could operate in spaces that did not impinge necessarily on others in the main village, and vice versa.adat social group. As long as Mun residents’ livelihood activities were unaffected, there appeared little interest in representation in decision-making processes of the LMMA village program. This was to avoid compromising that autonomy they maintained on the periphery. I-LMMA’s measures for input across the village, through insistence that meetings be held in Mun or by encouraging invitations for Mun residents to participate in project activities, were thus not only subject to adat domination of village leadership, but also to the reluctance by Mun residents to become involved or speak up.Members from Mun households who were not related to the 23 adat group. It is unsurprising then that interests were represented which primarily reflected their norms and ideals. The power differentials between groups within a village clearly play out in how decentralization and democratization of decision-making take shape . Despite this dominance there was significant evidence that the control over the LMMA village program was not entirely directed towards dominant group appropriation but also that needs of other groups were mediated and to a certain extent that wider benefit distribution occurred.The ongoing and effective collaboration with I-LMMA since 2005 functioned through direct links to the mediating adat core group, their involvement remained highly peripheral despite some participation measures fostered through I-LMMA. These mechanisms for broad representation were defused partially by the influential adat leadership and partially by Mun residents’ own reluctance to face adat leadership. Without active contestation from Mun, their absence in the adat core dominated decision-making process is likely to remain unaddressed. It is plausible that resistance by Mun residents to the LMMA village program may arise if measures are introduced that increasingly restrict access to important marine resources for them or that compromise important social-economic and cultural networks they maintain with outside Bugis fishers. In identifying such emerging tensions and with sufficient adaptive capacity in the management framework, adjustments can be made to expand participation and prevent collapse.External organizations seeking to establish collaborative arrangements with communities must acknowledge that such partnerships come to function in arenas where on the one hand established interests are likely to divert new paradigms of practice, but on the other hand local leadership constellations have the potential to benefit from the introduction of more inclusive governance practices. Individuals in leadership positions, who mediate between community and NGOs such as I-LMMA, channel information and guide project implementation according to established social relationships and accountabilities in these communities. It is important not only to recognize how dominant leadership groups function in relation to heterogeneous community constituencies they represent, but also to identify particular constituencies that do not receive representation. Mun residents’ position, as primarily fishers, makes them an important stakeholder in discussions on marine resource management. However with the majority of Mun residents having limited kinship or other associations with the adat core in Tanimbar Kei should not be interpreted to imply ‘failure’ or an unambiguous case of ‘elite capture’. This case supports arguments which suggest that cooperation by external agencies with dominant local groups and elite individuals provide valuable entry points for engaging communities in conservation and sustainable development initiatives. However, being aware of tensions and potential gaps in representation is critical to the adaptive local management and benefit distribution that would enable long-term sustainable management  interventions could bring about more effective resource governance.The positive conservation outcomes in the LMMA village program’s first decade of operation, suggest that the domination of the


Social mammals engage in affiliative interactions both when seeking relief from negative affect and when searching for pleasure and joy. These two motivational states are both modulated by μ-opioid transmission. The μ-opioid receptor (MOR) system in the brain mediates pain relief and reward behaviors, and is implicated in social reward processing and affiliative bonding across mammalian species. However, pharmacological manipulation of the μ-opioid system has yielded opposite effects on rodents and primates: in rodents, social motivation is generally increased by MOR agonists and reduced by antagonists, whereas the opposite pattern has been shown in primates. Here, we address this paradox by taking into account differences in motivational state. We first review evidence for μ-opioid mediation of reward processing, emotion regulation, and affiliation in humans, non-human primates, rodents and other species. Based on the consistent cross-species similarities in opioid functioning, we propose a unified, state-dependent model for μ-opioid modulation of affiliation across the mammalian species. Finally, we show that this state-dependent model is supported by evidence from both rodent and primate studies, when species and age differences in social separation response are taken into account. It is a popular belief that endorphins make us feel good. Surprisingly little evidence for this notion can be found in the scientific literature, however. It is well established that μ-opioids help us to regulate pain  theory in 1978. They argued that firstly, given the importance of social behaviors such as parental care and altruistic behaviors for survival of both the individual and the species, affiliative behaviors were likely to have evolved from more basic systems sub-serving pain perception. Secondly, several lines of evidence pointed to striking parallels between social attachment and drug addiction  on the μ-opioid receptor gene OPRM1 occur naturally and result in functional variants of the receptor. In humans, the OPRM1 A118G SNP is one of the most studied SNPs on the OPRM1 gene, and an analog is found in rhesus macaque monkeys (OPRM1 C77G). While the exact molecular function of the OPRM 118/77 G-variant is still unclear  model postulates that the diverging and paradoxical findings showing that MOR agonists in some cases comforting effect social contact has on separation distress is blocked by MOR antagonism (see Section Introduction), blocking MOR with an antagonist is not found sufficient to induce separation distress in itself. Naltrexone failed to induce distress vocalizations in infant rats when they were allowed to remain together with their siblings (Carden et al., reduced maternal infant grooming in mothers who were never separated from their infant (Martel et al., While studies of animals known to find social separation distressing, such as infant rodents; infant, juvenile and adult primates; and infants from other species, consistently show that the Since social play generally occurs only when an animal is free from physiological and social stress, it provides a useful behavior for investigating MOR effects in the absence of distress Loizos, . By the Increased MOR transmission was hypothesized to enhance the reward value of social interactions (Vanderschuren et al., Few studies have investigated the effects of experimental MOR manipulation on play behaviors