This cross-sectional study evaluated the growth and distribution of physicians in the Conrad 30 Waiver program during the past 2 decades. Noncitizen IMGs can legally train in US medical residency programs through the H-1B and J-1 visa pathways, with the vast majority entering through J-1.2 The Immigration and Nationality Act requires that those trainees return to their country of origin for 2 years when they complete their training. During that time, they may apply for a traditional immigrant visa to return to the US. However, the Conrad program waives the requirement by allowing those trainees to convert their J-1 to H-1B nonimmigrant status in exchange for a 3-year full-time commitment to practice medicine in underserved areas.3Physician shortage is a persistent challenge facing the US.4 Since 2003, Congress has increased the waiver cap to 30 per state per year. However, there is little information on the growth and distribution of Conrad physicians during the past 2 decades. This study aimed to fill this evidence gap.The Conrad program, authorized by the 1994 Immigration and Nationality Technical Corrections Act, is both the predominate pipeline for noncitizen IMGs with J-1 visas to enter the domestic workforce and the largest supplier of physicians to shortage areas.STROBE) reporting guideline. We assessed trends in the number of Conrad physicians and their distribution by specialty and geography. All tests were 2-sided, used an α level of .05, and were conducted in Stata statistical software, version 17.0 (StataCorp). The data were analyzed between May 30, 2022, and November 2, 2022.This retrospective cross-sectional analysis of all US states and the District of Columbia used data from 2001 to 2020 from the Rural Recruitment and Retention Network. These data were publicly available and determined as not human participant research by the corresponding author’s institutional review board. Informed consent was waived because the data were deidentified. The study followed the Strengthening the Reporting of Observational Studies in Epidemiology  supported by the program fell from 82% (n = 471) to 28% (n = 402) in the study period . The num5 However, considering the importance of specialty care physicians on health outcomes and continued shortages of those physicians, states should be encouraged to use the Conrad program to recruit those physicians to meet their needs.6 Declining Conrad physicians in rural areas suggests that the program may not have fulfilled its original goal of improving physician supply in HPSAs, of which the majority (65%) are in rural counties.This retrospective cross-sectional study revealed 2 trends in the Conrad program during the past 2 decades: the declining proportions of recruited PCPs and rural physicians. The decreased proportion of Conrad PCPs is a substantial finding given the severe shortage of primary care clinicians in the nation, with more than 86 million (26%) Americans living in primary care Health Professional Shortage Areas (HPSAs) in 2021.Although the present study assessed national trends of the Conrad program, we did not analyze state-level drivers of variations in program implementation. Further exploration of the Conrad program is needed, such as discussions with state officials about their definition of program success, their use of 10 additional FLEX slots, and their efforts to balance between PCPs and other specialists and between rural and urban areas. Identifying and sharing best practices across states can make the Conrad program more effective for improving physician supply in underserved areas.


This study evaluated the quality and accessibility of the websites of the Spinal Cord Injury Medicine (SCIM) fellowship programs to identify potential areas for improvement for future applicants. Twenty-four SCIM fellowship program websites were analyzed based on 44 predetermined criteria: website accessibility, education, research, recruitment, and incentives. This study found that many evaluated websites needed more information on didactics, educational resources, evaluation criteria, call requirements, schedules, and expected caseloads, which could lead to an incomplete understanding of the fellowship program. Additionally, more information on education and research can be needed for applicants to adequately compare programs and make informed decisions about which programs to apply to. Information about the selection process, current board pass rates, mentorship opportunities, technology/simulation, and alumni was limited across several evaluated websites. Incentives, fellow wellness, and harassment policies were also found to be insufficient or absent. The study emphasizes that SCIM fellowship programs should provide comprehensive and accurate information on their websites to facilitate applicants in choosing the program that aligns best with their professional goals. Including detailed and accurate information regarding general program qualities, educational and research opportunities, recruitment, and incentive data will provide prospective applicants with a holistic understanding of the program. By providing detailed and transparent information on their websites, SCIM fellowships can attract more qualified applicants and enhance the applicant pool, ultimately improving the quality of their program. Physical Medicine and Rehabilitation, commonly known as PM&R, offers various unique fellowship training experiences. One such discipline is known as spinal cord injury medicine (SCIM). PM&R residents and prospective SCIM fellowship applicants often utilize a fellowship program's website to learn about and choose between programs. While applicants are welcome to seek guidance from mentors or colleagues when selecting a program, the fellowship's website is regarded as the main source of information on which prospective fellows should base their decision . The easA cross-sectional analysis of 24 SCIM fellowship websites listed on the Fellowship Residency Electronic Interactive Database (FREIDA) on December 2022 was evaluated based on 44 predetermined criteria, including quantitative and descriptive statistics within four categories: website accessibility from FREIDA, education and research, recruitment, and incentives . The autAt the time of analysis, on December 2022, 24 active spinal cord injury medicine fellowship programs were identified . These pAll program websites  contained a description of the program and a contact email address Figure . One proBased on the evaluation, it was found that SCIM fellowship websites needed to be improved in several ways that applicants typically utilize to decide whether to apply for a fellowship Table . CriteriThrough a cross-sectional analysis of SCIM fellowship websites, this study focused on the presence or absence of key variables that can help applicants make informed decisions between programs of their choice. Many evaluated websites needed more information on didactics, educational resources, evaluation criteria, call requirements/schedule, and expected caseloads, which could lead to an incomplete understanding of the fellowship program. When such crucial information is unavailable, prospective applicants may need help understanding the objectives and expectations of a fellowship program. This lack of information could lead the applicants to apply for programs that do not align with their interests and career aspirations. It may also pose challenges for applicants to prepare for the program's rigors without having scheduling details. Furthermore, more information on education and research can be needed for applicants to adequately compare programs and make informed decisions about which programs to apply to or accept.Several evaluated websites needed information on selection, current board pass rates, mentorship opportunities, technology and simulation resources, and alums. The information about the selection process is vital for applicants to tailor their application materials to meet the program's selection criteria, which can impact their chances of being accepted into the program. The current board passes rates provide applicants insight into the program's quality and the graduates' success rate. Similarly, applicants need more alum information to gauge the program's effectiveness and career advancement opportunities after completion. Information on mentorship opportunities, technology/simulation, and expected caseloads is valuable for applicants to evaluate the program's quality and make informed decisions about their personal and professional development. Therefore, comprehensive and accurate information on recruitment variables should be provided on a fellowship's website to facilitate applicants in choosing the program that aligns best with their professional goals.Key information about incentives, fellow wellness, and harassment policies was insufficient or absent. These areas are integral to the decision-making process of prospective fellows. They should be a priority for fellowship programs to address to provide transparent and equitable opportunities to potential applicants -3. IncenSimilarly, compensation is essential to a fellow's financial security and stability throughout their training. Housing options are also a significant consideration for applicants who may be relocating for the fellowship program. The absence of such information may disadvantage applicants who require comprehensive details of these incentives before committing to a program. Moreover, fellowship programs must ensure their fellows' well-being and safety by providing resources and programs that promote wellness and address physical and mental health concerns. The absence of information on fellow wellness policies and resources may hinder prospective applicants from making an informed decision. It may lead to a mismatch between the expectations and reality of their work environment. This is particularly challenging for those applicants who may be relocating, where the availability of such resources may be unfamiliar.Similarly, the absence of information on harassment policies and procedures can create an environment that perpetuates harassment and negatively impacts the well-being and performance of fellows. Effective policies and procedures that address harassment and discrimination are essential for fostering a professional and safe work environment. Without this, prospective fellows may not feel comfortable reporting incidents and may be hesitant to apply to a program with a culture that is not conducive to addressing harassment effectively.Nearly all SCIM fellowship websites can provide prospective applicants with more detailed and transparent information. Accessibility to information is highly critical, especially during the current COVID-19 pandemic. As many fellowship interviews remain within the virtual space out of concerns for safety and feasibility, online platforms and their information are even more critical. Fellowship programs continuously strive to improve their processes to meet the diverse needs of applicants. This analysis of fellowship program websites is valuable for identifying improvement areas to enhance the match process's transparency and equity. Including detailed and accurate information regarding general program qualities, educational and research opportunities, recruitment, and incentive data will provide prospective applicants with a holistic understanding of the program. This can further assist applicants in making informed decisions about selecting a SCIM fellowship program that best aligns with their career objectives, which can improve the diversity of the fellows' cohort and ultimately elevate the quality of current programs.


