Alternative Design Trials (ADTs) and Adaptive Platform Trials (APTs) have enabled efficient large-scale testing of biomedical interventions during recent PHEs. Design features of these trials may have implications for engagement and/or informed consent processes. We aimed to rapidly review evidence on engagement and informed consent for ADTs and APTs during PHE to consider what (if any) recommendations can inform practice.:Method In 2022, we searched 8 prominent databases for relevant peer reviewed publications and guidelines for ADTs/APTs in PHE contexts. Articles were selected based on pre-identified inclusion and exclusion criteria. We reviewed protocols and informed consent documents for a sample of large platform trials and consulted with key informants from ADTs/APT trial teams. Data were extracted and summarised using narrative synthesis.:Results Of the 49 articles included, 10 were guidance documents, 14 discussed engagement, 10 discussed informed consent, and 15 discussed both. Included articles addressed ADTs delivered during the West African Ebola epidemic and APTs delivered during COVID-19. PHE clinical research guidance documents highlight the value of ADTs/APTs and the importance of community engagement, but do not provide practice-specific guidance for engagement or informed consent. Engagement and consent practice for ADTs conducted during the West African Ebola epidemic have been well-documented. For COVID-19, engagement and consent practice was described for APTs primarily delivered in high income countries with well-developed health service structures. A key consideration is strong communication of the complexity of trial design in clear, accessible ways.Conclusion: We highlight key considerations for best practice in community engagement and informed consent relevant to ADTs and APTs for PHEs which may helpfully be included in future guidance.Protocol: The review protocol is published online atProspero on 15/06/2022: registration number CRD42022334170. In the wake of the COVID-19 pandemic, preparing for effective responses to these events remains a priority for governments and international agencies such as the World Health Organisation (WHO). Clinical research is central to the response, particularly during novel infectious disease outbreaks where no known medical countermeasures exist. During a PHE, rapid recruitment of large numbers of research participants are likely to be needed to produce results that can be used during the active phase of an outbreak. As illustrated in the H1N1 pandemic where no clinical trial evidence was available to inform treatment, the time needed to establish clinical trials must be optimised to avoid missing outbreak peaks. Learning the lessons from H1N1, COVID-19 saw important advances to rapid production of evidence related to vaccines and therapeutics. These advances reflect innovation to the ways in which clinical research was designed and conducted during PHEs. In particular, the use of alternative design trials (ADTs) and adaptive platform designs (APTs) have advanced the potential for clinical research to produce timely evidence for public health and clinical responses to emergency events.Public health emergencies (PHEs) caused by novel or re-emerging pathogens present a significant threat to the health and security of people around the world. APTs are guided by a single master protocol which enables the comparison of several treatments/vaccines against a single control aimed at standardizing study procedures across participating sites and contexts in order to minimize the duplication of efforts, streamline ethical review and achieve adequate, and diverse participation when time is of the essence. A prominent feature in APTs is the ability to drop arms for futility or harm as trial data emerges, and also to introduce new treatment arms as new products become available for evaluation. Examples of this type of trial include the PRINCIPLE primary care trial, TOGETHER, REMAP-CAP, RECOVERY treatment trials, and SOLIDARITY which used an adaptive platform to evaluate new COVID-19 therapeutics or vaccines in multiple sites and often in multiple countries around the world. The RECOVERY trial, where recruitment is integrated with healthcare through the UKs National Health Service hospital network, has further been described as a pragmatic APT in that therapies are tested for effectiveness in routine healthcare practice. ADTs include seamless phase I/II/III trials aim at efficiency through combining RCT phases in a single protocol, and stepped wedge trials, which may introduce trial arms sequentially. Another ADT is the ring-vaccination cluster-randomised controlled trial design, which was used to randomize rings of individuals in close proximity to index cases for vaccination in West Africa during the 2013-2016 Ebola epidemic.Adaptive designs draw from knowledge gained during the trial to inform and amend subsequent actions pre-defined by the study protocol, for example, amendments in doses or target study populations. For this review, we use the term engagement to include Good Participatory Practice (GPP), Patient and Public Involvement (PPI), consultation, dialogue and information giving/gathering activities, with a range of public, community members and stakeholders, which are used to support, enable and strengthen clinical trials throughout their lifecycle. Guidelines for strong ethical practice for clinical trials, including those conducted during in PHEs, highlight the importance of engagement with communities, patients and publics throughout the conduct of clinical trials and the duty of care that researchers have to ensure that, prior to obtaining signed individual informed consent, participants have been provided with sufficient time and opportunity to consider participation, based on being provided adequate understanding of the research without coercion. It is currently unclear what, if any, specific considerations are provided for engagement and informed consent processes for ADTs and APTs during PHEs.Engagement and informed consent are essential elements of clinical trials, important within their own right, but also mutually supportiveThis rapid review is part of commissioned project from the WHO Ethics and Governance Unit. It aims to summarise guidance, reports and evidence on implementation of engagement or informed consent practices for ADTs and APTs during PHEs. We describe how challenges raised by the PHE context and the need for expeditious evaluation of new/repurposed therapies and vaccines were addressed. Based on this we make suggestions towards further research and consider implications for guidelines related to ADTs and APTs during PHEs.We aimed to rapidly review evidence on engagement and informed consent for ADTs and APTs during PHE to consider what (if any) recommendations can inform practice by asking the following questions:1.   What specific considerations, if any, are given to engagement and informed consent for ADTs and APTs during PHEs in prominent guidance documents?2.   How have stakeholders been engaged for ADTs and APTs during PHEs?3.   How has informed consent been undertaken for ADTs and APTs during PHEs?4.   What is the empirical evidence for the success, pitfalls and outcomes of engagement and informed consent approaches reported for ADTs and APTs during PHEs?. The review protocol is published online atProspero (published on 15/06/2022): registration number CRD42022334170.As is common for rapid reviews, our approach comprises a systematic literature search, screening and selection of studies, a narrative synthesis and dialogue with knowledge usersArticles were included if they met all of the following criteria:•   Articles documenting or describing stakeholder/public/community/ patient engagement/involvement and/or informed consent to support ADTs and APTs during PHEs – which comprise platform, cluster-randomised ring-vaccination, stepped-wedge, pragmatic, seamless multi-phase and adaptive design trials.•   Article type: Primary empirical studies, guidelines policy frameworks, programme reports, conceptual/ discussion papers, commentaries and letters to the editor•   Language: English language.•   Date: any dateArticles were excluded if they met all of the following criteria:•   Articles describing engagement and informed consent for non-ADT/APTs (e.g. RCTs), or trials in non-PHE , or articles reporting on research during PHEs with no content on engagement or informed consent•   Article type: Evidence reviews•   Language: Non-English language.•   Date: no exclusion based on dateOvid Medline,Ovid PsycINFO,Ovid EMBASE,Ovid Global Health, Scopus,Web of Science (All Databases),medRxiv andGoogle Scholar using a structured search strategy. The search strategy was developed in Ovid Medline and refined for each database (seeExtended data). Search terms for four domains were developed based on team experience in the field and drawing on key references. The domains were linked with Boolean operators as follows:We searched the following data bases from their earliest inclusion to July 2022:a)Community engagement and related terms; ORb)Informed consent and related terms; ANDc)); ANDPHEs declared by the WHO Adaptive platform trials . Further, we used the following two strategies to further supplement our search on ADTs and APTs during PHEs. The first was a hand search for protocols, participant information sheet and informed consent form for eight prominent adaptive trials for COVID-19. These trials were selected because they are the largest COVID-19 trials in terms of recruitment. They comprise six adaptive platform trials and two large non-adaptive platform trials for comparison. The second strategy comprised holding discussions with engagement and communications leads for two prominent trials (REMAP-CAP and RECOVERY).Supplementary searches were conducted of relevant core journals, snowball searching to check reference lists of included articles, and recommended sources were requested via expert networks. Grey literature was accessed through relevant websites  screened titles and/or abstracts of retrieved articles for inclusion/exclusion. A second reviewer (AB) independently screened a sample of 10% to identify any systematic screening errors. Full text articles were subsequently reviewed by the principal reviewer, with 10% independently reviewed by a secondary reviewer (IO). Disagreements between the principal and second reviewers were resolved through re-review and discussion.NVIVO14  and thematic approach based on the extraction criteria was used to describe the guidance documents and approaches for engagement and informed consent.The principal reviewer (AD), IO and AB extracted data using pre-defined and piloted data extraction sheets to capture details about the type of article, type of adaptive trial, PHE, engagement and consent approaches, and recommendations. Guidance document identified during the search were grouped together to address question 1. The remaining articles and documents were imported intoAfter removing duplicates, database searches (including Google Scholar) and supplementary (back-and-forth citation) searches yielded 469 articles for title and abstract screening. Sixty-four articles were identified, for full text review and from this 15 were rejected because they did not fit the inclusion criteria. Of the 49 documents included in the review, 10 were classified as ‘guidance documents’ because they presented guidance, a framework or related content related to engagement and/or consent to clinical research during PHEs. The remaining 39 comprised 14 articles on engagement, 10 on informed consent, and 15 discussed both concepts within a context of APTs during PHEs. Considerations for community engagement and informed consent for ADTS and APTS during PHES in included guidance documents., three for COVID-19, four referred to outbreaks or PHEs in general, and two gave general guidance for engagement in clinical research but not specific to PHEs. These documents highlight the value of ADTs or APTs and the importance of community engagement but do not provide specific