in primates, but the limited evidence suggests that the MOR system mediates social play in a similar manner to what is seen in rodents. In a study specifically designed to investigate MOR modulation of primate social play, marmoset juveniles living in a family group were injected with morphine, naloxone, or saline without prior social isolation-distress. Here, morphine specifically increased social play behaviors compared to both saline and naloxone, while naloxone led to slight, albeit not statistically significant, decreases in play behaviors compared to saline (Guard et al., In sum, and in line with SOMSOM, the evidence from rodent and primate studies shows that MOR activation in a context of positive motivation increased “appetitive” social play interactions, whilst MOR blockade reduced these behaviors, if to different degrees depending on species. The hypothesis that MOR activation enhances reward experienced during engagement in social play is in line with a large body of literature showing that MOR agonism enhances appetitive reward responses to food rewards (Berridge and Kringelbach, We started this review by presenting a paradox in the current literature on MOR modulation of social motivation, namely that MOR activation increases social motivation in rats, but reduces social motivation in primates. The experimental paradigms in most studies of rodents and primates include social separation followed by drug administration, and then social reunion. We reasoned that social separation would affect motivational state differently according to social dependency, such that for instance a socially dependent infant or an adult primate would seek comfort to regulate social distress. In contrast, an adult or juvenile rat would tolerate social separation and instead react to MOR activation with social exploratory behaviors. Importantly, the consistent correspondence between species in the reviewed literature on MOR modulation of reward processing, emotion regulation, and affiliation in humans, non-human primates, and rodents substantiates an interpretation of the initial paradox as a result of differences in motivational state caused by affective responses to the experimental conditions, rather than differences in neurobiology.Building on the Motivation-Decision Model for opioid modulation of pain Fields, , and on The SOMSOM is supported by the reviewed evidence from a large literature of psychopharmacological studies in rats and a few key studies of non-human primates. When factors such as species and age differences in social dependency are taken into account, effects of pharmacological MOR manipulation on social approach behaviors are similar across species. We therefore hold that the SOMSOM predicts state-dependent MOR modulation of social motivation in humans. While the reviewed evidence from human studies show MOR system modulation of social motivation and separable MOR activation for positive and negative social affect, future studies should empirically test for state dependency in MOR modulation of human social motivation. Little is known about the role of the human MOR system in social bond formation and attachment. μ-opioid mechanisms form part of a complex concert of neurobiological processes modulating social behavior, and future studies should aim to disentangle interactions between the μ-opioid system and other neurochemical systems relevant for social reward such as κ-opioids and δ-opioids, oxytocin, dopamine and serotonin.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Acute kidney injury (AKI) following coronary artery bypass grafting (CABG) results in significant morbidity, mortality and prolonged stay on the cardiothoracic ICU. We sought to determine the incidence of AKI in our cardiothoracic centre, hypothesizing a higher occurrence in patients undergoing CABG using cardiopulmonary bypass (ONCAB) compared with off-pump (OPCAB) surgery .Retrospective data from all nondialysed patients undergoing isolated CABG at our institution were collected for the year 2013. Propensity scoring using the software platform MatchIt® was used to match subjects from ONCAB and OPCAB groups with regard to preoperative variables: logistic EuroSCORE, creatinine clearance (CrCl), gender and operative urgency. Postoperative AKI was defined as a rise of 50% or more in baseline serum creatinine [From 500 cases , 262 subjects were included in the final analysis, with 131 in each group. There was a higher incidence of AKI and renal replacement therapy (RRT) in the ONCAB group, although this was not significantly greater than in the OPCAB group (Table Our study is limited by its size and the use of logistic EuroSCORE as a composite measure of risk factors. However, it has demonstrated that in our predominantly off-pump cardiac unit, OPCAB conferred no statistically significant advantage over ONCAB with regard to postoperative AKI. Studies to date have standardised patient-specific variables, but not the conduct of the procedure itself; for example, minimising renal hypoperfusion during OPCAB. This may be a reason for the lack of clear superiority in the continuing debate over choice of CABG procedure and reducing the risk of AKI.


HIV incidence remains high among young women in sub-Saharan Africa in spite of scale-up of HIV testing, behavioural interventions, antiretroviral treatment and medical male circumcision. There is a critical need to critique past approaches and learn about the most effective implementation of evidence-based HIV prevention strategies, particularly emerging interventions such as pre-exposure prophylaxis (PrEP).Women in sub-Saharan Africa are at increased risk of HIV during adolescence and into their 20s, in part due to contextual factors including gender norms and relationship dynamics, and limited access to reproductive and sexual health services. We reviewed behavioural, behavioural economic and biomedical approaches to HIV prevention for young African women, with a particular focus on the barriers, opportunities and implications for implementing PrEP in this group. Behavioural interventions have had limited impact in part due to not effectively addressing the context, broader sexual norms and expectations, and structural factors that increase risk and vulnerability. Of biomedical HIV prevention strategies that have been tested, daily oral PrEP has the greatest evidence for protection, although adherence was low in two placebo-controlled trials in young African women. Given high efficacy and effectiveness in other populations, demonstration projects of open-label PrEP in young African women are needed to determine the most effective delivery models and whether women at substantial risk are motivated and able to use oral PrEP with sufficient adherence to achieve HIV prevention benefits.Social marketing, adherence support and behavioural economic interventions should be evaluated as part of PrEP demonstration projects among young African women in terms of their effectiveness in increasing demand and optimizing uptake and effective use of PrEP. Lessons learned through evaluations of implementation strategies for delivering oral PrEP, a first-generation biomedical HIV prevention product, will inform development of new and less user-dependent PrEP formulations and delivery of an expanding choice of prevention options in HIV prevention programmes for young African women. Young women aged below 25 account for three of the almost four million young people in sub-Saharan Africa who are living with HIV and have