Canada has incrementally reduced restrictions to blood and plasma donation that impact men who have sex with men, gay, bisexual, and queer men, and some Two Spirit, transgender and non-binary individuals (MSM/2SGBTQ+). Prior to the launch of a pilot program in 2021 enabling some MSM/2SGBTQ + to donate source plasma, we explored the acceptability of the program among individuals who could become eligible to donate in the program.We invited men identifying as MSM/2SGBTQ + to participate in two consecutive semi-structured interviews to explore their views on blood and plasma donation policy, plasma donation, and the proposed Canadian plasma donation program. Interview transcripts were analyzed thematically and acceptability-related themes were mapped onto the Theoretical Framework of Acceptability.Twenty-seven men identifying as having sex with men participated in 53 interviews. Eighteen themes were mapped onto the seven construct domains of the Theoretical Framework of Acceptability. Underlying all aspects of acceptability was a tension between four primary values influencing participants’ views: altruism, equity, supply sufficiency, and evidence-based policy. The program was viewed as welcome progress on a discriminatory policy, with many excited to participate, yet tension with inequitable aspects of the program undermined support for the program and interest to contribute to it. The high demands of the program are unique for MSM/2SGBTQ + and are only tolerable as part of a program that is an incremental and instrumental step to more equitable donation policies.Findings highlight past experiences of exclusion in Canada as a unique and critical part of the context of the donation experience among MSM/2SGBTQ+. Despite the program’s goals of greater inclusivity of MSM/2SGBTQ + individuals, the anticipated experience of the program included continued stigmatization and inequities. Future research should seek to understand the experienced views of MSM/2SGBTQ + donors to ensure that as policies change, policies are implemented equitably.The online version contains supplementary material available at 10.1186/s12889-023-15424-1. In response to a tragedy involving transmission of HIV and hepatitis C through blood transfusion and plasma products in the 1980s, Canada and many other countries followed the lead of the US Food and Drug Administration by introducing restrictions on the donation of blood and blood components by groups identified at the time to be at high-risk of contracting HIV (See  for overwho is meant to be included in the MSM category varies and the appropriateness of this designation terminology is contested  if that information [the rationale and roadmap] was clear and transparent, that would make me feel better about it (P07).”Participants integrated the rationale given for the plasma program as an opportunity to collect safety data on donors who identify as MSM/2SGBTQ + into their consideration of the program. The transparency of the scientific rationale for the program, the program’s role in further change to policy and the plan for further changes improved participants’ evaluation of the program:…it still makes a distinct policy that gay men are risky…it doesn’t change equity at all. It takes a small portion of men who are in monogamous gay relationships, and let’s them go back. But I don’t know how many people that’s going to affect (P14).For a few participants, a plasma program did not provide meaningful progress to the MSM donor criteria, as one participant said:Participants described that MSM-specific donor criteria makes them feel that their blood is “tainted” or “dirty” and perpetuates societal stigma that sex between men is risky and requires special policy. Regarding the MSM plasma program specifically, some were concerned that a program developed in 2021 that still imposed additional criteria for MSM/2SGBTQ + and required a quarantine for plasma donated in the program further perpetuated this stigma. Furthermore, adding questions about sexual activity and asking these questions only to men with male sexual partners perpetuates the myth that only sex between men is a risk for HIV. One participant explained.I think it’s quite homophobic and it’s really HIV stigmatising as well. It really kind of comes out there and says, heterosexual people are not going to get HIV, and heterosexual people, you don’t have to ask if they have multiple partners […] Like are these questions founded in good science? Or is this just to make people feel better about having a blood transfusion from a monogamous gay man, like with a white picket fence, living in the suburbs and carrying on this very traditional view of marriage (P07).Some participants worried that the MSM plasma program would divide MSM/2SGBTQ + communities into those who can and cannot donate based on monogamy. Monogamy as an eligibility criterion was regarded as heteronormative by some participants. Several noted that people in closed relationships with more than one person who are all HIV negative have a similar risk profile yet are excluded from the program. One participant reflected that the separation of MSM/2SGBTQ + along lines of monogamy will perpetuate “the ongoing feeling of judgement and stigmatization of non-traditional relationships and how the queer community kind of pushes those boundaries and still is not accepted and still is looked down upon (P27).” The proposed program risks dividing up their communities into those who are acceptable for donation and those who are not, where acceptability is judged based on their conforming to a value that is viewed as heteronormative by many.However, this view was not shared by all. Some participants expressed hope that changes to the time-based MSM policy would bring greater awareness to the diversity within the MSM/2SGBTQ + communities. The addition of sexual activity questions in the MSM plasma program represents a move “towards understanding the community a bit better and that there are different practices within relationships (P03)” and acknowledges the existence of relationships between men who are at very low risk of sexually transmitted infections and therefore no increased risk to the blood and plasma supply.Participants widely held the view that any policy using differential criteria based on gender and sexual orientation is discriminatory. Many participants questioned how such policies were acceptable under Canada’s anti-discrimination laws. The policies were often described as institutionalized discrimination, “one remaining thing that’s actually coded in policy (P24).” As an organization, Canadian Blood Services was discussed as a health care environment due to the nature of the donation process and the presence of health care professionals such as nurses. A health care environment with a policy based on gender and sexual orientation seemed out of step with Canadian legislation to protect the rights and freedoms of people identifying as 2SLGBTQ+.For many, learning about a program that may allow them to donate brought up feelings of excitement. Previous changes in the policy resulted in no practical impact for most MSM/2SGBTQ+. For those in exclusive relationships, the program would open donation for them. Excitement for the approval and launch of the program dominated the discussion because it would allow them personally to donate and donation was very important to them. As one participant said: “It’s a positive step in that, you know, ‘Holy crap, I’m able to actually donate for the first time in my life! (P24).’” Others described very positive experiences of blood donation prior to becoming sexually active with men and were eager to continue this activity, “it would feel good to be able to donate again (P21),” and expressed interest in learning about the process of plasma donation. Some participants described cultures of blood donation in their families