guidance for engagement practice or informed consent for these novel trial designs in PHEs. Of the 10 guidance documents reviewed, 4 gave specific guidance for informed consent ADT/APTs in PHE contexts., and the extent to which local communities can influence decisions on multi-country standardised master-protocols of the sort used in platform trials during PHE contexts. Despite these constraints, researchers have a moral duty to deliver community and stakeholder engagement throughout the lifecycle of clinical trial. Prominent aims of community engagement include understanding community norms, values and traditions; identifying research priorities/questions informing trial designs; assessing acceptability and feasibility of trial designs; listening and respond to community concerns; and shaping public facing trial documents such as informed consent forms.Guidance documents highlight constraints to engagement in the context of PHE, including the urgency for action, the extent to which lay members of the public can inform complex biomedical research, and including these in funding applications and trial protocols. Community Advisory Boards and/or Patient and Public Involvement (PPI) groups are recommended for gaining diverse perspectives from affected communities and informing trial implementation. Practical guidance on how to work with CABs/ PPI groups included regarding working online with these groups during social distancing measures. No guidance is given specifically on engagement with CABs and PPI groups for APTs during PHEs.Guidance documents highlight the importance of documenting communications or engagement plans. Active CAB engagement can help to monitor community tensions, views and rumours, and advise on how to appropriately respond to them through contributing to culturally sensitive communications. This engagement is aimed at ensuring the trial is responsive to community views and support study accrual and follow-up. Little guidance is offered on engagement specific to the closure of adaptive platform trials in PHE settings. For clinical trials in general, several guidelines recommend stakeholder/community involvement in dissemination of results, and in including stakeholders in the planning and implementation of exit strategies.Throughout the implementation of clinical trials, documenting, monitoring and evaluating engagement activities and outcomes is recommended, for innovative approaches  to be used to support individual informed consent, for individual as well as ‘community gatekeeper’ (e.g. in West African countries) consent for ring vaccination cluster randomised trials. For vaccine trials informed consent should inform participants that they can be unblinded when efficacious vaccines become available. Consent processes and materials should be developed in collaboration with community stakeholders. Guidance is also given on deferred, waived consent and consent by proxy in PHE contexts for all trials. The following constraints to informed consent were highlighted: understanding complex (adaptive) trial designs, differentiating between care and research, and challenges raised by the PHE context, for example, fear, lack of alternative options, disruption, family separation, lack of access to basic resources and services.Guidance provided includes need for Ethics Review Committee capacity strengthening. Public engagement and/or involvement was used for COVID-19 practice, and UK-based COVID-19 trials used Patient and Public Involvement (PPI). One article spoke of Good Participatory Practices (GPP).Of the 29 included articles, 22 were discussion papers reporting expert views, opinions or experiences, 5 were reports of primary empirical research using qualitative (focus groups and interviews) and quantitative methods (public survey), and 2 were trial reports with no empirical data on engagement . The maj and ADTs such as the cluster-randomised ring-vaccination trials were considered more acceptable. Against a backdrop of public distrust of research and researchers, early engagement in West Africa reportedly promoted acceptability and buy-in for trial participation, and the incorporation of community views into decision-making about trial design and implementation. Early community engagement was described as important for informing respectful entry into the community, providing an understanding of traditional practices in disease transmission and changing attitudes, and for appreciating that community health priorities did not always match health challenges explored in trials. Early engagement also informed social and cultural sensitivity, for example, in guiding the need for individual and community consent, and through guiding trial-related consenting, communication and messaging.For trials in West Africa during the 2014-2016 Ebola epidemic, ADTs included cluster randomised ring vaccination and seamless phase I/II/III designs. Health and research stakeholders debated the ethical acceptability of randomisation and use of placebo in RCTs given the high mortality of Ebola disease. Explaining the purpose and procedures of research and providing accurate information was considered important to address rumours and misconceptions which could cause stigma and fear and consequently slow down recruitment. Rumours were described as being based on a lack of accurate information on Ebola and research in the community and, in settings where research was led by foreign researchers, mistrust, based on a history of colonial oppression. In Liberia, for example, research participation was likened to guinea-pig experimentation. Trial information was shared with communities through community meetings and question and answer sessions, engaging leaders including traditional healers and working with nurses to relay messages, and through distributing information materials. Engagement with community members also enabled researchers to select appropriate sites for research clinics to minimise stigma and undertake disease surveillance and trace contacts. Engagement strategies which were reported to strengthen retention of trial participants included ensuring that feedback from the community on rumours informed community engagement messages, that messages were given by hospital nurses, the use of local dialects was used and employing local ‘trackers’ to follow-up with trial participants.Community engagement aimed at raising awareness and understanding of trials was described as being key to strengthening relationships, trust and support for trials. However, other reports and personal communication with trial personnel illustrate multi-stakeholder engagement in APTs. In its trial protocol, PRINCIPLE , a UK national primary care platform trial for investigating repurposed therapies for COVID-19 treatment of older people in the community at high risk of complications, describes that prior to implementation, a panel of seven members of the public from the target recruitment age were offered an opportunity to review trial outcomes and design. The trial team report innovative approaches to inclusive recruitment among socioeconomically deprived and minority ethnic communities. These efforts included targeted efforts to reach diverse audiences in many languages through local and UK national media channels. They also conducted an online public survey to assess public acceptability of using contact data derived from COVID-19 tests to recruit participants.For COVID-19, included articles primarily address APTs delivered in high income countries with well-developed health services and structures . A publi. Given the lack of validated therapies and the urgent need for research at the early stages of the COVID-19 pandemic, clinicians were engaged to facilitate the RECOVERY and SOLIDARITY trials and to have clinical interventions to offer very sick patients guided by protocol. An internal report by the RECOVERY’s communication team describes consultation with the department’s pre-existing Public Advisory Panel about the trial, and the subsequent establishment of a RECOVERY-specific panel. REMAP-CAP and RECOVERY clinical trial teams described regular and extensive communications and interviews with local and mainstream media, where trial principal investigators were often directly involved. PPI groups and advisory panels also contributed to reviewing consent forms and animations, drafting communications to trial participants and advocating for trial participation through several media initiatives (LM Hayes (REMAP-CAP investigator), personal communication, 10th May 2022; and A Whitehouse (RECOVERY communications lead), personal communication, 18th June 2022).High level health and political stakeholder discussions were described as key to the successful and rapid implementation of the RECOVERY, SOLIDARITY, REMAP-CAP and UPMC Remap-Covid COVID-19 therapeutic trials.Empirical studies have highlighted general acceptability of ADTs and APTs among key stakeholder groups. A qualitative study among international health and research staff found support for adaptive/alternative designs and highlighted the importance of trial-specific early engagement to promote collaboration, incorporating community insights into decision-making, reflecting cultural values and norms, encouraging transparency, fostering trust and relationships and addressing rumours and fears. Publics generally supported the need for research during pandemics, a moderate proportion expressed willingness to participate, and publics shared their preferences on different approaches to informed consent. Regarding adaptive designs, participants considered it less important to understand the scientific design considerations and more important to know what the implications of the adaptive designs on their participation, including on risks, benefits and burdens. Qualitative approaches offered members of the public and health stakeholders a greater opportunity to share their views on adaptive trials. Whilst a few participants felt that dropping or introducing new trial arms may convey uncertainty on the part of researchers, members of the public generally supported the need for more streamlined enrolment procedures, consent waivers for very low risk studies, and the use of routinely collected medical data for research purposes. Dimairoet al., in their qualitative study report clear support for adaptive trials from UK health and research stakeholders but that educative sessions would be required to address general unfamiliarity with adaptive methods.Two empirical articles considered a hypothetical Influenza-like pandemic scenario to inform clinical research preparedness for the Platform for European Preparedness Against Re-emerging Epidemics (PREPARE). PREPARE hosted an EU-wide primary care network as well the REMAP-CAP network. These studies were conducted to inform clinical research preparedness regarding public acceptability of APT designs and alternate models of consent that may be better suited to a pandemic context. These studies identified broad support for APTsOf the 25 included articles, 17 were discussion papers reporting expert views, opinions or experiences, 4 were reports of primary empirical research using qualitative (focus groups and interviews) and quantitative methods (public survey), and 4 were trial reports with no empirical data on engagement . The maj. A common challenge reported for RCTs in general and also for therapeutic and vaccine ADTs was the complexity of research concepts and procedures and difficulties communicating these, including among participants with low literacy. Vulnerability, comprehension of trial concepts and therapeutic misconceptions  were described as challenges to autonomous, informed consent. Fostering culturally sensitive consent processes and an understanding of trial procedures through consultation with the community was recommended. Lengthy information sheets and informed consent forms may also present a barrier to full understanding of trial processes and to trial enrolment. The context of public health emergencies, where disruption, fear and confusion are common, was also described as presenting