Impact Triad, a bilingual multilevel intervention developed by our community‐based participatory research partnership to reduce STIs and HIV and address social determinants of health  among young GBMSM and transgender women of colour.Sexually transmitted infections (STIs) and human immunodeficiency virus (HIV) disproportionately affect young gay, bisexual and other men who have sex with men (GBMSM) and transgender women of colour. We explored the experiences of community‐based peer navigators (‘Community Navigators’) who participated in Impact Triad. Themes were identified through constant comparison.Individual in‐depth interviews were conducted with 15 Community Navigators who participated in Impact Triad  and (3) lessons learned for future interventions .Community Navigators' mean age was 31.4 years. Seven were self‐identified as African American/Black, 5 as Latine, 2 as multiracial/multiethnic, 1 as Asian American, 10 as cisgender men, 4 as transgender women and 1 as gender nonbinary. Thirteen themes emerged in three domains: (1) key aspects of the Community Navigator role ; (2) experiences implementing Impact Triad that can guide future efforts to address STI/HIV disparities and social determinants of health through community‐based peer navigation.Interviews identified important learnings about serving as Community Navigators and implementing Throughout this intervention trial, our partnership worked collaboratively with a study‐specific community advisory board (CAB) comprised primarily of young GBMSM and transgender women of colour. Members of this CAB participated in all aspects of the trial including trial design, intervention development, recruitment and retention strategies, data collection and analysis, interpretation of findings and dissemination. STI and HIV rates are highest among young persons,1.2The issues contributing to STI and HIV disparities experienced by young GBMSM and transgender women of colour are complex. Social determinants that influence the health of these communities include individual, sociocultural, environmental, system and policy factors. For example, GBMSM and transgender women, particularly those who are persons of colour, are more likely than heterosexual and cisgender counterparts to experience limited access to employment and education and face high rates of discrimination in a range of settings including health care, workplaces and schools.1.3CBPR, which engages community members and community organizations as partners in all phases of the research process,1.4Impact Triad, a bilingual (English and Spanish), multilevel intervention designed to reduce STIs and HIV and improve social determinants of health among young GBMSM and transgender women of colour in a high‐incidence community within the US South.CARS is a unique initiative of the US CDC that promotes the use of community engagement to increase STI and HIV prevention, screening and treatment and address related social determinants of health within communities disproportionately affected by STIs and HIV. The initiative focuses on identifying and implementing innovative community‐driven strategies that leverage community assets.1.5Impact Triad, we qualitatively explored the experiences of community‐based peer navigators within the intervention, using individual in‐depth interviews.A better understanding of the implementation of community‐based peer navigation interventions is essential to strengthening future STI and HIV prevention efforts among communities facing health disparities. As a component of the process evaluation of 22.1Impact Triad intervention trial was conducted by the North Carolina Community Research Partnership. This partnership is a long‐standing CBPR partnership comprised of community members, community organization and clinic representatives and academic researchers.The Impact Triad intervention, the details of which are described elsewhere.We first conducted a community‐driven needs assessment to identify and better understand needs and priorities related to STI and HIV prevention, screening and treatment and social determinants of health among young GBMSM and transgender women of colour locally, as well as existing community assets. Through this process, the CAB and CBPR partnership prioritized four social determinants of health as particularly salient for young GBMSM and transgender women of colour and their risk for STIs and HIV: employment, education, social support and discrimination. Based on needs assessment findings, the CAB and CBPR partnership developed intervention strategies to reduce STIs and HIV and improve these social determinants of health and integrated these strategies into the Impact Triad includes three primary multilevel strategies: community‐based peer navigation, use of social media and antidiscrimination trainings for community organization staff. The intervention involved training young GBMSM and transgender women of colour as community‐based peer navigators, known as ‘Community Navigators’ in English and ‘Navegantes Comunitarios’ in Spanish, to carry out helping activities with members of their social networks in the community within the context of their daily lives. In addition to one‐on‐one and group‐level in‐person helping to share information and resources related to STI and HIV prevention, screening and treatment and prioritized social determinants of health, Community Navigators created and updated intervention‐related social media accounts  and used their own social media accounts for messaging with social network members. Community Navigators were also involved in the development of brief online video testimonials designed to raise consciousness among community organizations about the challenges and barriers young GBMSM and transgender women of colour face when accessing services related to STIs and HIV and social determinants of health and ways to facilitate access (https://www.youtube.com/channel/UCd7gOGhBerT0w1CTq5BwMcQ).Briefly, 2.2Impact Triad Community Navigators. To be eligible to serve as a Community Navigator, a participant was 18 years of age or older; self‐identified as a person of colour; self‐identified as a man or as a transgender woman; reported sex with men and provided informed consent.Fifteen young GBMSM and transgender women of colour identified as informal leaders among their communities were recruited and trained to serve as Impact Triad intervention logo and intervention materials  to carry out their work within their social networks and communities of young GBMSM and transgender women of colour. Community Navigators worked informally and formally with members of their social networks for 12 months and met monthly as a group with one another and with members of the CBPR partnership in convenient locations within trusted community organizations to plan, coordinate and evaluate their activities.Community Navigators completed four 4‐h training sessions, in two cohorts of seven to eight Community Navigators each. They were trained to serve as (1) health advisors to provide information to social network members to meet needs and priorities related to STI and HIV prevention , screening and treatment, as well as social determinants of health , offering guidance on where and how to access available services; (2) opinion leaders to bolster healthy and reframe unhealthy norms and expectations related to STIs and HIV or social determinants of health  and (3) community advocates to bring the voices of young GBMSM and transgender women of colour to local community organizations by sharing feedback for improvement based on the perspectives of social network members. Community Navigators were trained to use an adapted version of the ‘ask‐advise‐assist’ model,Community Navigators were provided a $50 stipend for each training session and each month of the 12‐month intervention implementation. They also were provided $50 per month to compensate for transportation costs.2.3Impact Triad Community Navigators. Standardized interview guides were developed in English and Spanish with careful consideration of wording, sequence and content to explore experiences with the intervention and current issues affecting the health of young GBMSM and transgender women of colour. Abbreviated sample items from the guide are outlined in Table After the conclusion of intervention implementation, individual in‐depth interviews were conducted with all 15 n = 12) and Spanish (n = 3). Interviews averaged 45 min in length. All Community Navigators provided written consent and were compensated $50 for participating in an interview. Human subject protection and oversight were provided by the Wake Forest University School of Medicine Institutional Review Board.Because of the COVID‐19 pandemic, interviews were conducted via telephone. Two trained bilingual members of our CBPR partnership conducted the interviews in English  lessons learned for future interventions.Thirteen themes emerged from the interviews and were organized into three domains: (1) key aspects of the Community Navigator role, (2) experiences implementing the 3.2.1Impact Triad. These themes, along with selected quotations, are presented in Table Community Navigators identified several important aspects of fulfilling their role within Impact Triad intervention because of the opportunity to gain knowledge to share within their social networks and because they recognized the importance of both promoting sexual health and addressing social determinants that can make it difficult for community members to take care of their health. Community Navigators also appreciated that they made a genuine impact, which furthered their desire to continue being leaders within their social networks and communities. They felt pride in their roles as Community Navigators, saw themselves as fulfilling a need for social support within their communities, enjoyed building leadership skills that could potentially create opportunities for future careers  and demonstrated a desire to continue utilizing the knowledge and training they received postintervention.Community Navigators expressed that they valued serving as leaders and as resources to address social determinants of health within their communities. Among the Community Navigators, there was a common sense of intrinsic motivation to engage, be involved with and help their communities of identity—LGBTQ communities and communities of colour. Community Navigators reported that they were drawn to the Impact Triad. These connections led to increased initial levels of rapport with community members within Community Navigators' social networks, facilitated the process of recruiting social network members to participate in the intervention and were helpful for further building trust to have conversations about a wide array of health‐related topics.Community Navigators emphasized that being members of the communities in which they worked was fundamental to trust building and successful intervention implementation. Community Navigators had shared experiences and identities and felt a sense of belonging with others in their communities and were known and seen as leaders in their communities before becoming involved with Community Navigators reported that having official titles and roles that were linked to well‐known and well‐respected institutions , and having received formal training through these institutions, provided a sense of reassurance that helped to facilitate relationship building with members of their communities. As a consequence, Navigators felt more confident in their knowledge about sexual health and social determinants and perceived that they were more trusted to talk with others within the community about sensitive health topics. In addition, Community Navigators highlighted the importance of having a badge indicating their role in the intervention and emphasized that receiving a stipend for their time furthered their sense of legitimacy and validated the work they performed to assist their communities.Community Navigators shared that being connected to the other Community Navigators across gender identities, sexual orientations and racial/ethnic identities increased a sense of belonging, resource sharing, creativity and problem solving. Community Navigators expressed that monthly meetings with the other Community Navigators and intervention coordinators were a time and place for growth because they brought together diverse experiences and perspectives and provided an opportunity to exchange ideas with one another, as well as discuss challenges and ways to overcome them. Navigators noted that it was valuable to know that other Community Navigators, including those with different gender identities, sexual orientations and/or racial/ethnic identities than their own, had found themselves in similar situations and to learn from one another. Thus, these conversations fostered an environment where Community Navigators felt welcome to express themselves and their ideas about promoting health within their communities through engagement and education. While each Community Navigator carried out helping activities independently with their social network members, the Community Navigators also worked as a team by providing social support to one another. These connections took place both in meetings and more informally in one‐on‐one interactions outside of meetings  and continued after implementation ended.Impact Triad.Community Navigators reported hoping to continue their roles to improve sexual health and social determinants within their communities after intervention implementation officially ended. Many expressed a conviction to share the knowledge they had gained through the intervention, stressing that their social network members and other community members continued to come to them for information. Community Navigators reported continuing to engage in helping activities such as condom distribution and disseminating information through social media because the need within their communities persisted and because it felt natural to continue to draw on the training and resources provided by 3.2.2Impact Triad. These themes and selected quotations are presented in Table Another set of themes related to Community Navigators' experiences implementing Community Navigators shared that they had identified effective and innovative strategies to engage community