and among their circles of friends that they may now be able to participate in. The limitation of plasma was not a barrier: “I’ve of course talked to them after our first interview, and already they were saying, ‘This is so great. As soon as we can, let’s go book a time and go do plasma together (P24).’” They were very keen to donate, even if the opportunity was limited to plasma.For the most part, the MSM plasma program including the additional questions asked of men answering ‘yes’ to having had sex with a man, and the requirement for return donations, were not viewed as burdensome in and of themselves. Many were motivated to donate and keen for the opportunity the MSM plasma program would offer: “I just would be happy that they are willing to ask those questions instead of just immediately dismissing me (P09).” As a result, the differential treatment of the MSM plasma program was not viewed to be burdensome.were not applied to other donors. Participants talked about feelings of alienation, unique demands, the stress associated with outing, and the burden of continually advocating for themselves.The MSM plasma program was only viewed as burdensome due to the injustice that such conditions Before the MSM plasma program was explained in detail, participants anticipated positive feelings with donation such as satisfaction and the ‘warm glow’ associated with good deeds. The differential criteria and process involved in the MSM plasma program led participants to anticipate additional feelings of alienation. The program is an indication that they are viewed differently than other donors. As one participant put it: “Here we go. I’m the gay person. So, I have to be put aside and to do that, it plays with your worth. It will never feel good” (P12). Some participants referenced a mistrust of the medical community that is prevalent among MSM/2SGBTQ + communities:“There would be kind of a feeling of mistrust. When you’re part of this community that already has issues just in your regular life, trying to make sure that you have access to healthcare providers who understand what you do and what you’re going through, that’s not a great feeling.” (P27)More generally, the program provided a reminder of other experiences of being discriminated because they identify as MSM/2SGBTQ + and reinforcing a sense of alienation in the larger society that they live in. “There’s a lot of stress from being asked a set of questions which are unique to you as a gay man. There’s still some ostracizing happening (P14).”The MSM plasma program involved a number of requirements of MSM/2SGBTQ + donors that were not required of other donors For most, the unique demands were viewed as burdensome only because they were not required of donors who did not identify as MSM/2SGBTQ+.Some participants noted annoyance at “having” to go to the plasma donor centre rather than a more convenient mobile clinic in their neighbourhood. Others related that maintaining eligibility to make return donations in order to have their past donations utilized placed a burden not only on them personally, but on their partner due to the exclusivity requirement.The MSM plasma program invites MSM/2SGBTQ + to donate but requires them to be outed during the screening process. Some participants described a hypervigilance that may be experienced.Internal trauma’ for want of a better word (P25).When the question comes up, ‘have you had sex with another man in the last three months?’, there’s that kind of time stop or time slowdown in between them asking and wanting to answer, where you start picturing all of their potential reactions. […] I’m on edge, so I kind of interpreted it as a reaction, where there’s like a tsk or a mouth movement. You’re like, wait, what was that? There’s not really a space to ask or reconcile that at all. I can’t ask them, ‘Is that a problem?’ because they’re in a professional position where they’d say, ‘no, no, not at all, of course not’, even if it did kind of feel that way. ‘For some, this hypervigilance is related to the individual to whom the disclosure was made. For others, the hypervigilance extends to the whole donation experience. Participants described feeling that their sexual orientation had made them feel unwelcome in the donor centre. Some anticipated that they would be looking out for any indication that while they may now be allowed to donate as part of the program, they weren’t truly welcome: “I’d be quite sensitive to the interactions with anyone in that space that was sort of proposed that I’m not supposed to be there (P03).” The required outing by the MSM plasma program and the subsequent vigilance for signs of prejudice is an emotional vulnerability and stress not borne by other plasma donors.Some participants felt responsible to continually advocate for better policies. This included donating in the program if they could, given the rationale that the data collected in the program was necessary to support better policies. Participants also planned on sharing their views of the inequity of the policy with donor centre staff during a donation. Not only did they feel they had to take every opportunity to advocate for their community, but they also considered the experience of the recipients of their activism.I feel bad for the nurse, it’s not their policy, they’re just executing what the policy is, and I know my initial inclination is that I’d like to provide some comments back during each opportunity that I would have (P24).I’d like to say the priority is to increase the supply above all else, but obviously, coming from my point of view and what I’ve experienced […] the most important thing is to remove another thing that’s part of the legacy of discrimination for gay men (P08).The characteristics of participants’ value systems that were most frequently discussed in relation to their views on the MSM plasma program were altruism, equity, sufficient supply, and evidence-based policy Fig. , with alTFA construct 6 - Self-Efficacy.This process of how participants weighed these values in their decisions to participate in the MSM plasma program is discussed under the Two elements of the MSM plasma program were not clear to participants: plasma donation itself was not well known among participants, and participants disputed that these criteria would adequately safeguard the blood/plasma supply from HIV, particularly related to heterosexual activity.Most participants had heard little about plasma donation before participating in the study. They didn’t know what it was used for, yet with a small amount of education most made the logical leap that if it was a type of donation that could be made, then it must be needed and useful. Participants who were strongly motivated by altruism trusted that plasma donations were important and drew from their understanding of and motivation for blood donation to consider the MSM plasma program. “We don’t hear about it [plasma] enough to decide. So, I don’t really have a huge opinion on it. But what I did hear after I saw the post [study recruitment] was very intriguing. And I’m on board(P12).” Others expressed that they would need more information about who and how it helps.promiscuous, is also at high risk of HIV, depending on what their activities are. Why men are singled out in that respect is, to me, it’s kind of bizarre (P04).”Participants’ perceptions of the MSM donor criteria were that they were mainly meant to protect the supply from HIV. Many accepted that the ban was initiated at a time when HIV was poorly understood, and that HIV was more prevalent among MSM/2SGBTQ + communities. Participants believed that screening for HIV could only be effective when questions about sexual activity were being asked of all donors. “Somebody who is, to use the word Participants either knew that all donations were tested, or they deduced that some back-end technology enabled heterosexual donors to donate without screening their sexual activity. Participants felt that these processes should also be sufficient for donations by MSM/2SGBTQ+.Given an explanation of the need for donor screening due to the window period for blood-transmissible infections, participants often responded similar to “it’s not like straight people are excluded from having HIV (P14),” since the risk of window period infections would apply to all donors. “I would almost want to reverse argue that to the general public and say, ‘well, aren’t you more concerned with the fact that they’re not screening everybody else?’ (P13)”.some risk, particularly for those with higher numbers of casual partners. The lack of screening of heterosexual acts contradicted their understanding of HIV transmission and led participants to question the evidence base of the policies.The risk from heterosexual acts is not acknowledged by the current or proposed criteria, yet participants were certain that heterosexual acts carried TFA construct 6 - Self-Efficacy.The primary opportunity cost discussed by participants was the requirement to put aside or act against their values of equity. Many felt that participating (and donating) meant implicit agreement with the policy decisions. To participate, they would have to put aside their feelings that the policy, screening, and quarantine were unfair and ultimately put aside their personal right to be treated fairly. One participant described that he would “overlook the back-of-my-mind sentiment that this is unfair (P24).” Discussion on how this opportunity cost contributed to participation decisions is provided under the Participants who were primarily driven by their values of altruism were eager to donate whatever they could, whenever they could. “I would be the first to line up to donate for plasma if I was able to (P24).” Many responded to the question of whether they would participate in the MSM plasma program if they were eligible with a resounding and unqualified “yes”. Some participants with strong values of equity were also keen to donate to finally be included where they were not before: “I would probably donate just almost for the sake of, I can now, therefore I will. Like when you get a new right, the idea that you should exercise it (P06).” Given a concrete program that would soon become available, participants who believed they may be eligible were already planning how they would fit regular plasma donation into their lives. Participants who were willing either did not find the program burdensome or they were willing to endure the unique demands:…[the additional questions are] not saying that you can’t donate, it’s just saying, we need to know a little bit more about you before you can donate. If I was able to do it [donate plasma], then it doesn’t really matter what kind of process I’d have to go through to be able to do that(P15).Participants discussed their intention to donate as a result of weighing of their values. There was hesitation and pausing as they worked through their feelings. For example.It would be good to know that you’re helping someone with the plasma even though the policies are still there. So, I’m not sure. I would like to think that I would, but I wouldn’t know for sure. It still feels discriminatory (P22).It does feel a little bit isolating still, like you’re able to donate, but …almost feels like suspicious of your plasma. Like, “oh, we need another one to really make sure that it is safe”. It feels like a little untrustworthy, which I do understand because it could be like a high stakes thing because it’s given to someone, but yeah…(P09)For some, learning about the rationale for the MSM plasma program and that their participation may actually contribute to advancing the policy helped to lessen the feeling of inequity and thereby reduce the conflict of values. One participant summarized this integration when answering if they would consider participating: “Knowing what I know through this [interview], absolutely. I feel other people would as well if the communication is managed (P25).”For some participants, the costs of participating would be too great. One participant had been keen to participate in the MSM plasma program until he learned that any donated plasma would have to be quarantined. He said.Now you don’t have any of my support. So that’s my answer. […] If you’re only going to use my first sample after...like I fit the criteria and then you are still [..] doing something? No thank you. Have a nice day. I value myself way too much to be treated that way (P12).For others, participating would mean implicit agreement with the policies, which felt intolerable: “You need to be doing things equitably and properly in order for me to feel comfortable to participate. And until that happens participating it almost feels like you’re sleeping with the devil (P23).”Between limited eligibility among MSM/2SGBTQ + and unwillingness of some who would become eligible to participate, the program’s effectiveness would be reduced in that it would not enable great numbers of new donors identifying as MSM/2SGBTQ+. “I don’t know that gay men, or MSM who are in exclusive relationships who are interested in donating blood, is that large of a population (P11).” It was hard for participants to anticipate how many of those who were interested in the topic were actually interested in donating or because “it was a health organization that seemed like it was discriminating (P20).” Since it is such an important political issue to 2SLGBTQ + communities, some participants questioned if excitement about the change would actually translate to donors in chairs. Others were confident that “the subset who would be eligible would be very ready to donate (P09).”In this study, we interviewed men who would be impacted by a change in the MSM donor criteria and a new pilot plasma donation program they could become eligible for to explore the program’s acceptability. These findings offer significant insight into the views of the targeted community about an equity-focused policy change and intervention. The novel use of the Theoretical Framework of Acceptability enabled a nuanced description of not only participants’ views, but also the burden of differential treatment, the cost of putting aside a right to equitable treatment, the perceived incoherence of how the program screens HIV, the willingness of participants to donate within the MSM plasma program and the values that underpin their views.Our study found four primary values that provided the foundation upon which participants considered the MSM plasma program. With varying importance, participants considered the program in light of altruism, equity, supply sufficiency and evidence-based policy. Altruism is an important motivating factor for plasma donation in this population  and amonDifferential treatment was the most problematic aspect of the MSM plasma program. Although it was voiced primarily in relation to the additional screening questions, this may have been due to order effects during the interview. There are several unique costs and burdens to donors in the program. Donors would be outed, asked more personal information, and have to become regular donors in order to contribute. Many altruistically-motivated participants were willing to put aside their values of equity to exercise their altruistic motives. These findings are consistent with other studies, which found that some individuals who are excluded from donation due to the MSM donor criteria would be willing to donate if eligible even under policies they do not feel are fair , 30. In Our data collection differed from previous studies that examined acceptability of plasma-only programs in terms of the scope of education to participants, both regarding plasma and plasma donation, and the rationale for the program. This framing of the program may have enhanced