challenges for informed consent and potential for therapeutic misconceptions. Alirol and colleagues described this as ‘situational coercion’, and whilst this may result in increased trial participation, it could potentially lead to long-term public mistrust in research. For some trials, because of the PHE context, ethics review committees granted consent waivers and community members who wished to decline research participation could self-identify through wearing bracelets. Where informed consent was required by a community leader and the individual participant, trial staff used a combination of storyboards and flipcharts in group and individual meetings in an attempt to convey trial information to potential trial participants. Trial participation also raised community hopes of protection from vaccination, and for ring vaccination trials where community members desired immediate in preference to the delayed vaccination, randomisation into immediate or delayed vaccination was done prior to consenting to avoid selection bias.Included articles provided rich descriptions of informed consent challenges and approaches: For the REMAP-CAP trial, written or verbal consent was obtained for all patients or from their surrogates; for the CATCO trial, consent was obtained a priori or deferred; and for the RECOVERY trial, written informed consent was obtained from all patients or from a legal representative if they were too sick.COVID-19 trial reports provided short descriptions of their informed consent approaches. Potential challenges to simplified informed consent processes are unfamiliarity of research stakeholders with APTs and the possibility of therapeutic misconceptions, argued to be heightened in PHE contexts. Some articles call for clarity in informed consent forms and processes as a means of mitigating against therapeutic misconception and Palzzani, in her ethical discourse, highlights the importance of giving complete, non-paternalistic information and verifying the participant’s understanding. For APTs, Palazzani recommends a dynamic consent process emphasising that participants should be informed about; the trial design, its adaptive nature and the possible addition and removal of trial arms based on efficacy and futility respectively, how it differs from traditional trials, and implications for participation. Further, she recommends that re-consenting should inform participants of any new beneficial treatment uncovered since the initial consent was conducted. Formative research for clinical research in PHE from high income countries highlighted that publics prioritised information on the implications of adaptive designs on their participation, including on burdens, risks and benefits of research participation, over theoretical explanations of the study design.A key issue for informed consent to APTs relates to the information that is provided regarding trial-specific adaptations and the optimal level of detail about trial design. In a PHE, streamlined consent processes and simplified consent forms are important for rapid enrolment. One of the information sheets stated that participants would be notified if trial arms were ‘interrupted’ and another stated that“The study looks at its results as it goes and uses the results so that new patients in the study have a better chance of getting better treatments” (Assent Information form acquired from the REMAP-CAP research team). Of the remaining 5 APT information sheets, none provided information that new trial arms could be added. For the COVID-19 (TICO/ACTIV-3), Murrayet al., describe the use of "modular consent forms" with separate appendices for each trial arm giving detailed information to participants about the intervention they were randomised to. This presumably negated the need to give detailed information to participants on all trial interventions, thus shortening the informed consent form. This approach also eased the process of adding new trial arms, given that details for participants were added to the ICF and protocol as an appended module. REMAP-CAP described the adaptive nature of the trial in their public facingwebsite.Of Informed consent information sheets and assent forms (for minors) reviewed for 6 large COVID-19 APTs , five pr as well as COVID-19 trials. For COVID-19 APTs, face-to-face approaches were used for some studies as well as other innovative remote approaches. Remote consent approaches, though logistically challenging to implement, have been recommended to minimise infection, and with ethical approval, trials have embraced this approach both online and by phone. For REMAP-COVID, after screening, patients were introduced to the trial in a one-on-one 'teleconferencing' call with a trial staff member. Declaration of informed consent was then facilitated through a software platform facilitating signing and countersigning. Face-to-face support was also provided for consenting where it was needed and the team anecdotally report that remote consent was most effective when combined with bedside engagement, though they provide no detail of how this was assessed. Questions were raised in the literature about informed consent being administered by ‘treating’ clinicians with limited consent training (as opposed to trained research clinicians) in ‘pragmatic’ trials such as RECOVERY and about the validity of online and remote approaches in confirming with certainty, the identities of consent signatories. While RECOVERY provided mandatoryonline training for clinicians, Caseyet al., suggest that in ‘pragmatic adaptive platform trials’ consent processes could be supported by community consultation and information. Woodset al., provide a detailed description and comparison of different approaches of obtaining written consent whilst minimising the risk of infection through face-to-face, taking a photo of the form and usingDocusign software. The review has highlighted several innovations in modifications of consent processes to address PHE challenges, but no study described systematic methods to explore their effectiveness and / or the specific challenges related to APTs in this context.In PHEs there is a need to minimise and mitigate against infection during the informed consent process. Mitigating strategies, such as social distancing, isolation, and the need for research staff to wear PPE were described as barriers to communication during the consenting process for Ebola. For incapacitated patients, deferred consent, or consent by proxy by family members or legal representatives has been recommended and approved by ethics committees, with a further recommendation that patients can later be consented during therapeutic windows. Monachet al., describing the range in trial candidates, from RCTs exploring different doses of drugs with known safety profiles and off-label drugs with a well-described safety profile, to investigational drugs with unknown safety profiles, recommends a nuanced approach to consent. For low risk trial candidates, waivers (opt-out) they argue, can be considered, whilst opt-in oral and written consent is more appropriate for higher risk trial candidates with unknown safety profiles. Specific issues as they relate to APTs were not considered in these articles.Optimising recruitment and informed consent processes to enable rapid recruitment is a common theme to discussion articles on COVID-19 and on GHEs in general particularly for low risk studies involving repurposed drugs with good safety profilesIn this review of community engagement and informed consent for ADTs and APTs in PHEs, we found that current guidance documents place strong emphasis on the importance of community involvement in conducting trials, but little specific guidance on what this means in practice for ADTs and APTs. Based on reported experiences of conducting clinical trials in public health emergency contexts, important lessons have been learned regarding how community engagement and informed consent processes can be optimised. There is a gap in consistent reporting of these experiences and lessons, in particular as they relate to the novel aspects of trial design and the implication for participants. Based on this review, we highlight key considerations for best practice in community engagement and informed consent relevant to ADTs and APTs for PHEs which may helpfully be included in future guidance.. This demonstrates respect for populations, aims at nurturing trust in research and acknowledges that the perception of social value of research can vary between local stakeholders and research stakeholders, particularly in international research collaborations. The review has identified a range of approaches that reflect good practice for GPP/ engagement in alternative design trials for Ebola and also for multi-site, multi-country COVID-19 trials delivered according to a master trial protocol. However, we found limited description of pre-trial engagement that could meaningfully impact study design or implementation. The exception was qualitative work that considered public views of APTs and consent for pandemic relevant research that was conducted for PREPARE, a clinical research preparedness infrastructure and APT protocols that explicitly mentioned use of CABs and PPI panels (Re: PRINCIPLE). In a public health emergency the time to engage publics in design aspects is exceptionally tight. To enable pre-trial engagement in these contexts, strong engagement and communications practices need to be built into the infrastructure for these research platforms. Further, ground work for building CABs and public engagement links should be established between emergency events for rapid activation during readiness for research response. This work can and should include building a suite of public-facing communications tools that can be adapted to explain different aspects of ADTs or APTs relevant to PHEs. Capacity development materials for a wide range of stakeholders, including CABs or PPI groups would also be of value.Pre-trial engagement is important for gaining understanding of community norms, values and traditions which might have a bearing on the way in which a trial may be implemented, assessing trial acceptability and feasibility by the community, and drawing community insights to inform design selection. The dynamic nature of APTs delivered in PHEs mean that engagement regarding acceptability and social value should continue throughout the trial’s lifetime. First, adaptive trials, by design, aim at validating therapies/vaccines throughout their implementation. Thus, if they are successful, as they proceed new alternatives for addressing the health problem emerge. That social value, “a necessary component of acceptability”, is related to the availability of alternatives to address the problem, and implies that as validated alternative therapies/vaccines emerge, the social value of the trial changes correspondingly. Secondly, given the longer timescales of adaptive trials , the emergence of efficacious vaccines and dynamic biological factors including virulence, endemicity and heard immunity change over the trial’s lifetime, and therefore, correspondingly, so does the disease’s impact on populations. So, while continuous engagement throughout conventional RCTs may be important to re-assess acceptability and social value as new therapies may emerge and the disease evolves, arguably this is more important for adaptive trials because of their longer timeframes within a dynamic epidemic context, and because continuous identification of new therapies and vaccines as trials progress is at the heart of their design. Considerations for guidelines to inform engagement during the implementation of adaptive platform trials might include: how to engage communities when an arm is stopped for futility or efficacy; engaging communities for the introduction of new arms; and re-assessing social value as validated therapies/vaccines emerge.GPP-EP guidelines emphasise the importance of public acceptability of trials and appropriate ways of sharing trial results, in order to maintain trust and respectful ongoing partnerships, the review