members. Community Navigators utilized various strategies to reach the individuals within their social networks. At the beginning of intervention implementation, Community Navigators focused their recruitment efforts on social network members who they perceived as being more vulnerable or at risk and as needing social support and emphasized to these social network members the benefits of their participation. Through this process, Community Navigators were able to reach a broad range of individuals, including engaging nongay identifying MSM by building trust to overcome concerns about having their sexual behaviours exposed. In addition, Community Navigators used creative ways to share information about health and local resources through social media posts and by making in‐person events and gatherings as welcoming and comfortable environments as possible for social network members.Community Navigators reported meeting social network members' prioritized needs by educating and supporting them to access and use local resources. Community Navigators noted that their role provided them with insight that allowed them to pinpoint needs and priorities within the community. Community Navigators were able to effectively link social network members with the resources they needed, which helped social network members stay engaged in the intervention. Through communication and interaction with social network members, Community Navigators identified and filled knowledge gaps and guided social network members to resources that would meet their needs related to social determinants  and sexual health .Community Navigators emphasized that communicating about sexual health and addressing stigma and misinformation were difficult but overcome by building and nurturing trust. Many of the Community Navigators reported initial challenges in communication with social network members related to sensitive topics due to stigma and discomfort. Though Community Navigators had their social network members' trust more generally, they had to work on building further trust specifically around sexual health. To surpass this barrier, Community Navigators fostered an open and safe environment and worked to normalize talking about sexual health. To make social network members feel more comfortable, Community Navigators eased into conversations about sexual health, first starting with a topic that was less sensitive or emphasizing common experiences that the Community Navigators and social network members shared, including feelings of stigma. Social network members opened up to the Community Navigators and to one another over time, and conversations about sexual health happened more naturally over the course of intervention implementation as Community Navigators continued to promote a sense of community within their social networks.Community Navigators described using social media to complement personal interaction to further facilitate dissemination of information and support. Community Navigators reported that personal interactions were an important part of the intervention because they provided a more personable approach, particularly during the early stages of implementation and when recruiting individuals within their social networks to participate. Social media was also an essential tool utilized by Community Navigators throughout the course of the intervention in addition to these personal interactions, and after the COVID‐19 pandemic began many Community Navigators adapted their interactions to rely solely on social media. Community Navigators posted on their social media accounts about resources or community events, and these posts benefited not only their immediate social network but also extended their reach to their social network members' larger networks and individuals whom they would not have interacted with otherwise. Expanding reach in these ways had a dual impact on Community Navigators' work by strengthening both their confidence as Community Navigators and their rapport within the community. In addition, Community Navigators noted other advantages of social media, including that it was a direct and instant form of communication between Community Navigators and social network members and, in some cases, made conversations about sensitive topics easier and more comfortable than in face‐to‐face communication.Community Navigators considered important intervention successes to include increased awareness of prevalent health disparities and increased knowledge about sexual health and about resources to address disparities. Community Navigators expressed that, among their social networks, there was a general lack of awareness of how young GBMSM and transgender women of colour, and particularly those in the US South, were disproportionately affected by STIs and HIV and by social determinants such as unemployment. When educating social network members about these disparities many Community Navigators reported witnessing a ‘light bulb’ moment where social network members internalized information about sexual health and local employment and education resources.Impact Triad, Community Navigators and members of their social networks came to understand sexual health as also involving screening for STIs and HIV, access to treatment and other prevention strategies such as PrEP.Community Navigators also successfully promoted broader definitions of sexual health, noting that within their communities sexual health had typically been equated with condom use or abstinence only. Through participating in Community Navigators reported that the COVID‐19 pandemic hindered implementation and impacted Community Navigators in various ways. Because of the need for physical distancing, social media became the primary way the Community Navigators communicated with their social network members. Through social media Community Navigators maintained contact with their social networks, but Community Navigators expressed that members of their social networks felt isolated from one another. The connectedness Community Navigators fostered within their social network groups was reduced by the pandemic. In‐person interactions were postponed, and the closeness and ‘spirit’ or morale of the groups were negatively affected. Furthermore, Community Navigators faced additional challenges teaching social network members about certain sexual health topics such as how to correctly use condoms when they could not carry out these activities in person. However, Community Navigators were resilient and adapted quickly to utilizing social media to continue to maintain relationships with participants and engage and teach them.3.2.3Finally, Community Navigators highlighted learnings to inform future similar interventions. Related themes and selected quotations are presented in Table Impact Triad intervention should be expanded to facilitate access to a wider range of resources. Throughout intervention implementation, Community Navigators heard from their social network members that it would be beneficial to receive information about additional resources related to social determinants of health, such as transportation, food insecurity, financial literacy, housing and substance use, which also contribute to sexual risk. Other barriers such as access to health care more generally, including insurance coverage and mental health care, were also suggested for inclusion as outcomes in future iterations of Impact Triad. Community Navigators noted that young GBMSM and transgender women of colour in different geographical areas experienced different needs, highlighting the importance of expanding the resources shared through the Impact Triad intervention. Community Navigators also suggested potentially adapting the intervention to reach broader communities, such as non‐LGBTQ communities, or to meet the unique needs of specific subgroups such as bisexual men.Community Navigators reported that the Community Navigators indicated that future trainings should include activities to develop a more in‐depth and diverse skillset, including more practice communicating about sensitive topics and promoting healthy coping strategies. Community Navigators shared that their training prepared them well for interacting within their social networks but that they experienced challenges in a few areas. Community Navigators felt they would benefit from more skill‐building, particularly through role‐playing, that emphasized effective ways to talk about sensitive and complex topics, such as how to engage in dialogue around a recent positive HIV diagnosis. Many Community Navigators noted that they found it difficult to have conversations about mental health, healthy coping strategies and how to overcome fear among social network members to access services when needed. They noted that more training would be useful to build their skills and increase their self‐efficacy to have these difficult conversations.Impact Triad should foster more interaction among Community Navigators. Community Navigators reported that they formed a support network with each other during the monthly meetings with one another, during which they shared ideas, challenges and successes. Many expressed a desire for a greater frequency of these meetings to discuss barriers and receive feedback. To further increase interaction and learning opportunities among Community Navigators, Community Navigators suggested that in future iterations of the intervention, former Community Navigators could be invited to mentor newer Community Navigators and share their experiences, thus expanding the network of trained Community Navigators and building on real‐life experiences of serving as Community Navigators.Community Navigators expressed that future iterations of 4Impact Triad Community Navigators both highlighted the ways that intersecting factors magnify health risks among GBMSM and transgender women of colour and illustrated the strengths of the intervention in raising awareness and disseminating information pertaining to sexual health and social determinants of health. One of the greatest contributing factors to the success of the Impact Triad intervention was the Community Navigators' ability to forge and nurture connections and relationships with members of their social networks and then build on this foundation to discuss sensitive topics with confidence and increase awareness, knowledge and use of local resources among these social network members. This finding aligns with existing literature that points to the potential of community‐based peer navigators to reach marginalized communities affected by health disparities and to connect community members to services because community‐based peer navigators understand community needs and strengths on a personal level and reflect the ways that members of their communities communicate and interact.Analysis of in‐depth interviews with the Impact Triad was the Community Navigators' flexibility and ability to pivot and adapt to the unprecedented circumstances brought by the onset of the COVID‐19 pandemic. Initially, Community Navigators' interactions with members of their social networks included in‐person communication, which suddenly became no longer possible during the early phases of the pandemic. Adapting to the pandemic led to increased integration and utilization of social media platforms to cultivate and strengthen relationships. Shifting to an entirely virtual implementation of Impact Triad modified previous perceptions of how to connect with individuals and was consistent with documented changes in the ways in which networks provide social support in the context of COVID‐19 with shifts away from physical interaction and toward the use of technology.Another factor playing a role in the success of Impact Triad intervention to seek to further address and improve the quality of life among young GBMSM and transgender women of colour. A common thread across Community Navigators' experiences involved the intricate ways that interconnected social determinants impact health. To have a more profound impact, future efforts can expand the domains of resources and education provided by Community Navigators by incorporating into Community Navigator training information on how to address needs such as housing, food insecurity, transportation and others, in addition to employment, education, social support and discrimination. Furthermore, leveraging the experiences of existing Community Navigators to provide mentorship and support to future Community Navigators can lead to an increasingly cohesive group dynamic and greater community capacity. For example, future Community Navigator trainings and monthly meetings could include components in which Community Navigators from previous cohorts are present to share their experiences, offer ‘tips’, and answer questions from new Community Navigators.Interviews also identified implications for future iterations of the 4.1Impact Triad intervention, Community Navigators may have felt inclined to describe Impact Triad and their experiences with the intervention in ways that were positive and less comfortable sharing constructive criticism or difficulties they had faced as part of Impact Triad. We tried to mitigate this possibility and encourage open and honest responses by ensuring confidentiality and emphasizing that there were no right or wrong answers and that Community Navigators were experts in their own experiences. Furthermore, interviews were conducted by CBPR partnership members who were not directly responsible for training and supporting the Community Navigators.It is possible that social desirability bias could have influenced Community Navigators' responses to interview items. Given that interview data were collected and analysed by members of our CBPR partnership that had developed and implemented the 5Impact Triad and provided information to guide future efforts to address STI and HIV disparities and critical social determinants of health through community‐based peer navigation. Further research is warranted given that community‐based peer navigation remains an understudied yet promising approach to health promotion and disease prevention among communities and populations experiencing health disparities.These interviews identified important learnings about serving as Community Navigators and implementing The authors declare no conflict of interest.