acceptability as presentation of the intervention influences implementation success . Source Consistent with views on the last change to the MSM donor criteria in Canada , the MSMonly for donors identifying as MSM/2SGBTQ + may perpetuate the false and dangerous dichotomization that heterosexual acts are “safe” in contrast to homosexual acts that are “risky”.Participants considered the potential impact of the MSM plasma program on stigma impacting their communities. The public nature of this criteria and debate surrounding it provides broader reach of its impacts. Any policy changes may influence perceptions of the impacted communities among donors who must answer these questions, and within the larger Canadian society. Hofkirchner and colleagues examined bias against MSM/2SGBTQ + depending on the placement of the question about sex with men in the donor screening questionnaire . They coBlood operators are under pressure to evolve the MSM donor criteria, and participants emphasized that change in and of itself was positive. This desire for change, even if imperfect, is consistent with other studies in this population , 17. Cha“a single instance of anal sex (even with condom use and PrEP [pre-exposure prophylaxis] use) carries a greater risk to the blood supply than hundreds or thousands of instances of vaginal sex in the same period” [Since the collection of this data, a submission by Canadian Blood Services to Health Canada, the regulator of donor criteria in Canada, was approved, and new sexual activity questions will be asked of all donors. All donors  will be asked about new or multiple partners in the previous three months. Among those who have engaged in these activities in the last three months, those who have had anal sex will not be allowed to donate regardless of condom use. This policy is similar to the sexual activity criteria implemented in the United Kingdom . Critics period” , and maySimilarly, impacted communities may feel that blood operators do not understand or take into account the great advances in technology and practices that have reduced the risk of HIV transmission in their communities. Although receptive anal sex with an HIV positive partner without condom use or use of antiretroviral medication by the partner remains the type of sexual activity with the highest risk of HIV transmission, risk estimates drop dramatically when these protective measures are in place, even below that of unprotected vaginal sex with an HIV positive partner . Very hiWhere HIV continues to disproportionately affect MSM/2SGBTQ + communities, Pierik et al. argue that blood operators face morally and ethically challenging choices to develop policies that trade-off on values such as safety to recipient, right to equal treatment including nonstigmatization, and a sufficient blood supply . In the Two-part interviews enabled sustained engagement with participants and facilitated the development of a level of trust necessary to generate rich data . ParticiThe Theoretical Framework of Acceptability (TFA), enabled reporting of the acceptability of the MSM pilot plasma program along a comprehensive and diverse range of dimensions of acceptability. Building upon the conceptualizations of acceptability in the literature and using consistent language as much as possible enhances opportunities for researchers and policymakers to evaluate and compare programs aiming to implement more inclusive screening. Furthermore, the abstraction to higher level acceptability components enable comparison with other types of donor programs. Although deductive analysis risks losing nuanced understanding of the data , the comOur recruitment language focused on eliciting opinions about the proposed MSM plasma program and resulted in a highly motivated sample whose views may not represent all communities impacted by the MSM donor criteria. Yet, it is an important group to understand as they would likely be the first to participate if eligible. Similar to the donor pool in Canada and elsewhere , the majParticipants’ perspectives were collected in anticipation of the implementation of a policy change. It would be important to also assess the acceptability of the policy and its implementation among impacted communities and other implementation outcomes such as the appropriateness of the implementation, the coverage or reach of the implementation, and the sustainability, particularly given the high burden of the plasma quarantine involved in the program .This study elicited the views and the anticipated experience of the population targeted by a limited-term, equity-focused policy implementation that will open a form of blood donation for the first time in over three decades to some men who are sexually active with men. Four primary values support their views: altruism, equity, supply sufficiency and evidence-based policy. The conflict between the (in)equity of the program and an individual’s drive to engage in an altruistic action impacted their judgements of the program and their decisions about whether they could participate in it. The unique burdens and opportunity costs asked of newly eligible donors identifying as MSM/2SGBTQ + highlighted the potential for an inequitable experience despite more inclusive eligibility criteria. The incongruence of the criteria with current scientific knowledge on HIV transmission and risk reduction, particularly with respect to HIV transmission via heterosexual acts, must be addressed as it continues to fuel the belief that donation policies are not evidence-based. Furthermore, MSM or anal sex-specific policies have the potential to stigmatize MSM/2SGBTQ + communities. There are opportunities to mitigate negative impacts by acknowledging the harms and costs of these policies, communicating the process of policymaking and the supporting evidence, demonstrating allyship, and actively destigmatizing MSM/2SGBTQ+. Future research should seek to understand the experienced views of MSM/2SGBTQ + donors to ensure that policies are implemented equitably as they evolve.Below is the link to the electronic supplementary material.Supplementary Material 1


ARID1A is frequently mutated in cancers, especially in gynecologic ones, but very little attention has been paid to determine ARID1A levels in tumor specimen. Therefore, the main aim of this work was to develop an enzyme-linked immunosorbent assay (ELISA) to measure ARID1A protein levels in an accurate and precise manner. In addition, we performed western blot analysis to validate the ELISA results. As we can show the high specificity, accuracy, and precision of our assay, further research can now focus on whether ARID1A protein levels are of predictive value, as most current methods analyze its gene ARID1A only. In terms of functionality, ARID1A is a member of the SWI/SNF complex, but it is not clear how mutations in members of this chromatin remodeling complex lead to tumorigenesis. We hope to facilitate the quantitative analysis of proteins involved in tumorigenesis with this detailed ELISA protocol for the nuclear protein ARID1A.ARID1A is frequently mutated and ARID1A levels are lowered in several human cancers, especially gynecologic ones. A functional ARID1A loss may have prognostic or predictive value in terms of therapeutic strategies but has not been proposed based on a quantitative method. Hardly any literature is available on ARID1A levels in tumor samples. We developed an indirect enzyme-linked immunosorbent assay (ELISA) for ARID1A based on the current EMA and FDA criteria. We demonstrated that our ELISA provides the objective, accurate, and precise quantification of ARID1A concentrations in recombinant protein solutions, cell culture standards, and tissue lysates of tumors. A standard curve analysis yielded a ‘goodness of fit’ of R2 = 0.99. Standards measured on several plates and days achieved an inter-assay accuracy of 90.26% and an