yielded no descriptions of how this was done for any adaptive or alternative trial.While several guidance documents underscore the importance of planning respectful exit strategies through consultation, what level of detail on the adaptive/alternative nature of trials should informed consent forms convey; secondly, how effective are remote and online processes in achieving informed consent and ensuring the validity of participant identity; and lastly, for pragmatic APTs, how can modified consent processes be improved and ‘treating’ clinicians be supported further to administer informed consent which minimise therapeutic misconceptions? Palazzani emphasises that participants should be informed about the adaptive nature of the trial and research among European publics highlighted their preference to understand the implications of the adaptive nature of the design for them regarding the risks, burdens and benefits. Balancing the need to avoid PHE contexts precipitating research exceptionalism through enabling reduced quality processes, including in informed consent, with the need for the rapid ethical evaluation of therapies and vaccines, requires careful navigation. Casey and colleagues argue that tight regulation would have prevented the implementation of RECOVERY in the USA, but that the protocolisation of research integrated into care in the UK minimised the wide clinical use of unproven therapies like hydroxychloroquine. On one hand, over-complicated information materials, consent forms and processes can impede research, while therapeutic misconception, on the other, can lead to long-term mistrust in research.We highlight three important questions about informed consent forms and processes for ADTs/APTs in PHE contexts. Firstly, given the greater complexity of ADTs/APTs. However, the review revealed no empirical articles on consent for COVID-19 adaptive vaccine trials. Questions of relevance to these trials pertain to participation in trials during national roll-out of approved vaccines, and include: a) how have (or should) consent forms conveyed potential restrictions to participant freedom, for example, to travel or work, when they opt for vaccine trial participation instead of nationally provided vaccines; b) how do consent processes address the tension between encouraging uptake of nationally provided vaccines and recruiting trial participants; and c) how should consent processes and ICF content change with the evolving public health regulations in different countries.In the context of placebo controlled COVID-19 vaccine APTs, Singh and colleagues’ guidelines specify that when authorized vaccines become available, participants should be offered an opportunity for unblinding and vaccination with the authorized vaccine or the investigational vaccine if proven to be efficacious. Given this large number, the scarcity of engagement reports in the literature is surprising. There is a need for norms and guidance related to minimum standards for reporting of GPP-EP practices. In particular, reporting ways in which trial adaptations were communicated with trial participants and at which junctures would help to inform best practice in this work. Addressing this gap would further enable researchers to be accountable to their peers and broader publics in describing how public acceptability of research was determined; how public views were taken into account; how public input was incorporated into trial design and implementation; and if some views could not be incorporated, what were the reasons for the decisions taken.We identified some examples of good practice based on published reports and personal communication with those leading prominent APTs during COVID-19. However, there were many other platform trials delivered during the pandemic - one review identified 58 COVID-19 platform trials by May 2021Our review revealed novel approaches to informed consent aimed at broadening participation whilst minimising transmission, but no empirical studies explored what content informed consent forms adaptive platform trials should contain, nor the effectiveness of the novel delivery and consent training approaches. There was also no empirical evidence on the effectiveness of online or remote consent approaches and support materials . Further research is needed aimed at strengthening these areas. Given the significant challenges of conducting research on research, particularly during emergency events, we recommend that pragmatic, rapid operational approaches to evaluation are adopted and included in trial protocols. This planning is needed well in advance of emergency events.To our knowledge, this is the first review that considers the practice of community engagement and informed consent for novel trials conducted during PHEs. This review is timely given the rich learning that has happened through unprecedented investment in and delivery of clinical research during COVID-19. Further learning could have been gained by expanding our review to include oncology and critical illness clinical research, where adaptive trials and relevant aspects such as consent waiver/ deferral are more commonly encountered. We maintained our focus on PHE contexts, however, due to their specific features, including the urgency for rapid research responses and the unavailability of existing known medical countermeasures during these events. Our search was comprehensive and covered peer-reviewed and grey literature. We also drew on consultations and information for COVID-19 trials. Further information to inform key outcomes to this review may have been gathered through a greater focus on grey literature and talking to research teams. Given time constraints to conduct this work, we selected a rapid review methodology. One member of the research team identified included citations and extracted data, with 10% of the data double coded. This may have introduced error in the research process. Further, limiting our inclusions to English language papers only may have introduced bias in reporting.COVID-19 witnessed a step change in the delivery of clinical research during PHEs. These advances led to identification of effective medical countermeasures to save lives during the pandemic. Prominent clinical trials such as RECOVERY, SOLIDARITY and REMAP-CAP received widespread media coverage and investigators and their teams played significant and active roles in engaging the public with research. These breakthroughs demonstrate the added value of novel trial designs that enable rapid and responsive clinical research integrated into health emergency response. It is vital that lessons learned from these advances inform guidance for rapid research in future events, including for strong and consistent best practice for community engagement and informed consent.In our review, we identified a gap in current guidance documents to steer best practice for community engagement and informed consent for ADT and APTs during PHEs. We also found some description and evaluation of practice that can inform future guidance. To advance best practice and be accountable to collaborators and communities, trial teams must report on their engagement and informed consent practices for ADTs and APT in PHEs. This is a compelling review focused on identifying existing guidance, reports and evidence related to informed consent and community engagement for alternative design trials (ADTs) and adaptive platform trials (APTs) during public health emergencies (PHEs), mainly in relation to COVID-19 and the Western Africa Ebola epidemic. The authors conducted a meticulous and comprehensive interrogation of 8 electronic databases as well as grey literature to answer this question. Based on the 49 articles that met inclusion criteria, the authors found that while current PHE clinical research guidance documents appreciate the significance of ADTs and APTs in addition to the importance of community involvement in conducting trials, there unfortunately remains a lack of specific guidance as to what this means in practice for both these forms of trials. Another key finding from the rapid review involved the existing gap in reporting of experiences associated with conducting clinical trials during PHEs and how these experiences relate to novel aspects of trial design, particularly in terms of community engagement and informed consent processes. It follows that each of these findings are crucial especially as one considers aspects of best practice for optimising large-scale testing of interventions during PHEs based on lessons learned from previous trials. Overall, this is a well conducted and timely study (with clearly identified limitations) that draws attention to a pressing public health challenge, especially as emerging pandemics/epidemics spread faster and further.Are the rationale for, and objectives of, the Systematic Review clearly stated?YesIs the statistical analysis and its interpretation appropriate?Not applicableAre sufficient details of the methods and analysis provided to allow replication by others?YesAre the conclusions drawn adequately supported by the results presented in the review?YesReviewer Expertise:Global Health and Translational PsychiatryI confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard. At the behest of the WHO Ethics and Governance Unit and to inform potential practice improvements, the authors systematically reviewed literature concerning community engagement and informed consent in relation to Alternative Design Trials (ADTs) and Adaptive Platforms Trials (APTs) - clinical research approaches intended to generate evidence in support of appropriate responses to public health emergencies (PHEs) when time is of the essence. The authors have made clear their purpose: to identify what is known about engagement and informed consent practice in ADT/APT contexts and how clinical trials might improve going forward. They have also outlined in sufficient detail - that would allow for replicability - their methods for conducting the literature review.First, whereas prominent guidance documents argue for the importance of incorporating community engagement and informed consent for ADTs and APTs during PHEs, these reports provide limited instruction in best practice.Second, as input for filling this gap, recent clinical trials during PHEs - including COVID-19 and 2014-2016 Ebola - reveal a range of challenges and opportunities that emerge when investigators involve the people and communities directly affected by the research as collaborators rather than as mere study subjects.Lastly, the ad hoc nature in which researchers tend to report on engagement and informed consent processes suggests the need for greater documentation, transparency, and shared benchmarks regarding the social/relational aspects to ADTs and APTs, on par with the more technical/analytical dimensions. The authors have provided information on engagement and informed consent processes at such a granular level that it would be of immediate benefit to individuals planning ADTs/APTs should a PHE unfold tomorrow , and they have successfully catalogued concrete considerations with which clinical researchers and their partners could begin developing, over a longer term, more comprehensive guidance on best practices going forward. Three major, well supported observations emerge from the literature review:Are the rationale for, and objectives of, the Systematic Review clearly stated?YesIs the statistical analysis and its interpretation appropriate?Not applicableAre sufficient details of the methods and analysis provided to allow replication by others?YesAre the conclusions drawn adequately supported by the results presented in the review?YesReviewer Expertise:A medical anthropologist, I have worked as a researcher and policy analyst/advisor in the field of public health emergency management for over 20 years, with a focus on community resilience, community engagement, whole community approaches to disaster management, behaviorally realistic emergency planning, and crisis and emergency risk communication.I confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard.