More than 70% of new HIV diagnoses in the United States were among men who have sex with men (MSM) in 2019. Pre‐exposure prophylaxis (PrEP) is a transformative innovation for reducing human immunodeficiency virus (HIV) infections. Structural stigma against sexual minorities, including in the form of state‐level policies, may affect PrEP implementation. We evaluated whether lower structural stigma reflected by earlier year of state same‐sex marriage legalization was associated with increased male PrEP prescriptions and male PrEP‐to‐need ratio (PnR), a ratio of PrEP prescriptions to new HIV diagnoses.We used 2012−2019 AIDSVu data on male PrEP prescriptions and male PnR in each US state and year. We used generalized estimating equations to evaluate the relationship between the timing of implementing state same‐sex marriage policies and the outcomes of male PrEP prescriptions per 100,000 people and the male PnR. We adjusted for calendar year, Medicaid expansion and the political party of the governor in each state.State implementation of same‐sex marriage policies in earlier, relative to later, periods was associated with increases in the rate of male PrEP prescriptions and in the male PnR. Specifically, implementing state same‐sex marriage policies between 2004 and 2011 and between 2012 and 2013 were each associated with greater rates of male PrEP prescriptions relative to implementing same‐sex marriage policies between 2014 and 2015. Implementing state same‐sex marriage policies between 2004 and 2011 as well as between 2012 and 2013 were both significantly associated with a greater male PnR relative to implementing same‐sex marriage policies between 2014 and 2015. By 2019, the difference in male PrEP prescriptions was 137.9 (97.3−175.5) per 100,000 in states that implemented same‐sex marriage in 2004−2011 and 27.2 (23.3−30.5) per 100,000 in states that implemented same‐sex marriage from 2012 to 2013, relative to states that implemented same‐sex marriage in 2014−2015.Earlier implementation of state same‐sex marriage policies was associated with greater rates of male PrEP prescriptions. Reducing state‐level structural stigma may improve HIV prevention among MSM in the United States. More than 70% of new HIV acquisitions occur among men who have sex with men (MSM) , and theWith a transformative finding in 2010—that pre‐exposure prophylaxis (PrEP) was more than 90% effective for preventing HIV among those who adhered to it —there isUnequal rights for sexual minorities are a form of discrimination and structural stigma, defined as “the societal‐level conditions, cultural norms, and institutional policies and practices that constrain opportunities, resources and wellbeing” . FundameStructural stigma may affect PrEP awareness and use through several mechanisms. Sexual minority stigma could drive the extent to which states and cities invested in campaigns and programmes to promote PrEP among MSM and among healthcare providers. State‐level policies could also shape healthcare provider attitudes and behaviours, such as comfort asking patients about sexual orientation , 19 and We evaluated whether there was an association between the timing of state same‐sex marriage policies and male PrEP prescriptions in the United States. We focused on same‐sex marriage policies as a particularly salient change in sexual minority rights, with earlier adoption potentially reflecting and perpetuating lower state‐level structural stigma , 25. Our22.1The objective of the analysis was to estimate the association between the period of state same‐sex marriage policies and male PrEP prescription rates in the United States.2.2We hypothesized that states that implemented same‐sex marriage in earlier periods would scale up male PrEP prescriptions faster than states that implemented same‐sex marriage policies in later periods.2.3We used de‐identified AIDSVu data on the number of PrEP prescriptions per 100,000 males aged 13 or over in each state, from 2012 to 2019. AIDSVu PrEP data are the most comprehensive data available on PrEP prescriptions from a commercially available sample that includes more than 54,000 pharmacies, 1500 hospitals, 800 outpatient facilities, 80,000 physician practices and some clinics in academic settings. The dataset excludes entities that do not share their data, such as closed healthcare systems like Kaiser Permanente. The publicly available dataset was produced by excluding tenofovir disoproxil fumarate/emtricitabine prescriptions for HIV treatment, post‐exposure prophylaxis and hepatitis B based on medical claims. The dataset includes state‐specific upweighting of PrEP prescriptions to account for underestimates due to misclassified prescriptions. The dataset does not contain information on the race, ethnicity, sexual orientation or gender identity of people who receive prescriptions.We also used the AIDSVu dataset to estimate the male PrEP‐to‐need ratio (PnR), defined as the number of male PrEP users divided by new HIV diagnoses among males 13 and older in each state and year by sex , 29. We We linked AIDSVu datasets on male PrEP prescriptions and male PnR to the American Community Survey 1‐year population estimates of males aged 13 and older, using the estimates pertinent to each calendar year. To derive male sexual minority population estimates, we multiplied estimates of the male population aged 13 and older by the University of California, Los Angeles Williams Institute data on the adult lesbian, gay, bisexual and transgender population in each US state .We limited the samples for all analyses to people who indicated male sex. While PrEP is indicated for any males who have sex partners of unknown HIV status and do not always use condoms or who are people who inject drugs (PWID) , prior a2.4The main exposure of interest was the year of state same‐sex marriage policy implementation, ranging from 2004 in Massachusetts to 2015, when the US Supreme Court made same‐sex marriage legal in all 50 states. We considered states to have implemented same‐sex marriage laws if same‐sex marriage was legal by the first of January in each year. We grouped states into those that implemented same‐sex marriage between 2004 and 2011, in 2012–2013, and in 2014–2015 to ensure there were at least five states in each group. We used binary indicators for each of the two earlier time periods (before 2012 and 2012–2013) relative to the latter time period (2014 and 2015).2.5The main outcome of interest was the rate of male PrEP use per 100,000 males 13 or older in each state and year. A secondary outcome of interest was the male PnR.2.6States that implemented same‐sex marriage in earlier periods may systematically differ politically and with respect to other policies from states that implemented same‐sex marriage in later periods. To account for political differences that may also affect commitment to PrEP implementation, we adjusted for a binary indicator for having a Democratic governor, relative to a Republican or Independent governor, based on National Council of State Legislators data. To account for health policies that could affect PrEP prescription rates, we adjusted for state Medicaid expansion as a binary indicator based on Kaiser Family Foundation data . We incl2.7We first described the timing of same‐sex marriage policy by state. We estimated and plotted population‐weighted means of male PrEP prescriptions per 100,000 people and male PnRs in each calendar year, by period of state same‐sex marriage implementation.To evaluate the relationship between period of state same‐sex marriage policy implementation and male PrEP prescriptions, we used generalized estimating equations (GEE) negative binomial regression models to account for repeated observations of states with a log link, and log population offset. To account for the size of the sexual minority population in each state, we conducted a secondary analysis of the relationship between the period of state same‐sex marriage policy implementation and male PrEP prescriptions through GEE negative binomial regression with a log link and with a modification in which the log population offset was an estimate of the male sexual minority population. To evaluate the relationship between period of state same‐sex marriage policy implementation and male PnR, we used GEE linear regression models to account for repeated observations of states. In both analyses, we adjusted for calendar year, Medicaid expansion and Democratic governors. We weighted regressions by the population of each state. We used Stata 15.0 to conduct all analyses.To further describe the male PnR in 2019, we plotted the male PrEP prescription rate by new male HIV diagnoses for each state in 2019. We also conducted linear regression analyses of the relationship between new 2019 HIV diagnoses and the male PrEP prescription rate separately for each period in which same‐sex marriage was implemented, adjusting for Medicaid expansion and whether the governor was a Democrat.In a sensitivity analysis, we repeated the main analysis with 2015 as a separate period to investigate whether there were differences between states that implemented same‐sex marriage in 2014 and 2015, given that states that did not implement same‐sex marriage until the nationwide Supreme Court decision may have differed from those that implemented same‐sex marriage prior to the Supreme Court ruling.This analysis was considered non‐human subjects research by the Boston University Institutional Review Board. Because only de‐identified data were used and the research was considered non‐human subjects research, there was no consent procedure.3We observed each of 50 US states over 8 years from 2012 to 2019, summing to a total of 400 state‐years in the analysis. There were seven states that implemented same‐sex marriage before 2012, 10 states that implemented same‐sex marriage in 2012 and 2013, and 33 states that implemented same‐sex marriage in 2014 and 2015  and between 2012 and 2013  were each associated with greater rates of male PrEP prescriptions relative to implementing same‐sex marriage policies between 2014 and 2015 , while implementing state same‐sex marriage policies between 2004 and 2011  and between 2012 and 2013  remained associated with greater rates of male PrEP prescriptions relative to implementing same‐sex marriage policies in 2015 Table . In the 4We studied the association between two transformative developments for sexual minority men in the United States—equal marriage rights and the introduction of PrEP as a novel, highly effective approach to HIV prevention. Data collected since the start of PrEP availability in 2012 make it possible to evaluate how different policy environments have shaped the full course of PrEP implementation. We studied the period of state same‐sex marriage policies as an indicator of reduced structural stigma. We found that state implementation of same‐sex marriage policies in earlier, relative to later, periods was associated with increases in the rate of male PrEP prescriptions and in the male PnR.Throughout the study period and across specifications, US states that implemented same‐sex marriage policies in 2004–2011 had higher rates of male PrEP prescriptions and male PnR than states that implemented same‐sex marriage policies in 2014 or as a result of the federal Supreme Court decision in 2015. As PrEP prescription rates and male PnR increased across all states from 2012 to 2019, the absolute difference grew between states implementing same‐sex marriage in different periods. It is possible that