inter-assay precision with a coefficient of variation of 4.53%. When tumor lysates were prepared and measured multiple times, our method had an inter-assay precision with a coefficient of variation of 11.78%. We believe that our suggested method ensures a high reproducibility and can be used for a high sample throughput to determine the ARID1A concentration in different tumor entities. The application of our ELISA on various tumor and control tissues will allow us to explore whether quantitative ARID1A measurements in tumor samples are of predictive value. ARID1A is a subunit of the mammalian SWI/SNF complex, which is thought to regulate gene expression through restructuring chromatin structures. Its gene  As the mammalian homolog of the SWI/SNF complex (switch/sucrose non-fermentable complex), the BAF complex (short for cell BRG1/BRM-associated factor complex) has its role as an ATP-dependent chromatin remodeling complex in the nucleus and contains up to 15 subunits with varying combinations. These are encoded by 29 genes and take three differently assembled forms in humans: canonical, polybromo-associated, and non-canonical BAF  , Raab etARID1A gene has the highest mutational rate between 4.6% and 9% [ARID1A mutations were described first in gynecologic tumors, it seems as if their role in both endometrioid and clear-cell ovarian cancers is of particular importance [ARID1A mutation frequency rate of nearly 45.2% in those tumor entities [ARID1A [ARID1A promoter hypermethylation and it is likely that both mechanisms may work in combination for a tumor to achieve a complete loss of ARID1A proteins [In 2013, two independent studies described that approximately 20% of all human cancer types harbor mutations in the mammalian SWI/SNF complex and that the % and 9% ,6. Sinceportance ,8. Kadocproteins ,11. Due ARID1A-inactivating mutations lead to a change of the cell type and convey resistance against estrogen-receptor degrading treatment [ARID1A mutation is being investigated in a phase II study NCT05023655 [Consequently, the quantification of ARID1A seems to be of great importance. On the one hand, preserved ARID1A is regarded as a prognostic marker in some tumors, e.g., for stage I/II ovarian clear cell carcinoma and endometrioid ovarian cancers . As a prreatment . On the reatment . Severalreatment  and the 05023655 .On the technical side, there is a shortage of quantitative methods measuring the concentration of ARID1A in an easy and accurate way. Few commercial ELISA kits are available, which are, on the one hand, expensive (300 EUR per 96-well plate and higher) and, on the other hand, have not been used or referred to for research see . Also, tTo provide optimal binding conditions for the ARID1A protein to the plates, we analyzed the hydrophobicity of ARID1A using GRAVY (grand average of hydropathicity index), as proposed by Kyte and Doolittle (1982) , by ExpaARID1A knockout HEK-293T cell pellet  and the corresponding control cell pellet. Western blot analysis was performed using ARID1A wild-type and knockout western blot lysates . The primary antibody ab182560  binds a region between amino acids 1200 to 1350, covering the fragment’s epitope sufficiently. As a quantitative standard, we used an ARID1A fragment  containing amino acids 1216 to 1325 (NCBI Reference Sequence: NP_006006.3) and, to ensure specificity, we used an We performed tumor tissue analysis with 37 meningiomas resected at the Department of Neurosurgery, Saarland University, between 2018 and 2021, and subsequently diagnosed after neuropathological expertise according to the WHO classification of the tumors of the central nervous system . Ethicalg for 5 min. The treated tissue lysate was then fractionated into cytoplasmic, membrane-bound, free nucleus, and chromatin-bound fractions according to manufacturer’s instructions. This resulted in approximately 1000, 650, 225, and 170 µL of cytoplasmic, membrane-bound, free nucleus, and chromatin-bound fraction, respectively, with a total protein concentration ranging in average between 500 µg/mL and 10 mg/mL protein with the highest values seen in the cytosol. Knockout and wild-type cell pellets were prepared using 20 µL packed cell volume and following the manufacturer’s instructions corresponding to the protocol ‘Subcellular Protein Fractionation Kit for Cultured Cells’ .We chose the ‘Subcellular Protein Fractionation Kit for Tissues’  as this kit contains strainers to retain excess connective tissue or bone fragments that could contaminate the lysate and, thus, impair correct measurement. This characteristic was indispensable because tumor tissue is often attached to ligaments or other connective tissue, and we aimed at minimizing the variation in tissue quality due to inadequate lysate preparation for downstream applications. In brief, 100 mg tumor tissue were weighed and placed into the Precellys Ceramic tubes , and 1000 µL of cytoplasmatic extraction buffer (CEB) for tissues was added. The sample was homogenized two times for 20 s on speed 2 within the Minilys homogenizator . The lysate was placed onto the cell strainer within a falcon tube and centrifuged at 500× To measure protein concentrations in the lysates to ensure plate binding saturation, we used a ‘Pierce bicinchoninic acid (BCA) protein assay kit’  as the manufacturer’s instructions allow the use of our buffers from the Subcellular Protein Fractionation Kit, including cytoplasmatic extraction buffer (CEB), membrane extraction buffer (MEB), and nuclear extraction buffer (NEB). In brief, standards reaching from 20 µg/mL to 2000 µg/mL as well as 1:26 diluted lysates  were added on the NUNC MaxiSorp plate. The BCA working reagent was prepared, and 200 µL were pipetted per well. Incubation started with gentle shaking on a plate shaker for 30 s, then the plate was covered with parafilm and incubated at 37 °C for 30 min. Results were analyzed using the FLUOstar Omega Microplate Reader  at 562 nm.t-tests were performed using GraphPad Prism (version 9.4.1). Interpolation of data should be performed by the simplest fit available; therefore, a 4-parameter logistic fit (4PL) has been used. Some measurements needed a 5-parameter logistic fit (5PL) to improve the curve’s fit.Curve analysis and non-parametric fits as well as Student’s w/v) casein at room temperature (=RT) for 2 h on a plate shaker. Then, the primary antibody was diluted 1:1000 in antibody solution, and 100 µL were added to the wells and then incubated at RT for 2 h. The plate was treated with the secondary antibody diluted 1:2 analogously  as this was the most efficient setting (sometimes including anchor points at the high or low end). To maintain high reproducibility of the assay, run acceptance criteria included accuracy > 80% of the actual value  and precision <20% (expressed as coefficient of variation (CV), <25% for LLOQ and ULOQ) in a minimum of 75% of the standards. Additionally, correctness (R2) should be above 0.97 and, after excluding standards failing the above-described criteria, at least six standards should remain. For incurred sample reanalysis (ISR), our aim is that 67% of the samples should be within ±30% of the mean [For data analysis, we analyzed the absorbances with the MARS software provided by the FLUOstar Omega Microplate Reader, applying background corrections and using several replicates of eight differently concentrated calibration standards. Additionally, we measured six incurred samples from tumor tissue as quality controls at least in duplicate. Standard curve analysis was performed using GraphPad Prism  using a 5-parameter logistic with weighted fit : the standard deviation divided by the mean of an analyte, multiplied with 100 to express the results in percentage ,24.Western blot was performed according to the method of Laemmli (1970) . Equal aARID1A wild-type and knockout cell lysates, which revealed a significant decrease in