Graft-versus-host disease (GvHD) remains one of the major complications following allogeneic haematopoietic stem cell transplantation . GvHD can occur in almost every tissue, with the skin, liver, and intestines being the mainly affected organs. T cells are implicated in initiating GvHD. T cells identify a broad range of antigens and mediate the immune response through receptors on their surfaces . The composition of TCRs within a T cell population defines the TCR repertoire of an individual, and this repertoire represents exposure to self and non-self proteins. Monitoring the changes in the TCR repertoire using TCR sequencing can provide an indication of the dynamics of a T cell population. Monitoring the frequency and specificities of specific TCR clonotypes longitudinally in different conditions and specimens  can provide insights into factors modulating immune reactions following allogeneic transplantation and will help to understand the underlying mechanisms mediating GvHD. This review provides insights into current studies of the TCR repertoire in GvHD and potential future clinical implications of TCR sequencing. Allogeneic haematopoietic stem cell transplantation  is a well-established treatment procedure for haematologic diseases such as high-risk acute leukaemia. Allo-HSCT involves the transfer of haematopoietic stem cells (HSCs) obtained from related or unrelated donors to patients. Donor HSC engraftment and the transferred donor immune system contribute to the eradication of remaining malignant cells. This desired immune reaction is the graft-versus-leukaemia effect . HoweverThe general concept is that GvHD is initiated by the activation of donor alloreactive T cells, which recognise host-specific histocompatibility antigens presented on host antigen-presenting cells. The activation of donor alloreactive T cells leads to a clonal expansion of selected T cells and to the attraction of other proinflammatory effector cells –6. There19 . Di. Di32]. + and CD8+ cell TCR repertoire than in patients without aGvHD and mild grade 1 aGvHD  and 8 blood samples from 8 transplanted patients with acute GvHD were analysed. The TCR repertoire was more skewed in the biopsy samples than in the samples from peripheral blood. In skin biopsies from one patient, two TCR clonotypes represented 98% of the TCR repertoire of all T cells infiltrating the skin lesions . The finSo far, bone marrow samples of GvHD patients have not been analysed. To our knowledge, only one study included samples taken from bone marrow aspirates in the context of GvHD including only a sample collected from one donor prior to transplantation and not from the affected patient .Generally, the findings suggest that monitoring the TCR repertoires of peripheral blood is at best an indirect measure of what may be happening at the site of GvHD. Nevertheless, studies remain few, and comprehensive longitudinal studies are needed. Longitudinal immune profiling can help to identify changes in the immune receptor repertoire prior to important clinical events, like the onset of acute or chronic GvHD and beginning resistance to therapies. It can also provide insights into clinically permissive mismatches of minor and major histocompatibility antigens . In addiWith the emergence of TCR sequencing as a more broadly applicable technique, several major key questions will need to be addressed by future studies to define its clinical potential in GvHD Table . MeaningA second major challenge is the identification of shared GvHD mediating clonotypes that allow to predict GvHD. Other than the diversity, TCR sequencing data can be used to trace individual clonotypes across time or different tissue samples in an individual. It can also be used to identify overlapping clonotypes across individuals. While it is still early to say if there are any common clonotypes or target epitopes between individuals in GvHD-affected patients, single-cell paired chain TCR sequencing, as a more advanced technique, combined with longitudinal tracking of expanded clonotypes, may help to first identify recurring TCRs and then to investigate their target antigens. Single-cell TCR sequencing gives access to paired TCR information and thus to the whole TCR . AdditioWhile there are multiple studies of peripheral blood TCR repertoires in GvHD patients following HSCT, the majority of these studies have limitations that make it difficult to draw final conclusions. First, many studies are based on a limited number of patients and second, there are no existing gold standards for AIRRseq so far. Studies are therefore difficult to compare, due to these differences in input for sequencing, sequencing method, analysis tools used and normalisations performed during analysis. There is a need to develop standards for AIRRseq studies that allow for the comparison of different AIRRseq data, and the AIRR Community has been working towards setting these benchmarks , 27, 28.TCR sequencing has the potential to improve our understanding of GvHD, but standardised protocols are required before this technique can be implemented into clinical routine. Standardised approaches, together with prospective longitudinal study protocols combining assessments of both tissue and blood, should provide insight into targets and the potential use of TCR repertoires to monitor patients to better understand and treat post-HSCT GvHD and thus have potential to address key scientific and clinical questions in the field of GvHD.


Differentiating healthy from pathological aging trajectories is extremely timely, as the global population faces an inversion where older adults will soon outnumber younger 5:1. Many cognitive functions  decline with age, a process that can begin as early as midlife, and which predicts subsequent diagnosis with dementia. Although dementia is a devastating and costly diagnosis, there remains limited evidence for medications, therapies, and devices that improve cognition or attenuate the transition into dementia. There is an urgent need to intervene early in neurodegenerative processes leading to dementia . In this targeted review and commentary, we highlight transcutaneous Vagus Nerve Stimulation (tVNS) as a neurostimulation method with unique opportunities for applications in diseases of aging, reviewing recent literature, feasibility of use with remote data collection methods/telehealth, as well as limitations and conflicts in the literature. In particular, small sample sizes, uneven age distributions of participants, lack of standardized protocols, and oversampling of non-representative groups  limit our understanding of the potential of this method. We offer recommendations for how to improve representativeness, statistical power, and generalizability of tVNS research by integrating remote data collection techniques. The worldwide population is facing an inversion where older people will soon outnumber younger . DiseaseTranscutaneous vagus nerve stimulation was originally proposed as an alternative to the invasive stimulation of the vagus (iVNS) applied in treatment of epilepsy and other neurological conditions . It workThe advantages of tVNS are fairly straightforward: it is non-invasive, is generally regarded as safe with relatively few contraindications ; it is lIn this targeted review and commentary, we summarize the literature on cognitive effects of tVNS in healthy young and old adults. Several recent review papers address different aspects of this topic  yet noneLike many studies conducted in academic environments, the majority of tVNS studies on cognition in healthy participants are in college-aged samples (aka the “college sophomore problem”). A recent meta-analysis examining 19 studies with 718 healthy young (18–30 years of age) participants reported that whereas tVNS exhibited a small and positive impacts on overall cognition, its largest effects were on the executive function domain . In the In the domain of executive functions, the impact of tVNS stimulation has yielded mixed results. Studying cognitive control, many studies in this domain used a combination of behavioral and biomarker or EEG recordings to determine the effect of tVNS on cognition . Some stIn the field of attention, two studies investigated the impact of tVNS on auditory selective attention and the Locus Coeruleus-Norepinephrine/Noradrenaline (LC-NE/NA) system through auditory oddball paradigms. One found that tVNS increased P3 amplitude and reduced P3 latency in EEG recordings, with no change in behavioral performance . AnotherThree recent studies have examined the effects of tVNS on working memory and verbal order memory in healthy individuals , as wellIn contrast, a third study found that tVNS did not affect verbal memory performance in healthy volunteers . ParticiThese studies suggest that tVNS may have potential in enhancing working memory performance under sleep deprivation stress, as well as verbal order memory accuracy in phonologically similar words, but it may not have a significant effect on verbal memory in healthy individuals. The conflicting results from these studies emphasizes a need for further research to fully understand the potential of tVNS in improving memory or in being used as a useful intervention for improving cognitive function in sleep-deprived individuals.Emotional cognition refers to the individual’s self-awareness of their emotional state or that of others and is an indicator of emotion regulation. Several recent papers found positive effects of tVNS on