one of the highest HIV incidence rates globally . New preWomen are particularly vulnerable to HIV during adolescence and their early 20s due to biological, behavioural and structural factors. Biological factors that increase HIV susceptibility among women include co-infection with sexually transmitted infections (STIs) –7, genitHIV incidence remains high among young African women, and few strategies have demonstrated effectiveness in reducing new HIV infections in this population. Until recently, the mainstay of HIV prevention for young men and women was behaviour change focused on delay of sexual debut, decreasing the number of sexual partners and increasing condom use through interventions delivered to individuals, couples, families, peer groups or networks, institutions or entire communities , 27. SevThere is an urgent need for effective prevention for young African women given annual HIV incidence rates of 5–6% and higher in some settings. Oral antiretroviral pre-exposure prophylaxis (PrEP) is currently the prevention intervention for which the evidence for efficacy is greatest, if uptake and adherence are high, as described elsewhere in this issue and briefly summarized below. PrEP also is a strategy that can be independent of the partner's knowledge or “buy-in,” which could be relevant for young women who have a history of IPV or fear their partner's reaction to their efforts to reduce their risk of HIV. We focus on the barriers, opportunities and implications for implementing PrEP in young African women by reviewing behavioural and behavioural economic approaches to HIV prevention for this group. Although efforts to identify more effective and scalable behavioural and structural interventions and longer-acting, less user-dependent PrEP formulations for women must continue, it is important to evaluate the potential for PrEP as a core component of combination prevention for this key population that also includes behavioural and structural interventions, as recommended by the US President's Emergency Plan for AIDS Relief initiative for adolescent girls and young women: Determined, Resilient, Empowered, AIDS-free, Mentored and Safe (DREAMS) . Definin®) demonstrated substantial HIV prevention benefits (up to 75% reduction in HIV incidence) in four trials conducted among men who have sex with men (MSM) in a multicountry trial, injection drug users in Asia, and African HIV serodiscordant couples and young men and women [PrEP with oral tenofovir (TDF) or TDF co-formulated with emtricitabine . Study participants are counselled monthly that they may not be receiving active product, that the active product has uncertain efficacy, and they are provided with frequent reminders and encouragement to use product, which could have discouraged participants’ willingness to accurately report their adherence and study counsellors’ ability to address their concerns and barriers to adherence. Furthermore, study participants may feel less at risk over time in the context of monthly HIV testing, potentially coupled with less imminent concern about HIV in the trial communities, given expanded access to ART and declines in HIV mortality.A part of the rationale for learning from implementation of oral PrEP for young African women is that it has shown efficacy in multiple populations, is already available globally in branded and lower cost generic formulations, and that other PrEP formulations  have not yet consistently demonstrated efficacy. Specifically, 1% tenofovir gel dosed peri-coitally (two doses within 24 hours before and after sex) demonstrated moderate efficacy (39%) against HIV infection in the initial CAPRISA 004 trial in South Africa . Disappounknown efficacy may not predict uptake and adherence when patients in real-world settings are subsequently offered open-label product and counselled about known efficacy and the importance of adherence to achieve protection. Evidence of this has been demonstrated by the recent PROUD study, which offered immediate or deferred open-label daily PrEP among MSM in the UK and found high effectiveness (86% HIV protection) [Uptake and adherence among participants in clinical trials who are randomized to placebo or active product and counselled about tection) . A demontection) . Notablytection) ; daily dThese open-label PrEP studies demonstrate the feasibility of reaching at-risk populations and achieving higher effectiveness than was observed in placebo-controlled trials, in part due to populations who recognize their risk and are motivated to access a product with known high efficacy. These demonstration projects also indicate feasibility of public health delivery with quarterly visits, brief adherence counselling, and that adherence does not have to be perfect to achieve very substantial prevention benefits. The encouraging results from these initial PrEP implementation projects call for evaluation of open-label PrEP in young African women.A key gap is whether when counselled about the high safety, tolerability and effectiveness of PrEP in other populations, young African women who have substantial risk of HIV will effectively use PrEP until more prevention options are available. Young women may have less agency and face different circumstances and barriers than men and motivated couples in using PrEP. Specific issues for young African women include stigma about being sexually active, and limited access to youth-friendly services and reproductive health services. Thus, implementation science research is critically needed on PrEP for young women to assess their motivations for HIV prevention, PrEP delivery models including through family planning clinics and with community partners, and adherence strategies to address barriers to young women's adherence to daily pill-taking with PrEP. Innovative strategies to mitigate these barriers may include those that draw from behavioural economics and treatment adherence research with adolescents and young people, as summarized below.Behavioural economics, building on insights from psychology about predictable biases and mistakes that can make it hard for individuals to make healthy choices, provides a framework for understanding why young women find it hard to consistently engage in prevention even when they are informed about the benefits. “Present-bias” leads people to focus on immediate rewards or costs at the expense of their own long-term goals and objectives –67. HealDuring adolescence and their early 20s, many young women experience a period of rapid social, neurodevelopmental and physical growth. Studies indicate that brain development is not complete until the early 20s, with a lag between emotional and cognitive control maturation . NeurocoEven for young women fully intending to do everything they can to prevent HIV infection, prevention decisions are made on a continual basis. If adolescents have limited attention and are juggling chaotic lives with many priorities, threats and vulnerabilities such as poverty which reduces cognitive processing, prevention behaviours may suffer –75. AddiOne strategy for overcoming present-bias against prevention would be to increase the rewards for prevention and bring them closer to the present. Randomized trials have shown success in interventions that financially incentivize individuals to engage in prevention behaviours such as medication adherence, weight loss and smoking cessation , 78, altThe evidence on cash transfers and HIV prevention suggests that they may be useful tools for addressing structural barriers