structural stigma at the time of PrEP introduction played a formative role in early investments and efforts towards PrEP implementation. It is also possible that earlier implementation of same‐sex marriage policies is a reflection of enduring state‐level policy climates surrounding sexual minorities. State‐level structural stigma shapes institutional , interpeThe finding that state same‐sex marriage policies were associated with PrEP prescriptions is consistent with prior evidence indicating that state‐level policies related to sexual orientation are associated with changes in sexual minority health disparities , 12, 13.In 2019, there was a positive correlation between new HIV diagnoses and PrEP prescriptions, suggesting that PrEP was reaching states with the most need for it; however, this correlation was much stronger in states that implemented same‐sex marriage earlier relative to later. The states that implemented same‐sex marriage in later periods are also the states with the most new HIV diagnoses. There remains a need for further investment in PrEP implementation and structural supports such as Medicaid expansion in states with the highest new HIV diagnoses.This study has both strengths and limitations. A strength of the study is that it is based on a nationwide dataset of PrEP prescriptions, while a limitation is that the dataset omits some closed health systems, potentially restricting generalizability. Our findings are descriptive rather than causal and are vulnerable to confounding by unmeasured differences between states. Statistical power and inclusion of covariates were limited by the number of US states (50). Although the AIDSVu datasets have information on patient sex, they lack information on patient race/ethnicity as well as sexual orientation and gender identity, and some patients and PrEP users with male sex may identify as transgender women. We also lacked precise information on the population denominator of MSM, and this could vary by state. While we used estimates of the gay and bisexual population, these estimates were not disaggregated by sex at birth and do not capture all MSM, given that some MSM may identify as straight. The majority of male PrEP users are MSM , suggest5Earlier implementation of state same‐sex marriage policies between 2004 and 2011 and between 2012 and 2013 was associated with greater rates of male PrEP prescriptions relative to later implementation of same‐sex marriage in 2014 and 2015. Implementation of state same‐sex marriage policies between 2004 and 2011 was also associated with greater male PnR relative to later implementation of same‐sex marriage in 2014 and 2015. The findings are aligned with fundamental cause theory , 7 and pJR designed the study, obtained the data, conducted the statistical analysis and drafted the manuscript. DMC, AS, MLH, KHM and MDS contributed to the conceptualization of the study, interpreting data and critical revision of the manuscript.This study was funded by grants from the National Institute of Mental Health (K01 MH116817) and the Providence/Boston Center for AIDS Research (P30AI042853).The authors have no competing interests to declare.Table S1: Regression estimates of the relationship between period of same‐sex marriage implementation, male PrEP prescription rates and male PrEP‐to‐need ratiosClick here for additional data file.


People with motor neuron disease (pwMND) are routinely offered gastrostomy feeding tube placement and (non‐invasive and invasive) ventilation to manage the functional decline associated with the disease. This study aimed to synthesise the findings from the qualitative literature to understand how individual, clinical team and organisational factors influence pwMND decisions about these interventions.The study design was guided by the enhancing transparency in reporting the synthesis of qualitative research (ENTREC) statement. The search of five bibliography databases and an extensive supplementary search strategy identified 27 papers that included qualitative accounts of pwMND, caregivers and healthcare professionals' (HCPs) experiences of making decisions about gastrostomy and ventilation. The findings from each study were included in a thematic synthesis.Making decisions about interventions is an emotional rather than simply a functional issue for pwMND. The interventions can signal an end to normality, and increasing dependence, where pwMND consider the balance between quality of life and extending survival. Interactions with multiple HCPs and caregivers can influence the process of decision‐making and the decisions made. These interactions contribute to the autonomy pwMND are able to exert during decision‐making. HCPs can both promote and threaten pwMND perceived agency over decisions through how they approach discussions about these interventions. Though there is uncertainty over the timing of interventions, pwMND who agree to interventions report reaching a tipping point where they accept the need for change.Discussion of gastrostomy and ventilation options generate an emotional response in pwMND. Decisions are the consequence of interactions with multiple external agents, including HCPs treading a complex ethical path when trying to improve health outcomes while respecting pwMND right to autonomy. Future decision support interventions that address the emotional response and seek to support autonomy have the potential to enable pwMND to make informed and timely decisions about gastrostomy placement and ventilation.The lead author collaborated with several patient and participant involvement (PPI) groups with regards to the conceptualisation and design of this project. Decisions that have been influenced by discussions with multiple PPI panels include widening the scope of decisions about ventilation in addition to gastrostomy placement and the perceptions of all stakeholders involved . The risks and benefits associated with interventions are continually changing as the health threats presented by symptom progression escalate. King et al.The aim of this qualitative evidence synthesis is to understand how individual, clinical team and organisational factors influence the decisions that pwMND make about gastrostomy and ventilation (for the purpose of this paper ‘gastrostomy placement and ventilation [non‐invasive and invasive]’ will be referred to as ‘interventions’ from this point onwards).22.1A qualitative evidence synthesis was selected to systematically identify and synthesise the findings from the published qualitative literature, to gain a broad and rich understanding of the factors that influence decision‐making about interventions in MND care.2.2The search strategy was informed by a scoping search and in consultation with subject experts, academic information specialists, patient and public involvement groups and the research team. All searches took place between September and October 2021. Free text terms and subject headings related to the concepts ‘motor neuron disease’, ‘decision‐making’, ‘gastrostomy OR ventilation’ and ‘qualitative study’ were combined using the Boolean term ‘AND’. The search strategies were adapted for searches on five bibliographic databases: Medline, Embase, CINAHL, PsycINFO and Cochrane Library database  qualitative checklist was used to assess the quality and rigour of the included papers Table .26 The2.6N = 12), ventilation (non‐invasive and invasive) alone (N = 8) and both gastrostomy and ventilation (N = 7). The studies were conducted in a number of countries including: United Kingdom (N = 8); Australia (N = 5); The Netherlands (N = 2); Sweden (n = 2); United States of America (N = 2); Canada (N = 2); Ireland (N = 1); Japan (N = 1); Italy (N = 1); not available (N = 1). See Table This review includes a synthesis of the findings from 25 studies reported in 27 papers,  for coding and analysis by S.W. Only the text present in the findings section of the papers were extracted for the analysis.3Four analytical themes were developed describing the factors impacting on pwMND decisions about gastrostomy and ventilation: ‘An emotional response to interventions’; ‘Sharing the decision with others’; ‘Control’; and ‘Tipping the balance’ Figure . The ana3.1The prospect of starting an intervention represented a threat to pwMND sense of normality including the implications for their level of independence, freedom, and reliance on others. Additionally, pwMND perceptions were influenced by how they value an interventions' potential to prolong life and the quality of that remaining life.3.1.1pwMND deliberations about whether to commence interventions extend beyond the clinical problems they are proposed to ameliorate. Decision‐making is influenced by a range of emotional responses with regard to what the interventions signify and how daily life with them will compare to the current status quo.…A very obvious sign of being ill…a very concrete representation that he's seriously ill.’(H) ‘Discussions about interventions acted as an acute reminder for some pwMND of disease progression.An emotional response was generated when learning about the procedures involved,All participants talked about the affect of QOL  on decisions about assisted ventilation.’(R) ‘Additionally, pwMND were concerned about how interventions may impact on their current sense of normality. pwMND reported contrasting views about how an intervention may enable or hinder their ability to engage in social activities3.1.2Most participants suggested that losing independence rendered life less meaningful and that life‐sustaining interventions had the potential to prolong ‘suffering’.’(R) ‘Existential views on the potential for interventions to prolong life were integrated into pwMND decision‐making. A number of studies reported pwMND preference to prioritise quality of life over prolonging a life that lacked value to them.…the sensual qualities of the body surprised the gastroenterologist, who saw maintaining physical fitness and longer survival as the ultimate goals, and the feeding tube as a means towards this end…’(R) ‘Reassurance from others and an overriding belief that quality of life will be maintained or improved, promoted a positive perception of interventions.Any living person's will to survive is primordial and outweighs many other concerns or reasons.’(P) ‘pwMND reported considering how any extension to their lives may impact on their caregivers. Interventions were perceived to lengthen the time they are a burden on caregiverspwMND perceptions of interventions are both intrinsically generated and the consequence of interactions with multiple external agents. The following theme captures how HCPs, caregivers and other pwMND can influence the decision‐making process.3.2pwMND decision‐making involves interactions with a range of external agents. HCPs share information and attempt to guide pwMND through the decision; caregivers share some of the burden of decision‐making with pwMND; and knowledge of other pwMND can help clarify or challenge perceptions and values.3.2.1So, you know, some health professionals—I think periods of silence to listen to the client are needed without the health professional thinking, “I've got to tell them X, Y, Z…”’(C) ‘The style, amount, and pace of information shared by HCPs influenced pwMND experience of the decision‐making process. HCPs focusing on delivering comprehensive information about interventions, may prevent pwMND from having the opportunity to understand and explore the issues most important to them.HCPs were a trusted source of information and pwMND expected them to use their expertise to guide decision‐making.I think my…fear is you can get so many teams of people involved. […] the possibilities of confusion and misinformation are enormous…I was going to say warfare [can occur].’