emotional cognition. One study found that tVNS enhanced emotion regulation, measured as decreased reactivity to emotional photos and improved cognitive reappraisal . AnotherSeveral translational studies have also established a mixed body of evidence for the effect of tVNS on negative emotions. One study looked at high worriers and their ability to redirect attention away from emotional facial stimuli . They foStudies on fear conditioning and extinction found no effects of tVNS on extinction rates compared to sham in a prepared learning paradigm, as measured through physiological markers such as skin conductance and fear potentiated startle responses . These rAging is associated with many changes in brain structure and function including a decrease in neurotransmitter secretion which is evident for both GABA and NE . StimulaOne of the most studied domains in the field of age-related cognitive decline is memory. The neural underpinnings of memory abilities are scattered throughout the brain, spanning cortical and subcortical regions. It is suggested that tVNS enhances memory abilities through enhancing GABA, and by enhancement of long-term potentiation in the hippocampus leading to increased memory consolidation . Memory Importantly, studies in older adults try to characterize individual differences that would help learn who would benefit most from tVNS. Physiological factors include sympathetic prevalence ; GABA/NEIn our targeted review, between 2018 and 2022, 5 studies assessing the effects of tVNS on 292 older adults (mean age ranging between 45 and 67) were published. All five compared cognitive abilities between stimulation and sham. Three studies examined healthy community-dwelling older adults; one study examined the effect of tVNS in older adults with epilepsy; and one on individuals with MCI. The main findings are described below.In a large randomized controlled trial, Two studies examined the effect of tVNS on memory abilities. One study directly assessed the effect of tVNS on prosocial behavior in older adults with epilepsy . In thisNone of the studies published between 2018 and 2022 examined emotional cognition in older adults, however, two papers examined the effects of tVNS on quality of life (QoL) and sleep, reporting inconsistent findings. In a series of three studies examining 88 older adults, Understanding the mechanisms and factors that determine efficacy of tVNS requires multiple studies and large samples. This is both because of the wide potential parameter space  and the potential heterogeneity in response of individuals to tVNS . The pacWe propose that rather than resume studying convenience samples of students as restrictions are relaxed, researchers should leverage tools for remote data collection to study tVNS effects on cognition using more diverse and larger samples. Here we outline how some of the main limitations of previous work can be addressed using remote data collection. Interestingly, of the 30 studies reviewed here, none of those conducted in young adults were carried out remotely but two out of the 5 studies conducted on older adults employed remote data collection . AlthougConducting in-person studies is costly from a staffing and logistics standpoint. It requires one or more staff to be present, a testing room, and preparation of study materials . A 1-h data collection session can easily take several more hours of preparation and cleanup. Conversely, remote data collection enables lower staff burden and fewer logistical hurdles. As an example, imagine a scenario where a research coordinator consents the participant using encrypted email or PHI-compliant browser-based methods see . They scThe ultimate benefit of this approach is increased power to detect effects in a shorter time frame and with lower cost. Many studies calculate the minimum power needed to detect effects based on previous studies, which is a standard practice; however, when the previous studies are primarily in non-representatively homogenous samples  this means that true variance is likely underestimated. This is especially critical when studying tVNS effects in groups with a clinical diagnosis, particularly diagnoses such as dementia or depression which are highly heterogeneous. It is possible that many negative results are actually type II error  arising from lack of power. Tele-research methods can help address this by reducing logistical overhead and increasing accessibility for research participants.The recent tVNS literature reviewed here showed a variety of effects on cognition, consistent with a recent meta-analysis . Both poA strength of this work is the diversity of cognitive effects measured, ranging from memory , executiSeveral negative results were reported, some within the same study and population, as done in an elegant cross over design by One way to answer this question is utilizing repeated measures within-subjects designs involving using a cognitive task battery of multiple (3 +) tasks rather than a single task. With a large sample size, tasks with fewer items (such as the short form of the Delay Discounting measure) may still show sensitivity to effects. The advantage to having more tasks with fewer trials administered with sham and active stimulation within-subject is to better determine whether individual strengths and weaknesses of participants govern which domain of cognition is most impacted by tVNS. A proposed study design is pictured in The parameter space of tVNS refers to the combination of protocol, stimulation site, and testing paradigm  that is sensitive to the relevant individual differences in neurological or psychiatric state. A recent consensus paper on tVNS reporting standards found that there is wide variation in the protocol parameters used to administer tVNS . BrieflyRemoving the requirement of in-person participation increases both accessibility and generalizability of research. Accessibility refers to the degree with which anyone who wants to participate in research is able to. Normally, factors such as distance from the study location reduce the opportunities for those in rural or otherwise isolated or marginalized communities to participate. Opening participation to anyone with a computer and internet access and basic computer literacy massively increases the potential participant pool and facilitates more representative sampling than relying on student samples, or the community local to a university or hospital.Generalizability refers to the degree to which inferences tested in a sample of participants apply to the broader population from which they were drawn. Typically, tVNS studies suffer from low generalizability because of the use of convenience samples– e.g., testing only healthy undergraduate students, or older adults with specific medical conditions such as MCI . The resThere is also such a thing as too much variability–for example, age ranges that are very wide in a sample that is not adequately powered to account for such a large age range. For example, grouping 60-year-olds together with 80-year-olds , and defWhereas the study of the neuroscience of aging is gaining more attention, most studies examining change over time are still cross sectional, and those that do include repeated measures include a small number of time points . Using such designs limits our ability to differentiate within- from between-person variance and address questions related to changes over time . This beThere are several potential limitations to remote research protocols, including less guarantee of participant engagement or investment, potentially lowering data quality and increasing dropout. Ways to potentially mitigate this include providing appropriate compensation, including attention checks and breaks, and keeping study sessions as brief as possible. Technical difficulties  can also hinder research by delaying or preventing accurate data collection. This can be partially mitigated by screening participants’ technical environment in advance and providing real time support over email to troubleshoot issues and minimize data loss. Limited access to technology can also be an impediment, such as for elderly participants; this can be addressed by providing participants with tablet computers and access to training on how to use it, when recruiting populations with limited technological proficiency. Finally, some neurobiological variables cannot be easily measured remotely . However, increasingly some forms of biological measurement do have remote capabilities . Such advancements allow for a more extensive collection of cognitive-biological data.A recent body of literature on both healthy younger and older adults suggest that tVNS can modulate cognition. However, there remain many unresolved questions regarding which cognitive paradigms are reliably sensitive to detect stimulation-related changes in behavior; how and when to customize stimulation parameters and protocols; and how to account for individual differences in stimulation responsiveness (such as aging related changes), to name only a few. We propose that using remote research methods would improve the scalability, generalizability, parameter space refinement, and ability to draw causal inferences from longitudinal data, of tVNS research.SN and CM-F contributed to the conception, design of the study, and wrote the manuscript. AY organized the database and wrote sections of the manuscript. All authors contributed to manuscript revision, read, and approved the submitted version.