that increase young women's vulnerability to HIV, especially when provided at critical times. Given findings that women who have more education generally have lower HIV risk, interventions that keep adolescents in school would increase education levels in girls and potentially reduce their engagement in transactional sex . A succeMore work is needed to understand the mechanism driving divergent results on incentives for HIV avoidance, and for attaining sustained responses after incentives end. Although the psychology literature does not suggest that incentives “crowd out” intrinsic motivation when the baseline motivation for behaviours is low , more unPrEP is not suitable for all persons at risk, but may be feasible for a substantial portion of persons during “seasons” of high risk , which mYoung women may have greater difficulty with adherence than older women and other populations, in part due to cognitive development . PsycholWith respect to adherence support for young African women, recent meta-analyses highlight that cognitive-behavioural problem-solving , 104 andThe revolution in mobile phone technology creates new opportunities to engage youth and build new social relationships and networks with adolescents. These opportunities can be leveraged for health. SMS reminders provide cognitive reminders for adherence and can strengthen communications between patients and providers . A recenWith strong evidence for the efficacy and effectiveness of oral PrEP across multiple studies, it is essential to understand whether young women will be interested in using PrEP and able to sustain adherence in the context of clear positive messaging and integrated with delivery of other services that meet young women's needs . PrEP demonstration projects for young African women provide an opportunity for evaluation of delivery models, innovative communications, adherence and behavioural economics interventions to support uptake of effective, novel HIV prevention interventions. These opportunities include evaluating strategies to make risk salient to young women, understand and maximize women's motivations for prevention, and use of social support and social media to support PrEP uptake adherence, and delivery models, as summarized in The effectiveness of positive communication messages designed using insights from ethnographic research, mental models  and othePrEP delivery models need to be piloted for young women who have limited access to reproductive and sexual health services in many parts of Africa, in part due to provider attitudes towards sexually active unmarried women. Family planning clinics could be an efficient, existing delivery site for PrEP, by reaching women with overlapping risks for pregnancy and HIV and creating synergies in integrated rather than parallel delivery programmes. Women who are seeking services at youth-friendly clinics or family planning services are potential early adopters of PrEP because they are already engaging with the healthcare system and are already motivated by prevention . In addition, in some African countries legislation is needed to permit adolescents to access sexual and reproductive health services to remove this structural barrier to therapeutic and prevention services in general, including PrEP.PrEP implementation studies for young African women need to evaluate sociocultural contextual issues, caregiver support, peer norms and relations, and cognitive and environmental factors that influence uptake and adherence to biomedical HIV preventions. Ethnographic research is needed to better understand sexual partnerships, social influencers, and household factors  that shape young women's agency, priorities and ability to seek and adopt HIV prevention, including PrEP. Given the importance of context, sexual norms and expectations, and structural factors on increasing risk and vulnerability for young African women, PrEP may have greater uptake and adherence if it is provided in combination with counselling, peer support and referrals for women who have experienced sexual violence, have alcohol dependence or other needsPrEP demand should be quantified in terms of uptake and continuation rates among women of different ages and partnership characteristics in different settings as part of market segmentation research, which could also help forecast programme costs and supply chain needs. Scalable adherence strategies, such as brief counselling based on CBT, two-way interactive SMS messages as cognitive reminders, peer support groups and short-term incentives to support adherence behaviours need to be evaluated among young African women in open-label PrEP demonstration projects. Demonstration projects will be most policy informative if they are sufficiently large and designed to assess HIV incidence, either through a counterfactual or with immediate versus delayed PrEP use.Oral PrEP is a first-generation product, which has many similarities to the oral contraceptive pill which also has adherence challenges but made a significant impact on pregnancy prevention and paved the way for a multitude of contraceptive methods . Adheren


Despite continuous improvements in treating clinical symptoms and the identification of single compounds that effectively rescue some rare mutations in the cystic fibrosis transmembrane conductance regulator (CFTR), associated lung and liver pathologies remain largely untreatable and no real breakthrough is visible for the majority of patients suffering from cystic fibrosis (CF).Novel compounds have to be identified and tailored in combination to specific CFTR mutations, to different tissues, or even to the individual patient. Immortalized cell lines overexpressing mutant CFTR are typically used to screen candidate molecules but have proven to be poor predictors of clinical efficacy. The complexity of CFTR maturation and turnover requires the use of cellular models that closely recapitulate the specific properties of the clinically most affected organs. Importantly, current screening efforts based on primary airway cells or intestinal organoids cannot specifically target single rare CFTR mutations or mimic multiple cell types.In the near future, genetically engineered induced pluripotent stem cells will provide an excellent basis for personalized organotypic models of CF disease and biological screens for identification of CFTR potentiators and correctors. Thus, novel therapeutic concepts, as well as correctors showing clinical benefit and leading to a normal lifespan and the capacity to participate in social and economic life for patients carrying such mutations would entail substantial benefit for the community as a whole.Regardless of substantial clinical progress, cystic fibrosis (CF) is still a fatal congenital disease, affecting more than 70,000 patients worldwide, with high morbidity and a limited lifespan. Health care costs are estimated to be 3–4 billion € per year. Despite decades of intense research, gene therapy of CF did not enter clinical routine. Low transduction efficiencies in airway cells, immune reactions, and failure to achieve long-term expression in vivo prevented broader clinical application. Importantly, although the recent identification of cystic fibrosis transmembrane conductance regulator (CFTR) correctors and potentiators is promising, no compounds are available thus far which show significant clinical benefit in all F508del-carrying patients. In the case of other, more rare but substantial trafficking defect mutations  screens have identified