(H) ‘pwMND reported having multiple interactions with different HCP roles when considering interventions.3.2.2Some patients experienced their families more negatively, with the family members' emotional needs taking precedence over those of the patient.’(R) ‘Caregivers were reported to play a supportive role, through seeking information, expressing opinions and deliberating about options.3.2.3The decisive factor was meeting ALS patients already using it. These people with the same disease had a positive outlook on life, and this gave me the will to live as well. My uncertainty disappeared.’(P) ‘Understanding experiences of other pwMND facilitated some pwMND to clarify their own preferences, including learning about pwMND reflections of delaying decision‐making, reassurance that they could adapt to life with an intervention and informing values with regard to prolonging life.However, others reported meeting other pwMND would have been a barrier to decision‐making, reminding them about the future symptom burden they would be living with and may wish to avoid.The involvement of multiple external agents raises the question of who is responsible for making decisions and how interactions with others may influence the loci of control.3.3pwMND wanted to be in control of the decisions they made about interventions; a preference that could be facilitated or threatened by interactions with others.3.3.1John [dietician] came back out again and said as you get nearer for the PEG, don't let anybody bully you into it.’(P) ‘pwMND consistently reported a preference to remain in control over decisions about interventions.I mean the speech therapist came round, she said ‘well something you've got to start thinking about is this pipe’ and [MND Specialist Nurse] came round and she said about it and that other woman said something about it an' all. It felt like a lot of pressure was being put on me.’(P) ‘This quote points to the possibility that external agents may influence pwMND ability to exert autonomy during decision‐making, including convincing pwMND to make decisions that are not aligned with their preferences; a scenario that was described in a number of papers.In some studies, there was a sense of ‘side taking’, with HCPs and caregivers joining forces to project their own preferences for interventions.3.3.2I haven't discussed noninvasive ventilation because…how would he ever cope? So, I've made, on best interests, not to start discussing those issues…. His anxiety, it's just going to raise his anxieties.’(H) ‘pwMND perception of having choice about interventions was narrowed or removed by HCPs limiting the options presented or the significance of the health threat presented by the disease. While HCPs reported presenting options to commence or decline interventions, there were also examples where HCPs withheld optionspwMND were able to enact agency over decisions while they were coping with symptoms and choosing to delay or decline interventions. However, when symptoms presented a significant threat to pwMND health or life, interventions were often perceived to be the only choice available to prevent serious consequences.3.3.3Decision‐making often involved pwMND attempting to visualise how their future self may value an intervention. pwMND reported struggling to imagine how they would feel about an intervention when living with increased disease burden.pwMND wanted to remain in control of decision‐making. Interactions with HCPs and caregivers influenced pwMND perception choice and agency over their decisions. The timing of interventions is a challenging issue for all involved.3.4The timing of initiating discussions and commencing interventions was a source of conflict for all stakeholders. Commencing interventions often required pwMND to reach a subjective tipping point informed by disease progression, acceptance of need and recommendations of HCPs.3.4.1No, no, no. I'd rather not know until there's a reason to know. I don't want to know all the nasty possibilities that might be in front of me. You know, I just don't want to know the detail, until there's a reason to know it.’(P) ‘While HCPs advocated for an individualised patient‐centred approach, HCPs supported introducing intervention options early during the disease course.3.4.2It was a gradual change in my decision. As swallowing got worse I couldn't drink water and thickened stuff was not pleasant. So I thought to be hydrated in summer was a good idea and also taking medications would be easier through the tube.’(P) ‘With regard to the timing of interventions, HCP preferences for ‘earlier rather than later’ were informed by previous clinical experience of poor outcomes associated with late intervention.You don't know how it's going to proceed…whether it's going to proceed quickly…the uncertainty makes it far more difficult to make decisions because you don't know what tomorrow's going to bring. I mean I'm sure [patient] would find it easier, if she knew how it was going to progress and if we had some idea of timescale.’(C) ‘pwMND who perceived that their symptoms were not causing significant problems could continue to defer decisions about interventions, even when presented with objective measures of functional decline or the direct observations of others.They say make sure it's done sooner rather than later but what is sooner rather than later? They don't say we're talking next month, no definite time, it's down to you.’(C) ‘HCP guidance and recommendations were reported to influence the timing of interventions.44.1The review findings describe how decisions about interventions generate an emotional response that extends beyond consideration of the functional issues and are the consequence of interactions with a range of external agents. pwMND reflect on how life with an intervention will alter their independence, freedom and survival compared to continuing with the status quo, including concern for the impact on their caregivers. HCPs and caregivers played an integral role during decision‐making, through supporting pwMND to understand their options, retain control and make decisions aligned with their values. The sense of choice and agency experienced by pwMND during decision‐making was mediated by disease progression and the actions of others. The timing of interventions is a source of uncertainty, with decisions being driven by symptom severity, HCP guidance and pwMND acceptance of need for intervention.4.2Most studies reported pwMND associating interventions with a life with increased restrictions, burden and reliance on others. These findings are consistent with Foley et al.4.3Following the decision about ‘if’ they should accept intervention, pwMND are faced with the uncertainty about ‘when’ to commence the intervention. The review findings describe how decisions about timing of interventions are influenced by pwMND acceptance or understanding of need, and their response to HCP guidance. Decisions about the timing of interventions are important, with delays being associated with poorer outcomes, particularly in relation to gastrostomy placement.The perceptions of the disease and interventions are informed by an iterative updating of illness cognitions in response to pwMND evolving acceptance and adaptation to the relentless changes in their condition.4.4The review captured how external agents can facilitate individual autonomy,HCPs have an ethical and professional obligation to support pwMND to make autonomous, informed, values‐based decisions about interventions.Consistent with a previous review4.5A limitation of this review was the absence of a second reviewer to shortlist the references for inclusion, extract data and independently code the data which may limit the credibility of the study. However, this is mitigated to a degree by some of the methodological strengths of the review such as the systematic approach to the study design, including a comprehensive bibliographic and supplementary search strategy, a second reviewer screening 10% of references at the abstract and full‐text stages and discussions with supervisory team when developing the analytical themes.A further limitation relates to the review not making any distinctions between decisions made about gastrostomy, non‐invasive ventilation and invasive ventilation. These are interventions, with differing clinical indications, outcomes and implications for pwMND and their caregivers. There may have been valuable insights gained from exploring the consistencies and differences of the decision‐making process for the different interventions. A review of the data did not reveal enough rich data to provide a credible account of any such differences. Future qualitative research may benefit from comparing the contextual factors that influence decisions about different interventions to generate deeper analytical insights.4.6S.W. is a dietitian with experience of supporting pwMND to make decisions about gastrostomy placement. Prior experience and opinions of a researcher have the potential to affect how data are analysed and interpreted.4.7The emotional response to interventions highlights the importance of exploring the value pwMND place on the implications and outcomes of an intervention beyond the concern for clinical outcomes. Decision‐making should address the issues that matter most to pwMND including the existential debate pwMND have about an intervention's potential to affect their quality and length of life. While HCPs have an ethical responsibility to communicate with pwMND about the predicted disease course and timely consideration of interventions caution should be taken to respect individuals' preferences for information and control. Acknowledging early in the decision‐making process, the contribution pwMND, caregivers and HCPs make towards a relational conceptualisation of autonomy may facilitate a shared understanding of each other's role and boundaries, and promote meaningful engagement in decision‐making discussions.5Addressing the emotional response pwMND have to the prospect of interventions could improve engagement in decision‐making discussions. HCPs and caregivers have a complex ethical path to navigate when seeking to protect pwMND autonomy while simultaneously attempting to optimise health outcomes. Decision support strategies that mediate the emotional response and promote autonomy have the potential to enable pwMND to make timely, values‐based decisions about interventions.Funding acquisition: Sean White, Alicia O'Cathain, Vanessa Halliday and Christopher McDermott. Conceptualisation and design: Sean White, Alicia O'Cathain, Vanessa Halliday and Christopher McDermott. Study screening and selection: Sean White and Liz Croot. Analysis, synthesis and interpretation: Sean White, Alicia O'Cathain, Vanessa Halliday, Liz Croot and Christopher McDermott. Writing—original draft: Sean White. Writing—review and editing: Sean White, Alicia O'Cathain, Vanessa Halliday, Liz Croot and Christopher McDermott. Supervision: Alicia O'Cathain. Vanessa Halliday and Christopher McDermott have provided on‐going supervision of the work.The authors declare no conflict of interest.Supporting information.Click here for additional data file.Supporting information.Click here for additional data file.Supporting information.Click here for additional data file.