ARID1A concentration in the three subcellular fractions, cytosol, free nucleus, and chromatin. Moreover, all these results were confirmed by a complementary western blot analysis.To validate the provided technically simple and robust enzyme-linked immunosorbent assay (ELISA) protocol, we first analyzed our calibration curves and determined a quantitative range between 0.78 ng/mL and 50 ng/mL ARID1A. Because this range allows optimal ARID1A analysis in our tumor lysate dilutions, we consequently performed specificity analyses in The sensitivity  of our ELISA was 0.39 ng/mL as this was the minimal concentration that could be detected with acceptable precision and accuracy see A. Howeve2), which represents the ‘goodness of fit‘, regarding the AE standard curve was 0.987 in a very robust model that included all experiments conducted for this paper. When considering each plate individually (=EP model), nine out of eleven tests for the resulting calibration curves had an R2 value above 0.99. The theoretical model, thus, describes reliably the dependence of absorbance signals and ARID1A standard concentrations.The coefficient of determination  and the other one being ARID1A wild-type (=WT). In theory, a complete knockout, as caused here by a 11 bp homozygous deletion in exon 1, leading to a truncated ARID1A protein, should deplete the ARID1A signal in our ELISA measurement. In the knockout cell line, a signal decrease across all four fractions is visible  in knockout cells (see ARID1A wild-type and knockout (ab278824) according to p ≤ 0.01) in signal intensity at the 242 kDa band is evident in all four fractions . A band at nearly 242 kDa is only visible in the wild-type lysate see . Performells see D. We nexractions C,E.ARID1A deletion, it might be unspecific binding. In addition, only in the chromatin fractions is an additional band of almost 16 kDa present  demonstrated no improvement for our assay.In the enzyme-linked immunosorbent assays, chromatin fractions had high background signals at about 40% of the back-calculated concentration and varied only minimally compare A. Detailp = 0.0009) higher signal in the chromatin fraction but in no other, indicating the unspecific interaction of our secondary antibody with the buffer ingredients  and wild-type (WT) lysates and found a complete annihilation of the knockout signal (0.027 OD) in the chromatin fraction when the blank value of 0.0315 is subtracted (see p > 0.05). This could be a great improvement for further ARID1A analysis in cell cultures or tissue homogenates, as it is very straightforward to implement. However, these results should be further validated.In this work, we demonstrated that our ELISA is specific for ARID1A see A, but chcted see . Wild-tyARID1A mutants, as many tumors carry ARID1A point mutations [ARID1A, however, leads to an exchange of the amino acid glycine at position 2087 to valine, arginine, or glutamic acid  of 0.99 is an indication of the high representability of the standard curve that can be obtained with the fragment  is a protein that shares a nearly 60% sequence identity with ARID1A . In termions see A. These r WB see B,D, or aents see C,E. Sincents see . The antWith this ELISA, we hope to provide a useful tool for research and clinical application in the near future. To use a synthetic lethal effect in tumor cells, knowledge about the actual expression of ARID1A is essential.2 of 0.99 regarding the standard curve across all assays performed on different days. The accuracy and precision of the standards meet with 90.26%, and a coefficient of variation with 4.45%, respectively, the EMA and FDA criteria, even across several plates. Additionally, our ELISA clearly distinguished HEK-293T wild-type cell lysates from homozygous ARID1A knockout cells. The results were further confirmed by western blot. Furthermore, an analysis of the accrued samples showed that the combination of lysing and measuring with this protocol yielded a precision with a coefficient of variation of 11.78%.Here, we present an enzyme-linked immunosorbent assay (ELISA) to quantitatively measure ARID1A levels in tumor tissue or cell culture lysates. In brief, lysates are coated on a high affinity plate that has improved conditions for hydrophilic proteins such as ARID1A. To avoid effects due to dilution, total protein concentrations should be above 20 µg/mL. Validation of our assay showed a quantitative range from 0.78 to 50 ng/mL ARID1A and RARID1A wild-type and mutated tumors. In the future, it may be used for prognostic and predictive purposes in tumor entities and their therapies, especially since the use of synthetic lethal effects in tumor cells is gaining momentum in phase II studies. Biochemical assays requiring moderate technical equipment and using standard chemicals and consumables like our proposed ELISA method allow a high sample throughput and will accelerate personalized medicine and treatment.Our ELISA can help to detect and understand protein expression changes in


Digital health programs that incorporate frequent blood pressure (BP) self-monitoring and support for behavior change offer a scalable solution for hypertension management.We examined the impact of a digital hypertension self-management and lifestyle change support program on BP over 12 months.t tests and linear regression were used to measure the changes in systolic blood pressure (SBP) over 12 months overall and by SBP control status at baseline (≥130 mm Hg vs <130 mm Hg).Data were analyzed from a retrospective observational cohort of commercially insured members (n=1117) that started the Omada for Hypertension program between January 1, 2019, and September 30, 2021. Paired P<.001). Members with uncontrolled SBP at baseline also had significant reductions in diastolic blood pressure , weight , and BMI . Those with controlled SBP at baseline maintained within BP goal range. Additionally, 48% (418/860) of members with uncontrolled BP at baseline experienced enough change in BP to improve their BP category.Members were on average 50.9 years old, 50.8% (n=567) of them were female, 60.5% (n=675) of them were White, and 70.5% (n=788) of them had uncontrolled SBP at baseline (≥130 mm Hg). At 12 months, all members (including members with controlled and uncontrolled BP at baseline) and those with uncontrolled SBP at baseline experienced significant mean reductions in SBP (mean –4.8 mm Hg, 95% CI –5.6 to –4.0; –8.1 mm Hg, 95% CI –9.0 to –7.1, respectively; both This study provides real-world evidence that a comprehensive digital health program involving hypertension education, at-home BP monitoring, and behavior change coaching support was effective for self-managing hypertension over 12 months. Hypertension, which is defined as systolic blood pressure (SBP) ≥130 mm Hg or diastolic blood pressure (DBP) ≥80 mm Hg, impacts nearly 1 in 2 adults in the United States and increases the risk for heart disease and stroke, 2 of the leading causes of death both in the United States and globally . A stronVarious interventions that incorporate evidence-based behavioral strategies such as self-monitoring of blood pressure (BP) -9 and heIn support of using home blood pressure as part of the management of hypertension, the American Heart Association (AHA) and the American Medical Association reviewed the evidence for the use of home blood pressure monitoring (HBPM) . HBPM isDigital health and mobile health solutions combine the advantages of HBPM and the provision of data-driven insights with programs designed to support patients through self-management, goal setting, behavior change, and healthy lifestyle education . Some diAs health care grapples with hypertension as a persistently undertreated and costly chronic disease, more pragmatic solutions are needed to address the significant time required to support lifestyle modifications, improve HBPM adherence, and respond to the real-time