CFTR potentiators, which restore the channel activity by enhancing gating , 5 and rIt is therefore clear that in the case of F508del and other trafficking mutations, novel compounds have to be identified. Indeed, current data indicate that a combination of CFTR correctors, potentiators, and molecules that prevent an excessive turnover of mutant proteins will be required . This coMost screens have therefore been performed using immortalized cell lines overexpressing CFTR mutants and halide indicators . Only thIt is therefore not surprising that immortalized cell lines overexpressing mutant CFTR variants are poor predictors of clinical efficacy and that alternative screening methods are required. It is consensus that those HT and medium throughput (MT) assays which have been used for identification of existing potentiators and modulators are suboptimal, in particular because all of them relied on immortalized cell lines overexpressing mutant CFTR variants without considering the patient’s genomic background and specific cellular and molecular characteristics of primary airway and bile duct epithelium.Addressing at least some of these limitations, a method to propagate intestinal organoids from individual CF patients was recently developed, which is now used as a novel, individualized screening platform for small molecules . CertainUntil recently, screening activities aiming at the identification of novel correctors and potentiators were hampered by the lack of a suitable source of expandable patient-derived cells that can be easily genetically engineered. These limitations were recently overcome by two groundbreaking developments: In 2006, Yamanaka demonstrated the possibility to reprogram somatic cells into the so-called induced pluripotent stem cells (iPSCs) , a findiMeanwhile, the generation of human iPSCs has become a standard procedure in many laboratories and it is now clear that these cells are almost indistinguishable from embryonic stem cells (ESCs) with respect to their phenotype, culture characteristics, and potential for proliferation and differentiation . RemarkaFrom a practical standpoint and industrial perspective, it was mandatory to address further issues that are critical for large-scale application of iPSC derivatives in drug screening and safety pharmacology. This includes the hitherto inability to produce large cell masses of iPSC in defined culture media. As for reprogramming efficiencies, major progress could be achieved also in this field and our group was able to demonstrate the possibility of long-term expansion of human-induced pluripotent stem cells in scalable suspension culture under defined conditions , 20. MeaThe lack of robust and efficient differentiation protocols enabling the directed derivation of specific cell lineages has been another limiting factor for the development of stem cell-based therapies. However, sequential inhibition and activation of molecular differentiation pathways now allow a targeted and efficient differentiation of human pluripotent stem cells into various lineages. Of special relevance for CF, hiPSC-derived bile duct epithelium can be obtained if suitable differentiation protocols are applied . Also, rIn contrast to primary bronchial cells, which presently provide the standard in differentiated airway cell culture, iPSCs show an unlimited potential for proliferation and differentiation. Also of relevance in particular for automated high throughput drug screening is the possibility to apply novel site-specific gene editing in hiPSCs including TALENs . This opRemarkably, while gene editing in intestinal organoids that are generated based on patient-specific intestinal stem cells from gut biopsies currently requires antibiotic selection to obtain transgenic stem cell clones, footprintless gene editing of isogenic iPSC lines has been proven feasible through TALENs/single-stranded oligonucleotides (ssODNs) without antibiotic selection or FACSorting . This ofGenetically engineered reporter iPSCs can finally be differentiated into CF relevant cell types such as respiratory , pancreaThe impressive progress in the generation and differentiation of iPSCs and in targeted genome engineering clearly provides manifold new opportunities for disease modeling and drug screening. In fact, there are already various examples for the decipherment of pathomechanisms especially of cardiovascular  and neurOn the other hand, it has to be emphasized that there are still various technology-related imponderables and critical hurdles to overcome. One of these hurdles is the lack of robustness of most differentiation protocols. Even in case of the most efficient targeted differentiation approaches that rely on fully defined media and application of small organic compounds, the success and efficiency is not always reproducible. Even though it is obvious that failure of individual preparations is frequently based on the quality of the starting stem cell population, it is still barely possible to exclude such failure. Clearly, resulting variations in the composition and purity of the target cell population significantly complicate the conduction of high throughput screens and their routine application in drug validation and safety pharmacology.As discussed above, one major advantage of disease modeling and biological screens based on iPSCs is the availability of patient-specific cells with defined genetic background that theoretically allows the direct correlation of the observed cellular phenotype with clinical data. However, it is increasingly recognized that individual iPSC clones generated from one donor can display a high degree of variation in culture and differentiation characteristics that can sometimes even exceed phenotypic differences between iPSC clones of different donors.Moreover, the experimental requirement for suitable control lines poses another problem: Because of the well-known influence of genetic modifiers and the individual genetic background even in so-called monogenic diseases, it is meanwhile considered state-of-the-art that isogenic gene-corrected iPSC lines are used. It is noteworthy, however, that although the availability of modern genome engineering approaches renders this technically feasible, it is increasingly recognized that the single cell cloning procedures required to select genetically engineered cells may result in iPSC clones with properties different from the original cells.In general, and although underlying mechanisms are widely unknown, altered characteristics of individual iPSC clones are likely due to culture adaptation and selection of (epi)genetic subclones not only during genetic engineering but also during iPSC generation, single cell cloning, and iPSC expansion. At this point, it is still unclear whether such differences affect only culture and differentiation behavior or may extend to functional properties of differentiated derivatives. Therefore, it remains to be investigated, whether the use of gene-corrected isogenic control lines is sufficient to overcome clonal effects on cellular assays designed to mirror a disease of interest in the dish.The use of genetically engineered patient-specific iPS cells can be considered as a highly innovative and valuable new platform not only for a better understanding of the different CF disease phenotypes but also for the identification of drugs that are able to functionally correct the organ-specific consequences of the different classes of common and rare CFTR mutations of wide clinical applicability.