The endoscopic management for malignant gastric outlet obstruction has expanded with the advent of endoscopic ultrasound‐guided gastrojejunostomy. Delayed perforation after endoscopic ultrasound‐guided gastrojejunostomy is an important yet rarely reported adverse event, and it is unclear why some patients may suffer this complication. We present a case of intestinal perforation occurring one month after endoscopic ultrasound‐guided gastrojejunostomy and discuss potential mechanisms which may contribute to this outcome. Malignant gastric outlet obstruction (GOO) is an important manifestation of advanced foregut cancer, associated with deterioration in the quality of life and reduced survival. Enteral stenting (ES) and surgical gastrojejunostomy are effective methods for relieving GOO and restoring the flow of gastric chyme into the small bowel. However, issues with therapeutic durability and confinement of the biliary outflow with ES, as well as peri‐operative risk for surgery, represent limitations to these established options.Endoscopic ultrasound‐guided gastrojejunostomy (EUS‐GJ) is a technique gaining popularity as an alternative therapy for GOO. EUS‐GJ has the advantage of creating a gastrojejunal conduit that bypasses the area of disease, resulting in a more durable treatment that does not interfere with the biliary system. EUS‐GJ has now matured into a phase of technical standardization and holds promise in becoming the preferred treatment for GOO.A 48‐year‐old male with unresectable pancreatic adenocarcinoma complicated by biliary obstruction managed by stenting and GOO with prior ES presented with recurrent GOO. Nine weeks prior to presentation, the patient underwent initial ES placement to treat a malignant stenosis located in the second and third portions of the duodenum. He had done well until two weeks prior to the presentation, when he experienced recurrent GOO due to aboral ES migration. An overlapping co‐axial ES was placed, however, the patient developed recurrent GOO one week prior to presentation due to another aboral migration of the internal, overlapping stent. At this time, a third co‐axial ES was placed with the proximal flange positioned in the duodenal bulb. Despite these efforts, he continued to have GOO and it was felt he had developed concurrent progression of gastric contractile dysfunction secondary to late‐stage malignant GOO Figure . The patHe was started on a standard full‐dose daily proton pump inhibitor and later dismissed from the hospital. At a post‐admission clinic visit, he graduated to a soft diet two weeks after EUS‐GJ and was gaining weight. Four weeks after EUS‐GJ, he presented to the emergency department with acute abdominal pain and distention. A computed tomography scan revealed pneumoperitoneum and a jejunal defect adjacent to the lumen‐apposing metal stent (LAMS) Figure . ExploraEUS‐GJ for malignant GOO has many advantages over conventional methods. A primary barrier to the widespread adoption of EUS‐GJ may be largely due to the perceived risk for perforation. Therefore, substantial efforts have focused on addressing these concerns through the development of a standardized technique, identifying factors influencing technical success, and characterization of safety events and their potential for endoscopic remediation.Delayed intestinal perforation after EUS‐GJ appears to be rare and mostly reported in single‐case reports Table . When deSince most patients do not suffer delayed perforation after EUS‐GJ, it is likely that this is a manifestation of a multifactorial process that begins with ulcerogenesis. Several facultative  and other risk and protective factors are known to impact the integrity of the gastrointestinal mucosa. Stent implantation introduces an additional risk factor that is felt to be related to chronic stent‐related pressure ischemia, and this may manifest in different patterns of injury. Perforation is a severe complication of gastrointestinal ulcers, and studies have implicated smoking tobacco, nonsteroidal anti‐inflammatory drugs (NSAID), older age, and alcohol use with perforated peptic ulcer disease.In conclusion, delayed perforation after EUS‐GJ is rare and is likely to be the result of multifactorial mechanisms. Chronic stent‐related pressure ischemia may play a central role in this process and manifest as direct contralateral or ipsilateral wall contact injury. While these mechanisms are not readily addressable, apart from stent re‐design, we should expect to learn more about EUS‐GJ safety over time. In the meantime, modifiable factors such as gastric acid suppression and mitigating tobacco, illicit drug, or NSAID use are actionable interventions that may minimize these events.NoneInstitutional review board review is not required for case reports with no identifiable health information. Consent for publication of the submitted manuscript and associated images was obtained from the patient's next of kin. The patient was deceased at the time of manuscript preparation.


Asthma and bronchiolitis in children are considered common clinical problems associated with gut microbiota. However, the exact relationship between gut microbiota and the above‐mentioned diseases remains unclear. Here, we discussed recent advances in understanding the potential mechanism underlying immune regulation of gut microbiota on asthma and bronchiolitis in children as well as the role of the gut–lung axis.We retrieved and assessed all relevant original articles related to gut microbiota, airway inflammation‐induced wheezing in children, and gut–lung axis studies from databases that have been published so far, including PubMed/MEDLINE, Scopus, Google Scholar, China National Knowledge Infrastructure (CNKI) and the Wanfang Database.The infant period is critical for the development of gut microbiota, which can be influenced by gestational age, delivery mode, antibiotic exposure and feeding mode. The gut microbiota in children with asthma and bronchiolitis is significantly distinct from those in healthy subjects. Gut microbiota dysbiosis is implicated in asthma and bronchiolitis in children. The presence of intestinal disturbances in lung diseases highlights the importance of the gut–lung axis.Gut microbiota dysbiosis potentially increases the risk of asthma and bronchiolitis in children. Moreover, a deeper understanding of the gut–lung axis with regard to the gut microbiota of children with respiratory diseases could contribute to clinical practice for pulmonary diseases. Gut microbiota dysbiosis potentially increases the risk of asthma and bronchiolitis in children. Moreover, a deeper understanding of the gut–lung axis with regard to the gut microbiota of children with respiratory diseases could contribute to clinical practice for pulmonary diseases. APRILa proliferation‐inducing ligandBAFFB cell activation factorBALFbronchoalveolar lavage fluidCOPDchronic obstructive pulmonary diseaseC‐sectionscaesarean sectionsDCsdendritic cellsFut2fucosyltransferase 2GLAgut–lung axisGlcNAcN‐acetylglucosamineGpr43G protein‐coupled receptor 43HMOshuman milk oligosaccharidesIBDinflammatory bowel diseaseIBSirritable bowel syndromeICOSinducible T‐cell co‐stimulatorIFNARIFN‐1 receptorILC33 innate lymphoid cellsIL‐22interleukin‐22MLNsmesenteric lymph nodesMPPMycoplasma pneumoniae pneumoniaPRRspattern recognition receptorsRegIIIregenerated islet‐derived protein 3RSVrespiratory syncytial virusSAAserum amyloid ASCFAsshort‐chain fatty acidsSFBsegmental filamentous bacteriaTh1 cellstype 1 T helper cellsTLRstoll‐like receptors1Mycoplasma pneumoniae pneumonia (MPP), with the first two being the most frequent causes.Wheezing illness manifested by a continuous whistling sound during breath, suggests that some parts of the respiratory airways are narrow or obstructed, which is often led by airway inflammation, airway hyperresponsiveness, bronchospasm and airway remodelling. Among them, airway inflammation‐induced wheezing in children is common, including bronchial asthma, bronchiolitis and 22.1Escherichia coli to investigate the coexistence of bacteria driven by the combination of motility and spatial competition. In the study, they found that there was a growth‐migration balance in the gut microbiota. In this case, the fast‐growing groups intended to occupy the original space, whereas the fast‐moving ones were more likely to reside in the remote area. This observation may explain how the intestine promotes ecological diversity.The intestine is often referred to as the ‘second brain’ of our body, and the gastrointestinal tract harbours the majority of microbes that are essential for our health.2.2Micrococcus can adapt to the foetal environment and suppress inflammatory responses. It takes about 1 year for newborns to colonize the maternal bacteria to establish and develop their own gut microbiota.Bacteroides and Bifidobacterium, but more pathogenic bacteria present in their gut.Bifidobacterium and Lactobacillus in gut microbiota than formula‐fed infants because of the compounds contained in breast milk, such as immune active molecules, vitamins, probiotics and oligosaccharides.Bifidobacterium and Lactobacillus) and increased pathogenic ones (Staphylococcus and Enterococcus) in the gut of pre‐term infants.It was originally believed that the gut microbiota did not colonize in the relatively sterile environment of the uterus. However, Jiménez et al.2.3Gut microbiota can communicate with the host on the intestinal mucosa surface to coordinate with each other and achieve mutually beneficial symbiosis. The intestinal mucosa is continuously exposed to foreign antigens and colonized microorganisms. And the intestinal mucus layer, epithelial cells, lamina propria and gut commensal bacteria constitute a barrier that protects the intestine by restricting close contact between bacteria and intestinal epithelial cells. The above mechanism modulates the composition of microorganisms on the surface of the intestine and quickly identifies the infiltrating bacteria to suppress inflammatory responses.