Most of the body and wings of mature adults of most species of dustywings (Neuroptera: Coniopterygidae) are covered with a superficial coating of pale waxy particles. This white-to-gray waxy ‘dust’—from which the common name of the family derives—is secreted onto the outside of the body by wax glands that open on the head, thorax, and abdomen. Each gland opening produces a pair of tiny, curled wax filaments, which eventually break off as minute wax rings. The rings are subsequently distributed across most of the body and wing surfaces by the insect’s legs. Within the order Neuroptera, coniopterygids are unique in this form and use of waxy compounds, and it constitutes a distinctive shared feature of species in the subfamilies Aleurop-teryginae and Coniopteryginae (wax glands are apparently absent in the subfamily Brucheiserinae). Despite the interesting adaptive features that this system implies, wax production and its associated morphological features and behaviors are poorly known and rarely studied. In this paper, we examine the comparative morphology of wax gland head ultrastructure in 2 subfamilies, 9 genera, and 28 species of dustywings—the most diverse sample of dustywing taxa examined to date for this morphological feature. We report similarities and differences among the examined taxa and identify ultrastructural characters useful for taxonomic and phylogenetic differentiation at higher levels within the family.Aleuropteryx, Coniopteryx, Coniocompsa, Conwentzia, Cryptoscenea, Heteroconis, Semidalis, Spiloconis, and Thecosemidalis), and 28 species of Palearctic and Oriental dustywings collected from a variety of sites across China. We propose a new descriptive terminology to concisely characterize the major elements of gland head ultrastructure and then identify similarities and differences among them and provide detailed descriptions of the wax gland heads found in each of the nine genera examined. Based on the range of taxa examined, we propose hypotheses about the functional morphology of some of the ultrastructural elements examined and relate them to wax ring formation in dustywings. An identification key for the examined genera based on gland head morphology is also presented.In the largest comparative study of coniopterygid wax gland head morphology to date, we used scanning electron microscopy to illustrate the ultrastructure of gland heads found in 2 subfamilies (Aleuropteryginae and Coniopteryginae), 5 tribes , 9 genera ( Many different groups of insects utilize exocrine glands to deposit waxy compounds onto the outer surfaces of their cuticles. This form of wax production has been studied in some detail in certain taxa of many insect orders, e.g., scale insects, aphids, planthoppers, psyllids, and whiteflies in the Hemiptera ,3,4,5,6;The family Coniopterygidae (Insecta: Neuroptera) is a group of small predaceous insects that feed principally on small arthropods such as scale insects, aphids, whiteflies, and mites. They can be used in biological control and are potentially important economic insects ,18,19,20Adult coniopterygids are commonly called ‘dustywings’ because the bodies and wings of most species are covered with a superficial layer of pale, waxy, extracuticular particles. The waxes in this case are produced by glands that deposit curled wax filaments loosely onto the cuticle, which are then spread across the surface of the body by movement of the legs. The biological function of these particles is not well understood, but Gebhardt et al.  suggesteAleuropteryx, Coniopteryx, Coniocompsa*, Conwentzia, Cryptoscenea*, Heteroconis*, Semidalis, Spiloconis*, and Thecosemidalis*), and 28 species of Palearctic and Oriental dustywings. We identify new characters and character states that may be useful in future taxonomic and phylogenetic studies of the Coniopterygidae and propose hypotheses about the possible functions of some of the novel structures found.The purpose of the present work is to expand our knowledge of wax gland head morphology by examining a broader range of coniopterygid taxa than have been studied previously. Here, we illustrate (using SEM), describe (using a newly proposed terminology), and compare the ultrastructure of exocrine wax gland heads found in 2 subfamilies , 9 genera   and then observed and imaged using a low-vacuum tabletop scanning electron microscope (Regulus 8100) at 10 kV.Although we have not conducted comparative tests with other preservation, drying, and imaging techniques, it is likely that some of the techniques used here—particularly air-drying specimens from ethanol—have produced artifacts in the imaged surfaces that are not present in the cuticle of living or recently killed specimens. This pertains particularly to the development of irregular shrinkage ridges in the membranous cuticle surrounding each wax gland head, and the skewing of microtrichia and other structures borne on those surfaces. While most or all of the central region of the wax gland head appears to be sufficiently well sclerotized  to resist distortion from air drying effects, such effects are clearly present toward the outer margins of many of the gland heads imaged in this work, where the rigid parts of the head grade laterally into surrounding membranous tissue. These drying effects are individual to each specimen imaged and particularly affect the apparent shape, depth, and extent of the pella and possibly the orientations of structures borne on it . As drying effects are expected to manifest especially in areas of weakly sclerotized cuticles, images of teneral specimens could display more widespread effects across the broader surface of a gland head. We are cognizant of these effects and took them into consideration in the development of our descriptions of gland head structures. The interpretations of gland head morphology contained in this work are based on the SEM images included herein, together with numerous other SEM images that were produced as part of the research for this work but are not published here.To facilitate the description and discussion of the primary ultrastructural features found in coniopterygid wax gland heads, we propose and define below a new terminology that we believe to be suitable for these purposes as no such terminology currently exists. We base most of the new terms on classical Greek and Latin words to encourage their international adoption. We use the phrase ‘wax gland head’ (short form: ‘gland head’) to encompass the morphological region centered on a wax gland foramen complex and extending laterally in all directions around this complex out to and including any other modifications of the cuticle that surround the foramen complex  and which differentiate that cuticle from the ‘normal’ cuticle that surrounds the gland head . We assume here that the cuticle of the wax gland head region is sufficiently rigid  to resist distortion by drying (or other effects) out to its transition zone to the membranous cuticle at the outer margin of the pella. Thus, we assume (unless otherwise noted) that the microstructures displayed in the SEMs are accurate representations of wax gland head structure in mature adults. We use the term ‘opposite’ to refer to multiple structures that lie along  one horizontal line drawn through the center point of the embola; the structures may lie along the line on the same side or on different sides of the embola. The term ‘alternate’ is used to refer to multiple structures that lie along  two different horizontal lines drawn orthogonally through the center point of the embola.In the examined species of Coniopteryginae, a typical gland head consists of the following primary substructures:foramen, a hole or opening) of the wax gland duct is the narrow, irregularly annuloid space that forms the external opening of the wax gland duct, and through which secreted wax must pass to reach the outer surface of the insect’s cuticle ((1) The ‘foramen’  is the morphological structure that partially blocks the center of the wax gland duct, diverting secreted wax compounds laterally as they exit the gland duct through the foramen ((2) The ‘embola’  is the morphological structure that surrounds the upper end of the wax gland duct and bears the embola ((3) The ‘foramen sheath’  The phrase ‘foramen complex’ may be used to denote the combined foramen sheath + foramen + embola.cupula, a small tub or vat; adj. = cupular) is a concave (viewed from above) lateral flaring that subtends and surrounds the base of the foramen complex ((5) The ‘cupula’  is the columnar stalk below the cupula that supports the cupula + foramen complex and raises it above the floor of the pella  The ‘pedicel’  The phrase ‘central complex’ may be used to denote the combined foramen complex + cupula + pedicel.pella, a cup or bowl; adj. = pellar) is (in Coniopteryginae) the concave depression within which the central complex sits and from the base of which the central complex arises  distinctively located and modified microtrichia. These flank one side of the margin of the cupula  and arise from the pella adjacent to the pedicellar ridges. We refer to these microtrichia as ‘guard microtrichia’ ((8) The ‘pella’  The foramen slit appears somewhat wider than in Coniopteryginae due to the more loosely fitted margins of the adjacent embola and inner wall of the foramen sheath B, for.Spiloconis ((2) The general outline of the embola is rectangularly quadrate (not cruciform) B, emb. Iiloconis D, emb, oAleuropteryx; Cryptoscenea and Spiloconis; Coniocompsa and Heteroconis; Aleuropteryx and the two marginal concavities in Cryptoscenea and Spiloconis lie alternate to the foramen sheath inner wall ridges. Two of the six concavities in Coniocompsa and Heteroconis lie alternate to the foramen sheath inner wall ridges, while the other four flank the rounded lobes that lie opposite the foramen sheath inner wall ridges.