The Editorial on the Research TopicBiomass Modification, Characterization, and Process Monitoring Analytics to Support Biofuel and Biomaterial productionThis Frontiers Research Topic journeys through various challenges facing researchers seeking to develop fuels and products derived from lignocellulosic biomass. These challenges include: the rapid quantification of plant cell wall chemistry, enabling yields of potential monomeric sugars to be assessed, identification of plants possessing ideal trait that can be brought to the forefront of research efforts; once the native plant chemistry is known, how can yields be improved by chemically or genetically altering plant cell walls to reduce recalcitrance; does genetic modification of plants to increase accessibility to saccharification enzymes hinder the plant’s growth and/or function; are the innovative methods identified by researchers cost-effective and scalable to a commercial level? These topics are a sampling of the obstacles researchers combat when nominating a specific plant for downstream applications or implementing new deconstruction, genetic, or measurement strategies. How well can different plants can be broken down into useful, downstream precursor molecules? Efforts to develop a lucid picture of the chemical composition of abundant, diverse plants being explored as potential starting feedstocks has resulted in the evolution of high-throughput techniques that permit many more samples to be screened in much shorter periods of time. Advances in thermochemical and spectroscopic techniques have enabled the screening of thousands of plants for different phenotypes, such as cell-wall composition and monomeric sugar release. Some instrumental methods have been coupled with multivariate analysis, providing elegant chemometric predictive models enabling the accelerated identification of potential feedstocks. Rapid instrumental techniques have been developed for real-time monitoring of diverse processes, such as the efficacy of specific pretreatment strategies, or downstream products, such as biofuels and biomaterials. Real-time process monitoring techniques are needed for all stages of the feedstocks-to-biofuels conversion process to maximize efficiency and lower costs by monitoring and optimizing performance. These approaches allow researchers to adjust experimental conditions during, rather than at the conclusion, of processes, thereby decreasing overhead expenses.Evaluating Lignocellulosic Biomass, Its Derivatives, and Downstream Products with Raman Spectroscopy” illustrates how advances in Raman instrumentation, and the use of multivariate analysis has aided researchers in developing efficient, rapid methods to quickly evaluate diverse varieties of plants. Another hot research topic is how can we make better, more efficient enzymes beyond what may be naturally available? Just as high-throughput and automated methods are desirable to partition a diverse portfolio of potential feedstocks, gaging enzymatic performance and efficiency presents similar challenges that can be alleviated by employing techniques such as that illustrated in the two articles “Use of Nanostructure-Initiator Mass Spectrometry to Deduce Selectivity of Reaction in Glycoside Hydrolases” and “Development of a High Throughput Platform for Screening Glycoside Hydrolases Based on Oxime-NIMS”. Studies like these have probed a variety of phenotypic traits, including the assessment of dominant plant cell wall chemical constituents , and the quantification of products from enzymatically deconstructing the plants into simpler, molecular building blocks. “Immunological Approaches to Biomass Characterization and Utilization” reviews recent advances in the use of glycan-directed probes to evaluate plant cell walls, including glycan-directed monoclonal antibodies, in efforts to understand cell-wall composition and structure, and how manipulations to these affect the biosynthetic processes. Assessing the study and function of proteins, called proteomics, is typically throughput limited. “Standard Flow Liquid Chromatography for Shotgun Proteomics in Bioenergy Research” validates the standard flow technique, and shows how 800–1000 different proteins could be identified in complex samples. Pyrolysis of plants to form bio-oil presents an interesting option for the synthesis of fossil fuel replacements. Before these oils can be utilized, they must be fully characterized. How will the intrinsic biomass chemistry affect the resultant bio-oil? The article entitled “Relationships between Biomass Composition and Liquid Products formed via Pyrolysis” explores this topic.The article in this book entitled “Optimization of Alkaline and Dilute Acid Pretreatment of Agave Bagasse by Response Surface Methodology” describes a technique for optimizing the deconstruction of agave cell walls to maximize the total reducing sugars produced during saccharification. Various techniques used to combat biomass recalcitrance in eucalypts have been outlined in the article “Efficient Eucalypt Cell Wall Deconstruction and Conversion for Sustainable Lignocellulosic Biofuels”. Plants with high polysaccharide and lower lignin contents are known to breakdown to monomeric sugars more readily, but what happens if a plant does not naturally possess the ideal traits for biofuel production, like high cellulose and low lignin? Researchers can purposely tailor the plant’s chemical composition to be more favorable for conversion to sugars, fuels, or other value-added products. In “Potential for Genetic Improvement of Sugarcane as a Source of Biomass for Biofuels”, different strategies for improving the degradability of sugarcane are reviewed. Increases in the total biomass yield, cellulose content, or saccharification efficiency through, for example, reductions in lignin content, are pathways being evaluated to genetically improve plants as feedstocks for biofuels and bio-based chemicals. The biological pathways with which the plant cell wall is fabricated can shed light on potential genetic manipulations that can favorably alter the cell wall chemistry. The articles “Phenotypic Changes in Transgenic Tobacco Plants Overexpressing Vacuole-Targeted Thermotoga maritima BglB Related to Elevated Levels of Liberated Hormones” and “Identification and Molecular Characterization of the Switchgrass AP2/ERF Transcription Factor Superfamily, and Overexpression of PvERF001 for Improvement of Biomass Characteristics for Biofuel” illustrate this technique. Although plants have been previously domesticated for food and fiber production, the collection of phenotypic traits prerequisite for biofuel production may necessitate new genetic breeding schemes.These important traits can aid in gaging biomass recalcitrance, enabling researchers to devise appropriate deconstruction strategies. The article “Book Review: Socio-Economic Impacts of Bioenergy Production” of the recent Springer publication Socio-economic impacts of bioenergy production.Lastly, the economic and social ramifications of using lignocellulosic biomass, such as the food versus fuel conflict, have been well documented. Can marginal lands provide us with the land required to achieve our energy needs in a cost-effective way? Cost-effective enough that we can seriously consider supplanting some fossil fuel usage on a much larger scale? This Research Topic includes a book review “This collection of papers demonstrates how advances at multiple levels are likely to contribute to the successful industrial scale production of biofuels and biomaterials. Innovations in biomass composition have a major role to play in facilitating conversion and appropriate analytical methodologies are fundamental to managing the industrial process and guiding research and development.JL wrote the editorial for this research topic. BS and RH critically read and edited the document.