+ plasma cells in the lamina propria of the intestinal mucosa.Minimizing the contact of microbes in the lumen with the surface of intestinal epithelial cells is key for maintaining homeostasis. This process requires mucus, antimicrobial peptides and IgA to strengthen the physical barrier. The mucous glycoproteins secreted by the goblet cells of the intestinal epithelium form a mucus layer that coats the surface of the epithelial cells to restrain bacterial penetration and direct contact of bacteria with epithelial cells.2 promotes ILC3 proliferation and IL‐22 production in vivo via the PGE2‐EP4 signalling pathway, thereby strengthening intestinal immune function and inhibiting inflammatory responses.Bacteroides) that are symbiotic with the host can ingest the carbohydrates produced by the host in a unique foraging way; that is, when the symbiotic microorganisms properly stimulate ILC3, IL‐22 produced by ILC3 can stimulate the fucosylation of intestinal epithelial cells. The terminal fucose fragment can be catalyzed by bacterial‐derived fucosyltransferase 2 (Fut2), which is not conducive to bacterial colonization.Koalabacteria by promoting glycosylation of the host's mucus N‐acetylglucosamine (GlcNAc), and this enriched microbe subsequently inhibits the growth of Clostridium difficile by consuming succinate.Gut microbiota usually protect the host from pathogens and maintain tolerance to commensals while producing certain immune effectors for maintaining equilibrium and avoiding harmful overreactions.+ plasma cells.+ T cells can proliferate and differentiate into functionally distinct subsets of T cells, such as Th1, Th2, Th17 and Treg cells+ monocytes to produce IL‐23 and activate ILC3 to secrete IL‐22, producing epithelial serum amyloid A (SAA) in a STAT3‐dependent manner and promoting local effector Th17 responses.Lactobacillus, Bacteroides and Clostridia, revealed that Clostridia clusters XIVa, IV and XVIII are correlated with an elevated frequency of Treg cells in the colon and induce the production of important anti‐inflammatory molecules, such as interleukin‐10 (IL‐10) and inducible T‐cell co‐stimulator (ICOS).Clostridia‐produced short‐chain fatty acids (SCFAs) can not only activate the signalling pathway via GPR109a to induce anti‐inflammatory responses in DCs but also promote Treg cell proliferation and differentiation by activating GPR43 or inhibiting histone deacetylase.The immune system can identify and eliminate bacteria that penetrate intestinal epithelial cells. This mucosal immune mechanism involves the uptake and phagocytosis of innate immune cells and T cell‐mediated responses. In innate immunity, mononuclear phagocytes such as macrophages (MΦ) and dendritic cells (DCs) serve as sentinels for peripheral tissues and are present in the lamina propria.2.4+ T cells into Treg cells and impair Th2 differentiation, creating an anti‐inflammatory environment.The gut and lungs are anatomically distinct, but potential anatomic communications and complex pathways involving their respective microbiota have emphasized the existence of a GLA.33.1Bronchiolitis and asthma are both airway inflammatory diseases. Bronchiolitis is a common lower respiratory tract infection in infants that is mainly caused by viruses of bronchotropic epithelial cells, of which respiratory syncytial virus (RSV) is the most common pathogen and also the most likely to cause severe disease and even outbreaks.3.2Bifidobacterium and Akkermansia in the gut increases the risk of suffering from asthma in the future. This observation can be attributed to the dysfunction of the neonatal gut microbiota that may cause an alteration in the proportion and function of CD4+ T cells.Bronchial asthma is the most common chronic respiratory disease in childhood, which is characterized by airway inflammation and hyperresponsiveness. ‘Hygienic hypothesis’‐based ‘microbial hypothesis’ clarifies the cause of asthma.3.3Bronchiolitis is a common lower respiratory tract infection in infants and young children. Infection with a virus, especially the RSV, is the common cause of bronchiolitis, accounting for more than 40% of the cases.4By retrospecting the relevant studies, this paper reviews the impact of gut microbiota on airway inflammation‐induced wheezing in children, in which the GLA plays a key role. Gut microbiota dysbiosis not only regulates the immune response of the gastrointestinal tract but also affects the immunity of distal organs such as the lung and respiratory tract,Sichen Xue and Manhuan Xu drafted the manuscript, and Manhuan Xu and Rukkaiya Abdullahi collected the data. Sichen Xue, Rukkaiya Abdullahi and Miaoshang Su provided necessary logistic support and formal analysis. Sichen Xue, Miaoshang Su, Naisheng Wu and Jishan Zheng provided critical comments on the manuscript. All authors have read and approved the manuscript.The authors declare that they have no conflict of interest.Not applicable.


Double‐pigtail stents are commonly used for drainage in cholangitis to prevent stent migration. We report a case in which a double pigtail stent had migrated proximally into the bile duct and was successfully retrieved after endoscopic papillary large balloon dilatation (EPLBD). An 86‐year‐old man underwent endoscopic papillary sphincterotomy for cholangitis due to common bile duct stones and had a double‐pigtail stent placed in the common bile duct. The patient presented a week later for endoscopic biliary stone removal, but the stent had migrated proximally and could not be visualized during the endoscopy. Endoscopic papillary large balloon dilatation was performed to dilate the papilla to a diameter of 12 mm, following which the stent was grasped and removed. The biliary calculi were subsequently extracted, and the procedure was completed without any complications. This case highlights the potential usefulness of endoscopic papillary large balloon dilatation for retrieving a double‐pigtail stent that has migrated to the bile duct. Stent migration is a known complication of endoscopic retrograde cholangiopancreatography with stent placement, and previous studies have reported varying rates of stent migration.An 86‐year‐old man presented to our hospital for endoscopic biliary stone removal. The patient had a history of postoperative gastric cancer following distal gastrectomy and Billroth I reconstruction, as well as hypertension, and had been taking oral medications, such as nifedipine, amlodipine, and esomeprazole.Six days prior to the presentation, the patient underwent endoscopic papillary sphincterotomy at a different hospital. A double‐pigtail stent (details not available) was placed in the bile duct for cholangitis due to common bile duct stones. The patient was discharged with the advice of follow‐up for biliary stone removal once the cholangitis subsided. The patient was admitted to our hospital for endoscopic biliary stone removal. Endoscopic retrograde cholangiopancreatography was performed the next day. Although the abdominal radiograph showed that the patient had a double‐pigtail stent with a loop diameter of approximately 24 mm Figure , the steStent migration is a known complication of endoscopic retrograde cholangiopancreatography with stent placement, with varying rates reported in previous studies. According to a review by Dumonceau et al., which was used to develop the European Society of Gastrointestinal Endoscopy clinical guidelines, the migration rate for plastic stents and partially covered self‐expandable metal stents is around 5%. In comparison, uncovered self‐expandable metal stents have a migration rate of 1%, and fully covered self‐expandable metal stents have a rate of 20%.Double‐pigtail stents have been developed to prevent or reduce stent migration and are used alone or to anchor other stents.While most cases of distal stent migration lead to the spontaneous passage, proximal migration of stents into the bile duct and pancreatic duct requires endoscopic extraction.In our case, EPLBD proved to be a successful method for treating a narrow papilla and helping retrieve a migrated double‐pigtail stent from the bile duct when conventional methods such as balloon catheters and basket catheters proved difficult. This experience suggests that EPLBD may be a useful step in the treatment of proximally migrated double‐pigtail stents in challenging cases, particularly in scenarios with a narrow papilla and a stiff, large stent loop.None.