(3) The foramen sheath B, fs is (4) The foramen complex (foramen sheath + foramen + embola) is inset within, and distinctly separated from, the margin of the adjacent tumular platform by a deep circular cleft, which closely surrounds the base of the outer wall of the sheath B,D, ccl.tumulus, a mound or hillock; adj. = tumular), or tumular platform, is the low disk-shaped mound within the center of which the foramen complex is set  The ‘tumulus’ . Where multiple congeneric species have been examined, the descriptions incorporate observations on all examined species.For definitions of morphological terms, see “Aleuropteryx ; foramen sheath: outline subcircular, relatively thin walled, inner face two-ridged (opposite the embola notches), distal margin extending slightly beyond the top of embola and notched with one distinct concavity ; cupula: absent; pedicel: absent; tumulus: bearing one or more non-serrate carinae opposite each foramen sheath ridge; carinae irregular but arched and concentric around the foramen complex; carinae absent or obsolete alternate to the foramen sheath ridges; serrate carinae and recumbent papillae absent; pella: a depressed ring surrounding and delimiting the tumular platform; wax guide microtrichia present, two (opposite foramen sheath ridges), not morphologically differentiated from the ‘normal’ microtrichia; guard microtrichia absent.ropteryx B—embola:Heteroconis ; foramen sheath: outline subcircular, relatively thin walled, inner face two-ridged (opposite the embola notches), distal margin extending well beyond the top of the embola and strongly crenate (six-lobed); cupula: absent; pedicel: absent; tumulus: bearing one serrate carina opposite each foramen sheath ridge; carinae somewhat irregular but arched and concentric around the foramen complex; carinae absent alternate to the foramen sheath ridges, with this surface sometimes bearing short simple ridges; outer faces of serrate carinae flanked by a row of recumbent papillae; secondary arched carinae may be present between the serrate carinae and the foramen sheath; pella: a depressed ring surrounding and delimiting the tumular platform; wax guide microtrichia present, two (opposite foramen sheath ridges), morphologically differentiated from ‘normal’ microtrichia ; guard microtrichia absent.eroconis E,F—embolConiocompsa ; foramen sheath: outline subcircular, relatively thin walled, inner face two-ridged (opposite embola notches), distal margin extending well beyond the top of the embola and strongly crenate (6-lobed); cupula: absent; pedicel: absent; tumulus: bearing one or more non-serrate carinae opposite each foramen sheath ridge; carinae irregular but arched and concentric around foramen complex; carinae absent or obsolete alternate to the foramen sheath ridges; serrate carinae and recumbent papillae absent; pella: a depressed ring surrounding and delimiting the tumular platform; wax guide microtrichia present, two (opposite foramen sheath ridges), morphologically differentiated from ‘normal’ microtrichia ; guard microtrichia absent.iocompsa B—embola:Cryptoscenea ; foramen sheath: outline subcircular, relatively thin walled, inner face two-ridged (opposite the embola notches), distal margin extending slightly beyond the top of the embola and notched with two distinct concavities ; cupula: absent; pedicel: absent; tumulus: bearing one or more non-serrate carinae (opposite the sheath ridges); carinae irregular but arched and concentric around the foramen complex; carinae absent or obsolete alternate to the sheath ridges; serrate carinae and recumbent papillae absent; pella: a depressed ring surrounding and delimiting the tumular platform; wax guide microtrichia present, two (opposite foramen sheath ridges), not morphologically differentiated from ‘normal’ microtrichia; guard microtrichia absent.toscenea D—embola:Spiloconis , side/margin two-notched (opposite foramen sheath ridges); foramen sheath: outline subcircular, relatively thin walled, inner face two-ridged (opposite embola notches), distal margin extending well beyond the top of the embola and notched with two distinct concavities , bottom of one concavity sometimes bearing a small tooth  not morphologically differentiated from ‘normal’ microtrichia; guard microtrichia absent.iloconis D—embola:ll tooth D; cupulaConiopteryx ; foramen sheath: outline subcircular, relatively thick walled, inner face four-ridged (opposite embola notches), distal margin weakly crenate to truncate; cupula: present; outline distinctly oval (due to upturned cupular lobes); four cupular cusps present, with the cusps arranged in two pairs, one pair on margin of each cupular lobe, gap centers between the cusp pairs aligned with midline of the short arms of the embola, cusps angular to short protruding; pedicel: present, short, longitudinal ridges absent, deep circular cleft at the pedicel–pella junction absent; pella: a deep, more-or-less hemispherical depression; wax guide microtrichia present, two (opposite cupular cusp gaps), base broad and flattened, flattened and attenuate distally, often inflexed; guard microtrichia absent.iopteryx A—embola:Thecosemidalis ; foramen sheath: outline subcircular, relatively thick walled, inner face four-ridged (opposite embola notches), distal margin weakly crenate to truncate; cupula: present; outline oval (due to upturned cupular lobes); cupular lobes rounded, lacking marginal cusps; pedicel: present, short, longitudinal ridges absent, base surrounded by a deep circular cleft at the insertion within the pella; pella: a deep, more-or-less hemispherical depression; wax guide microtrichia present, two (opposite cupular lobes), form not differentiated from ‘normal’ microtrichia; guard microtrichia absent.emidalis —embola: Conwentzia ; foramen sheath: outline subcircular, relatively thick walled, inner face four-ridged (opposite embola notches), distal margin weakly crenate to truncate; cupula: present; outline subcircular ; four cupular cusps present, arranged in two pairs, one pair on the margin of each cupular lobe, the gap centers between the cusp pairs opposite the midline of the short arms of the embola, cusps protruded as short acute processes; pedicel: present, short, one face with two longitudinal ridges present, deep circular cleft at the pedicel–pella junction absent; pella: a moderately deep rounded depression; wax guide microtrichia present, two (opposite cupular cusp gaps), form not differentiated from ‘normal’ microtrichia; guard microtrichia present, three , arising from the floor of the pella adjacent to, and separated by, the pellar ends of pedicellar ridges, form: base circular, broadened and flattened medially, distally narrowed and acuminate.nwentzia C—embola:Semidalis ; foramen sheath: outline subcircular, relatively thick walled, inner face four-ridged (opposite embola notches), distal margin weakly crenate to truncate; cupula: present; outline oval to subcircular (depending on upturn angle of cupular lobes); four marginal cusps present, arranged in pairs, one pair on the margin of each cupular lobe, the gap centers between the cusp pairs opposite the midline of the short arms of the embola, cusps simply angular, or as short acute processes, or protruded as distinct, parallel-sided processes; pedicel: present, short, longitudinal ridges absent, deep circular cleft at the pedicel–pella junction absent; pella: a deep, more-or-less hemispherical depression; wax guide microtrichia present, two (opposite the cupular cusp gaps), spatulate, with a broad flattened base, a medial constriction, and a flat, ovoid, distal expansion; guard microtrichia absent.emidalis A—embola:Coniopteryx, Conwentzia, and Semidalis—most genera currently documented for wax gland head morphology are still known from only a single species. The ‘genus level’ generality of all of the traits utilized in this preliminary key requires further verification across a broader range of taxa.To highlight the most easily observable differentiating traits found in dustywing abdominal wax gland heads we present below a preliminary key to the nine coniopterygid genera that have been documented for this character complex to date. The key is based primarily on work undertaken for the present paper, but also incorporates observations from other published illustrations of coniopterygid wax gland heads. Although multiple species have been examined for several genera—i.e., Key to genera of Coniopterygidae based on abdominal wax gland head traits1Cupula: present  21′Cupula: absent  52(1)Guard microtrichia: absent Cupula: cupular cusps present Wax guide microtrichia: evenly attenuate, apex acuminate  Foramen sheath: distal margin uni- or bilabiate Foramen sheath: distal margin bilabiate  (nations) D76′Foramen sheath: distal margin unilabiate  (ination) FAleuropteryx7(6)Tumulus: arched carinae non-serrate, recumbent papillae absent Tumulus: arched carinae non-serrate, recumbent papillae absent , all congeneric species exhibited very similar gland head structures, but differences were apparent among the genera (as noted above). This observation supports the hypothesis that gland head structure may be broadly conserved within coniopterygid genera as they are currently defined. But only 9 of the 23 extant coniopterygid genera (39%) have been documented to date for gland head morphology, and multiple species have been documented for only 4 of those genera . Because of the observed similarity in gland head structure among the congeneric species, we focused the descriptive and comparative aspects of this work on the higher taxonomic levels of genus and subfamily. The new terminological and descriptive framework erected here for wax gland heads should facilitate the integration of additional taxa into future and more comprehensive surveys and assessments of this character complex.Although minor differences in gland head structure may exist in some congeneric species, the preparation techniques and the conspecific specimen sample sizes used in this work were insufficient (and not designed) to differentiate between intra- and interspecific variation in these traits. Within all three genera for which we examined multiple species , so it is still unclear how well the identified characters and states will stand up to rigorous comparative examination of additional taxa. Many of the characters/states that are of taxonomic interest will also prove to be of phylogenetic interest. However, as the phylogeny of the Coniopterygidae is currently not well resolved, it is difficult to be certain about polarities among the states of many of the gland head characters identified here; so we resist making phylogenetic statements in this work.Thecosemidalis pedicel homologous or analogous? If homologous, do they provide any insights into the origins of the central complex and tumular platform? (4) How do the individual elements of the wax gland head function together to produce the wax rings that are so characteristic of adult coniopterygids, and does that functionality vary among different lineages of dustywings?Several outstanding questions that particularly merit future investigation in a more rigorous phylogenetic context include: (1) is the absence of wax glands in Brucheiserinae plesiomorphic or a derived secondary loss within the Coniopterygidae? (2) The central complex and tumular platform are dominant characteristics of the subfamilies Coniopteryginae and Aleuropteryginae, respectively; what are their precursors and how did they evolve? (3) Are the deep circular clefts that surround the bases of the aleuropterygine foramen complex and the The expanded array of coniopterygid taxa examined in this work clearly identifies wax gland heads as a state-rich character complex that contain traits of both taxonomic value and phylogenetic interest. Our ability to develop a preliminary genus-level key based solely on gland head traits demonstrates that many of the traits in this complex correlate with current generic and/or subfamilial divisions of the Coniopterygidae and suggests that the complex merits additional study as a potential source of additional novel traits of taxonomic value. The higher-level taxonomic value  of many of the identified gland head traits suggests that they may also be of considerable antiquity and of significant phylogenetic interest, but our ability to interpret the traits in a phylogenetic context is hampered by the relative immaturity of the phylogenetic studies currently available for the family. Our extended documentation of the diverse array of fixed elements within the wax gland head character complex provides an additional data set from which to begin the development of hypotheses concerning the formation of the highly distinctive wax rings produced by dustywings.