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Background: patient and public involvement (PPI) in research can enhance its relevance. Older care-home residents are often not involved in research processes even when studies are care-home focused.Objective: to conduct a systematic review to find out to what extent and how older care-home residents have been involved in research as collaborators or advisors.Methods: a systematic literature search of 12 databases, covering the period from 1990 to September 2014 was conducted. A lateral search was also carried out. Standardised inclusion criteria were used and checked independently by two researchers.Results: nineteen reports and papers were identified relating to 11 different studies. Care-home residents had been involved in the research process in multiple ways. Two key themes were identified: (i) the differences in residents' involvement in small-scale and large-scale studies and (ii) the barriers to and facilitators of involvement.Conclusions: small-scale studies involved residents as collaborators in participatory action research, whereas larger studies involved residents as consultants in advisory roles. There are multiple facilitators of and barriers to involving residents as PPI members. The reporting of PPI varies. While it is difficult to evaluate the impact of involving care-home residents on the research outcomes, impact has been demonstrated from more inclusive research processes with care-home residents. The review shows that older care-home residents can be successfully involved in the research process. Despite the increasing emphasis on PPI, marginalised groups, such as care-home residents, can be overlooked when including people in the research process.Patient and public involvement (PPI) has developed into an integral part of research practice over the last 25 years. Many funding bodies and ethics committees now require PPI to be part of research protocol development . Research and guidance in this area have considered: the involvement of older adults in research processes , three-quarters have cognitive impairment [14] and many are nearing the end of their lives, so stay in care homes for relatively short times [15]. Consequently, care homes are unique research settings and care-home residents need specific consideration in relation to how they may be involved in research. Recently, guidance has been developed for conducting research in care homes [16] and a resource produced to inform researchers planning to involve care-home residents, relatives and friends as PPI members in their research [17]. Learning from previous research involving older care-home residents as PPI members is vital to improve the effective inclusion of this marginalised group in future studies so they can have a voice and active role in research.Care homes in the UK provide 24-h residential care  or nursing care . Settings vary in size, ownership and specialisms [12]. Groups with a stake in care-home provision include commissioners, owners, managers, staff, residents and relatives. Care-home residents typically have high levels of physical dependency . The researchers also aimed to build a collaborative research team which included older care-home residents and people with an interest in care homes to assist with the review.Studies were included if they reported a PPI element involving older care-home residents. To maximise learning, any research topic, methodology, study design or type of PPI was included. Studies were excluded if there was no PPI element, the PPI element did not include residents, the age of the residents was not 65+ and the residential setting did not aim to accommodate older people.A search of 12 electronic databases  was conducted in September 2014.A supplementary lateral search was conducted. For example, searching reference lists of papers and key websites such as INVOLVE and the TRIP database. Searches for related papers and reports of included studies were conducted to try to determine more about the residents' involvement in those studies. When necessary, we contacted authors to attempt to locate further publications.The search syntax used was as follows: (Advisory OR client OR engagement OR participatory OR ‘participatory research’ OR ‘patient and public involvement’ OR PPI OR stakeholder OR ‘user involvement’) AND . Limits were set for post-1990, ‘human’ and ‘English’.Study selection was undertaken in three stages: first titles were screened, second abstracts were screened and finally full texts were obtained for eligible papers or where eligibility was unclear Figure . Two autAge and Ageing onlineSupplementary data, Appendix A, available in ) which enabled the extraction of information relating to PPI elements. The form was piloted by collecting data from two included studies to see whether the extraction categories were plausible and provided useful results. The extraction form was refined and questions relating to: the length of study, the methodology, the direct voice of residents and the decision or advice PPI were involved with added at a project team meeting (which included PPI) before two authors undertook data collection in consultation with each other. Three papers located through supplementary searches [21] were included in the review but did not have data extracted as they presented very limited information about PPI.A data extraction form was developed  and two authors thematically analysed the data within and across them. Our PPI team members discussed the findings by reviewing the resulting two key themes and providing their thoughts on their plausibility.To synthesise the data, extraction categories were grouped into 13 themes  fulfilling the inclusion criteria. All identified studies were included in the review to maximise the knowledge we could obtain.26]. Table All 11 studies had a predominantly qualitative research design; however, four also included a quantitative element [27]. An Australian study explored factors influencing the quality use of medication [28]. The other three were part of the research programme, Prevention of Abuse and Neglect in the Institutional Care of Older Adults (PANICOA). The large research projects were set up and led by the researchers, but contained within them different advisory groups or defined elements of collaboration. The researchers aimed to consult with multiple stakeholder groups at various points during the projects, which typically resulted in complex studies.These five studies involved eight or more care establishments, were multi-method studies and all, but one, were UK based. The topics of the studies varied. One researched the role and contribution of long-term care within the whole spectrum of future services [29], care-home residents had partial involvement. For example, residents did not play a part in stakeholder events but could be members of specific advisory groups and panels. Additionally, two studies included peer researchers [29], but these were older people from the community, not care-home residents.The involvement of residents was often limited compared with other stakeholders such as care-home staff, relatives or health professionals. In two studies [29], with relatives and carers [30], or in mixed stakeholder groups [28]. Various methods of involvement were employed including workshops [27], nominal groups (defined by Delbecq [31]), focus groups [28], interviews [27] and panel groups [30].When residents were involved in the studies, they were consulted in groups on their own [23] and one involved four [32]. The small studies focused on the immediate care-home environment and emphasised partnerships. The four involving only one care home followed a participatory action design focusing on actual or potential interventions and/or their evaluation. Researchers aimed to collaborate with residents (and others) as partners, involving them in decision-making to examine aspects of the care/service provided. The studies reflecting three or four homes focused on culture change in care homes and involving care-home residents (and others) as co-researchers. The comparative design of these two studies had no input from care-home residents or other parties. Therefore, they shared the same participatory action design as the one-site studies. In such designs, the researcher was viewed primarily as a facilitator [32].Four of the six small studies involved only one care home, one study involved three care homes [33] and representatives of the NHS Trust and Housing Association [24]. Involvement by the different groups varied at different times. Most studies had a collaborative process; however, the Hewitt study incorporated a more structured approach where residents could vote on 23 potential interventions and prioritise them [25].All the small studies involved residents and care staff. In addition, most also included as participants, family members and management, while some aimed to involve all people in the care-home community, so including administrative and maintenance staff [24]. However, this and other small studies made attempts to enhance resident involvement; for example, some used informal conversations to enable residents to be involved [25] and others used interviews or focus groups [23] as a tool to bring residents' voices to the negotiating table [34] or to ensure their participation was maximised [25].One small study that took