Deep learning is increasingly being proposed for detecting neurological and psychiatric diseases from electroencephalogram (EEG) data but the method is prone to inadvertently incorporate biases from training data and exploit illegitimate patterns. The recent demonstration that deep learning can detect the sex from EEG implies potential sex‐related biases in deep learning‐based disease detectors for the many diseases with unequal prevalence between males and females. In this work, we present the male‐ and female‐typical patterns used by a convolutional neural network that detects the sex from clinical EEG (81% accuracy in a separate test set with 142 patients). We considered neural sources, anatomical differences, and non‐neural artifacts as sources of differences in the EEG curves. Using EEGs from 1140 patients, we found electrocardiac artifacts to be leaking into the supposedly brain activity‐based classifiers. Nevertheless, the sex remained detectable after rejecting heart‐related and other artifacts. In the cleaned data, EEG topographies were critical to detect the sex, but waveforms and frequencies were not. None of the traditional frequency bands was particularly important for sex detection. We were able to determine the sex even from EEGs with shuffled time points and therewith completely destroyed waveforms. Researchers should consider neural and non‐neural sources as potential origins of sex differences in their data, they should maintain best practices of artifact rejection, even when datasets are large, and they should test their classifiers for sex biases. Deep learning is increasingly being proposed for detecting neurological and psychiatric diseases from electroencephalogram (EEG) data but the method is prone to inadvertently incorporate biases from training data and exploit illegitimate patterns. In this work, we derived the male‐ and female‐typical patterns used by a convolutional neural network that detects the sex from clinical EEG and we found electrocardiac artifacts to be leaking into the supposedly brain activity‐based classifiers. None of the traditional frequency bands was particularly important for sex detection and we were able to determine the sex even from EEGs with shuffled time points and therewith completely destroyed waveforms. Per recording , 50 non‐overlapping segments (4 s length) were selected using the Autoreject method. Autoreject scanned through the data and returned segments with low noise and artifact load, regardless of the underlying status of the recording. The first 2 min of each recording were skipped, as readjustments of the electrodes often occur at the beginning, leading to an increased number of bad channels  . The artifactual ECG and EOG components were semi‐automatically selected and removed using the Corrmap method .We built a CNN that detects a patient's sex from few‐second segments of EEG. We designed an extremely small and shallow network architecture under the conjecture that findings from this architecture generalize to most deep learning architectures for EEG analysis; whatever this CNN can detect should easily be detected by deeper networks because of their higher fitting capacity .We used a one‐sided binomial test with Bonferroni correction for 2.4Kk, matches with the data. Then, the sign of the weights, Wk, in the dense output layer tells whether matching with an individual kernel turns the prediction toward male or female.Our shallow network architecture brought the advantage that the distinctive patterns could be directly read from the learned weights. The learned weights consist of the elements of the convolutional kernels and of the dense output layer. The network, up to the next‐to‐last layer, yields how well each kernel, relevanceR of the EEG signal at each channel and time point for the network's decision between male and female. The shallowness and simplicity of the network allowed for a short derivation of R without involving an extensive explainability framework: The CNN scans through each 4‐s EEG segment, X, in 40 overlapping windows, Xi, of 300 ms length and 100 ms overlap. Within these windows, only the parts with the maximum correlation between the data and the kernels contribute to the final prediction. The scanning first leads to the cross‐correlation time courses Ck between the data matrices and a kernelsWe determined the Ri,k at the maximum correlation time points in each window from each kernel, we first definedXargmaxCi,k is a submatrix of the same size as the kernels, and ⊙ denotes the element‐wise Hadamard product. Next,To calculate the relevance matrices We then summed up the relevances from the different segments at their corresponding time points, which yields kernel‐specific relevance matrices with the same dimensions as the data matrices. Finally, the sum over all kernel‐specific relevance matrices was used to determine the total relevance that we then overlayed in a red and blue tint on top of the data Figure .∣R∣ with averaged time courses of the ECG around the QRS complexes.The sum of a relevance matrix over all channels yields a relevance time course. We used these relevance time courses to assess the impact of electrocardiac artifacts on the CNN's predictions, by comparing averaged time courses of the absolute relevance 2.5and evaluation data) to probe the origin of the sex differences in the EEG:We tested if we could isolate the origin of the sex difference to one of the traditional frequency bands by bandpass filtering.time domain, we randomly shuffled the time points of the EEG signals within each segment, destroying waveforms and cross‐temporal connectivity. We repeated this on band‐filtered data in the traditional EEG bands. These experiments required altering the network architecture to only learn topographic kernels (i.e. EEG patterns from a single time point).To assess the importance of the spatial domain, we destroyed the topographies: we randomly moved each channel in each segment up to 200 ms forward or backward . This kept the waveforms and frequencies within each channel intact.To assess the importance of the We computed the accuracy of detecting the sex directly from a single ECG channel instead of from the EEG.To assess the influence of artifacts, we compared the accuracies and relevances with and without ICA filtering. On the ICA‐filtered data, we tested different preprocessing on the entire dataset  when patients presumably presented with the sex information related to their legal documents, at that time containing the sex assigned at birth rather than their self‐identified gender.We use the patient sex from the metainformation of the EEG data, encoded as 0 or 1, as the target of our neural network. Throughout this work, we discuss 33.1p<.001, balanced accuracy, majority vote over 50 segments per patient, accuracy from single segments was 73% ± 1%). After artifact removal, the balanced accuracy dropped to 74% ± 2% p<.001. Repeating the entire pipeline (training and prediction) with band‐filtered data . The p‐values from pairwise significance tests between the frequency bands are provided in Table p=.002). The detection from topographies was also possible from band‐filtered data in each of the frequency bands and even lead to higher accuracies (up to 5% increased). Again, none of the frequency bands stood out. The largest difference between any two of the frequency bands was only 3% (between α and γ). The p‐values from pairwise significance tests between the frequency bands are provided in Table p=.17). We estimated a balanced accuracy of 81% for this architecture and dataset with the ensemble prediction from 30 networks with an increased number of kernels (512).Table p=.20).We searched for commonalities between the falsely classified patients, but errors were found for all kinds of patients: males and females, young and old, with and without medication, and with diverse medical histories. The confusion matrix for the experiment with ICA‐filtered data and spatio‐temporal kernels Table  showed np=.22). For single EEG channels, the frontal channels reached the highest accuracies When allowing more and more channels and always adding the optimal next channel, the selected sensors spread across the head. Six channels  already led to an accuracy >70%. Figure A single‐channel adaptation of our shallow CNN could not predict the sex from an ECG channel  and estimated the relevance of the data points for a prediction from each segment. We refrain from neural interpretations of the spectra and the waveforms in the kernels Figure  as they The shallow network architecture facilitated tracing back the relevance of each data point in the EEG to a given prediction. We observed an uneven distribution of relevance over time when we worked with raw EEG data: the relevance was attributed mostly to artifactual signals during the electrocardiac QRS complexes, and not to neural waveforms. There are two possible explanations why the network focuses on the EEG‐visible heart activity: There could be sex differences (i) directly in the source of the electrocardiac activity, or (ii) in the volume conducting body that lead to differences in the electrical potentials at the sensors. Electrocardiac sex differences are well known .5We replicated neural network‐based sex detection from EEG. Our work introduces a method for relevance attribution for the case of a shallow neural network and presents the sex‐related patterns in the EEG data. None of the traditional frequency bands were particularly important for sex detection. Non‐neural sources, particularly from the heart, were found to inflict sex‐biased components to the EEG, but even after rejecting these artifacts, the sex remained highly detectable.Our findings suggest that sex is easily detectable by practically any neural network for EEG analysis. For the many neurological and psychiatric diseases with unequal prevalences for males and females, sex is therefore a likely hidden confounder. Disease classifiers should therefore be analyzed for sex biases, for example by comparing if the detection performance for one sex is different for male‐ or female‐only trained models.Researchers using large datasets should aim to maintain best practices of artifact rejection and employ explainability methods to identify illegitimate patterns, such as the heart‐related signals revealed in our study.The authors declare no potential conflict of interest.Figure S1. Average artifact load over time. At the beginning of a recording, the number of bad channels is typically increased, for example, due to increased movement or sensor readjustments. This graph shows that for the dataset used in this study, the average number of bad channels was stable after around 100 s. In our work, we always skipped the first 120 s.Figure S2. Accuracy of the sex detection from different electroencephalogram (EEG) segment lengths. Markers denote the median value from five repeated experiments, and the error bars range from the best to the worst result. Preferably, the segments are as short as necessary. The influence of the segment length was small and flattened after a value of 4 s. Therefore, we chose 4 s as the segment length in this study.Figure S3. Accuracy of the sex detection from different kernel matrix lengths and numbers. The kernel length is given in matrix elements, where one element is 4 ms long. The differences between the resulting accuracies at different parameters were below the standard deviation (3%) except for very few and very short kernels (upper left corner of the map). We chose a rather small number of kernels for better interpretability and to visualize them in a printable format (16 kernels with 19 samples = 76 ms length).Figure S4. Spatio‐temporal kernels, trained on raw data without artifact removal. Some of the learned waveforms seemingly resemble neural oscillations. Still, the relevance attribution  shows that the most relevant data points are associated with electrocardiac artifacts during the QRS complexes.Table S1. Two‐tailed paired t‐test between the  accuracies of the models trained on different physiological bands of the ICA‐cleaned data. The table shows the pairwise p‐values.Table S2. Two‐tailed paired t‐test between the  accuracies of the models trained on different physiological bands of the ICA‐cleaned and time‐shuffled data. The table shows the pairwise p‐values.Table S3. Patient demographics of the separate evaluation set. The information was derived by a neurologist from the clinical reports in the TUH EEG corpus. The reports contain unstructured text that describes the patient, relevant history, medications, and clinical impression.Click here for additional data file.


When this article was originally published in Epidemiology & Infection, the funding statement was inaccurate. This has been updated in the article to the following:Financial support. The study was supported by the Italian Ministry of Health through the Strategic Project ‘Ricerca Corrente IZSVE 01/20 RCS’. This research was partially supported by EU funding within the NextGenerationEU-MUR PNRR Extended Partnership initiative on Emerging Infectious Diseases . Istituto Zooprofilattico Sperimentale dell’Abruzzo e del Molise (IZSAM) was also funded by the European Union’s Horizon 2020 Research and Innovation programme .