place in a home specialising in dementia care had minimal resident involvement ; residents' trust in researcher confidentiality could impact on their willingness to be involved [25]. Valuing residents' involvement [32] and creating a safe space for them to voice ideas could enhance their involvement [35]. Residents' confidence levels [34] and whether they had a low or agitated mood [29] also affected their participation, while some residents and staff could be reluctant to engage with new ideas [23].The development of good relationships with residents aided involvement. Trust and transparency were important [23] or were prevented from taking an active role in meetings [24]. Sensory impairments such as hearing difficulties and poor vision could hinder participation [25]. To accommodate the changing health of some residents, Killett et al. [29] held their final meetings with residents in care homes rather than at external venues.Resident and researcher skills could impact on resident involvement. Cognitive impairment sometimes presented a barrier, since it meant some residents had poor knowledge and negotiating skills [34], foster good relationships with a variety of individuals [35] and offer continued encouragement and support to residents [32].Researchers' communication and interpersonal skills were essential. Investigators had to take on the role of a facilitator or mediator in meetings or negotiations [32]. Action research required financial resources to allow the implementation of the changes identified [35]. Spending time gaining residents' confidence and getting to know them were essential to increasing participation but, due to financial constraints, were difficult to sustain [34]. One study did not provide feedback to PPI members at its conclusion due to time limitations [27]. Two studies offered care-home residents remuneration for their involvement [29].Time and money were cited as barriers. In one study, a lack of funds meant that not all residents interested in contributing to the research could be involved [23]. In contrast, fragmented leadership and the attitudes and abilities of key powerful individuals could work against residents' involvement [25].A supportive organisational culture where management and staff valued the residents' participation in research and were open to change which might enhance involvement and helped the implementation of action research [35]. Flexibility, which could similarly encourage residents' involvement, was shown in using informal conversations or one-to-one discussions [29]; identifying a main contact or source of support for residents [29]; and allowing ad hoc contact with researchers [24]. However, allowing ad hoc contact with researchers could be a challenge for research staff to respond to.An emergent design was seen to be important to empower residents, since it allowed them to set the agenda and have some ownership over the study  discussed resources and flexibility in relation to conducting research in care homes, this review outlines specific ways in which these aspects can facilitate older care-home residents' involvement as PPI members . This review also augments the knowledge available for researchers who plan to involve care-home residents, relatives and friends as PPI members [17], by providing examples and detailed information about how care-home residents have been involved in past research and the barriers to, and facilitators of, their involvement. The high proportion of residents with cognitive impairment and frailty in UK care homes mean that many residents encounter individual-level barriers to involvement. Residents with cognitive difficulties were often screened out from studies or only informally involved. If involved, cognitive difficulties could greatly restrict residents' involvement. Future research should explore the best ways to involve residents with cognitive difficulties in studies, so that their voices can be heard.This review adds to the literature by providing knowledge about the involvement of older care-home residents in research processes, based on research experiences. The findings add to the general guidance for conducting research in care homes specific knowledge and learning points about having care-home residents as PPI member. For example, although Luff Structures surrounding research funding and ethical protocols could inhibit taking some lessons learned from this review forward. For example, some funding bodies are not open to emergent designs, and ethical approval may have to be sought multiple times as a flexible study design takes shape. Additionally, some methodologies are not suited to an emergent design. Therefore, unless residents are involved in the development of a funding bid, it may be difficult to enable them to have much control over the research design.Given the nature of the review focus on what is usually a secondary aspect of published research (PPI), it was often difficult to determine whether any involvement had taken place in studies. Consequently, the main limitation of this review is that PPI is not always reported in study outputs; therefore, the findings may not reflect the total range and scope of older care-home residents' involvement in the research process. There was also a blurring between PPI members and participants in some studies, and the processes of resident involvement were not always stated or clearly explained. This presented difficulties in determining the exact nature of resident involvement. Additionally, the impact of resident PPI on the studies was not formally evaluated  or clearly reported, making it difficult for the review to assess this element. Due to inconsistent and partial PPI reporting, we found some of the critical appraisal questions difficult to apply. The papers often did not state the aims of PPI and the impact of PPI on the study. Therefore, a full understanding of the value of PPI with this population could not be determined. Consequently, for this review, the achievement of involving older care-home residents as PPI members constitutes success.Throughout the systematic review, we intended to involve our own PPI team members (including care-home residents); however, although they were offered opportunities to comment on data extraction criteria and papers, the labour-intensive nature of the work, complexity and technical vocabulary meant that it was only possible to involve them meaningfully in discussing the findings. These discussions occurred through meetings and one-to-one conversations about data relating to the two key themes.Few studies have attempted to involve older care-home residents in the research process. Nonetheless, some have managed to do this successfully. Older care-home residents have been involved as PPI members in two ways: as collaborators in small-scale participatory action research and as advisors on large studies. Multiple barriers to and facilitators of involving residents as PPI members were identified and can be grouped under social factors, skills, resources, care-home organisational factors and the organisation of the research. All studies involving residents in research have been predominantly qualitative in design. Future research is needed to test whether care-home residents could be successfully involved in research with a quantitative design and/or as collaborators or peer researchers, particularly in large studies involving several care homes.Older care-home residents have successfully collaborated or advised researchers in a variety of studies.Involvement of older care-home residents in the research process has differed depending on the size of the study.Involvement of older care-home residents as PPI members has been found in studies with largely qualitative research designs.There are multiple facilitators of and barriers to older care-home residents being involved in the research process.The reporting of PPI varies. Comprehensive reporting would allow readers to better assess the impact of PPI on the research. While it is difficult at present to evaluate PPI impact in research outcomes, such impact has been demonstrated in more inclusive research processes with care-home residents.Age and Ageing onlineSupplementary data mentioned in the text are available to subscribers in .None declared.National Institute for Health Research (NIHR) Collaboration for Leadership in Applied Health Research and Care East of England (CLAHRC EoE), at Cambridgeshire and Peterborough NHS Foundation Trust. The views expressed are those of the authors and not necessarily those of the NHS, the NIHR or the Department of Health.The research was funded by the