data being collected through HBPM to ensure that appropriate and timely care is being delivered.The Omada for Hypertension program is a digital health behavior change solution that combines HBPM with human-led coaching support and a comprehensive lifestyle modification curriculum. A recent pilot study demonstrated that Omada for Hypertension members improved BP control after 3 months ; howeverThis was a nonrandomized, retrospective observational cohort study evaluating the clinical outcomes from baseline to 12 months among commercial health plan members enrolled in the Omada for Hypertension program. To enroll in the Omada for Hypertension program, individuals were required to meet the following criteria: (1) have coverage from their employer or health insurance plan for the benefit; (2) be ≥18 years old; (3) have a self-reported diagnosis of hypertension; and (4) not have any medical contraindications. All members self-enrolled in the program and were not compensated for their participation.To be included in the current analysis, members met the following criteria: (1) previously or currently enrolled in the Omada for Hypertension program; (2) completion of baseline and 12-month home BP readings (following the procedures described in the Measures section below); and (3) a program start date (defined as the date of first home BP reading uploaded) between January 1, 2019, and September 30, 2021.The study was a secondary analysis of previously collected deidentified commercial data and thus was deemed exempt from ethics approval by the WCG institutional review board (confirmation ID: 45104379).The Omada for Hypertension program is a digitally delivered hypertension self-management program that pairs asynchronous human support through health coaches and hypertension education specialists with a virtual platform that is accessed either through a website or through an app available on web-enabled devices . The program offers both a hypertension education curriculum and comprehensive lifestyle self-management support using behavior change techniques, in addition to a cellularly connected BP cuff for HBPM  and a cellularly connected digital scale .Program members are paired with an Omada care team, which includes a health coach and a hypertension education specialist  who communicate with members through an asynchronous messaging platform. Members are instructed to take BP measurements at home on a monthly basis (per the protocol described in the Measures section below), as well as prior to a scheduled visit with their doctor, after a change in medication, and according to their doctor’s instructions. The health coach supports members’ progress throughout the program, provides feedback to members regarding HBPM, encourages medication adherence, and prepares members for their doctor visits. The hypertension education specialist reviews members’ BP data and provides individual feedback and counseling on nonpharmacological treatment for BP pattern management as needed.Additional program components include hypertension education content, lifestyle modification advice , social support, goal-setting tools, self-monitoring capabilities via cellularly connected devices, feedback on self-monitoring data, BP pattern management, and check-ins with members to encourage communication with their health care providers when adjustments to medication or care may be needed. Recommendations made by the Omada care team are done in alignment with the member’s care plan created by their regular treating provider. In addition, members are placed in a virtual peer support group and can communicate with other program members through a secure group discussion board.Members measure their BP (mm Hg) with a Food and Drug Administration-cleared cellularly connected BP device, which is connected to the member’s account and requires no additional setup. Members also had the option of using their own BP device and manually reporting their readings in the app or website, but only approximately 2% of members used this option. Members were provided with instructions for how to perform accurate BP measurements at home  and wereMembers’ BP measurements were averaged if the measurements met the following minimum criteria at baseline and 12-month follow-up: (1) 3 or more measurements taken over at least 3 days with at least ≥1 measurement collected per day or (2) ≥4 or more measurements taken over at least 2 days with ≥2 measurements collected per day . The basTo keep consistent with AHA/American College of Cardiology–recommended treatment goals for those with hypertension, the normal and elevated HBPM categories were consolidated into an “At Goal” category. Thus, HBPM categories were defined as (1) At Goal: SBP<130 mm Hg and DBP<80 mm Hg, (2) Stage 1: SBP between 130 and 134 mm Hg or DBP between 80 and 84 mm Hg, and (3) Stage 2: SBP ≥135 mm Hg or DBP≥85 mm Hg ,21.2 vs without obesity <30 kg/m2).Body weight (lbs) was collected with an Omada-provided cellularly connected digital scale, which is linked to the member’s account. The baseline and 12-month data were calculated as the average of all weight measurements on the day with at least 1 weight measurement closest to the program start date within the window of 7 days prior to and 30 days post the program start date and within an 11- to 13-month window from the program start date, respectively. Absolute change in body weight and percent weight loss from baseline to 12 months was calculated. BMI was calculated from self-reported height and measured weight and categorized into an obesity indicator variable , race and ethnicity , annual income , and educational attainment (college education and above and less than college education), upon enrollment in the program. Self-reported medication usage was collected during account setup and further categorized into a 2-level variable for whether members were taking hypertension-related medications versus not at baseline .Program engagement was measured by counts of actions taken within the program app or website each week in the program and included six components: (1) number of conversations started on a group discussion board; (2) number of comments (replies to conversations) made on the group discussion board; (3) number of hearts (likes) shared on the group discussion board; (4) number of messages sent to their Omada care team; (5) number of meals tracked; and (6) number of lessons completed. The median of the average weekly activities for all members was used as the cutoff point for high versus low engagement .Additionally, activities related to self-monitoring behaviors were captured by the average number of times per week that members recorded a physical activity as well as the average number of times per week that members recorded weight. BP engagement was assessed by the average times per month that members used their BP cuff or manually entered BP readings.t tests. Changes in clinical outcomes  from baseline to 12 months were assessed using paired t tests. Differences in the proportion of hypertension members within each stage  were analyzed using a marginal homogeneity test of symmetry to determine whether there was a significant shift of members within each stage from baseline to 12 months. Linear regression was used to model the change in SBP at 12 months overall and stratified by SBP control status at baseline. Unadjusted, minimally adjusted , and fully adjusted models  were fit. Model assumptions and goodness of fit tests were assessed, and the fully adjusted model was selected as the final model. All analyses used 2-sided hypothesis testing and were conducted in R  and Stata .Differences in baseline demographic characteristics and clinical measures between members with uncontrolled (≥130 mm Hg) versus controlled (<130 mm Hg) SBP at baseline were tested using chi-square and The final sample size for Omada for Hypertension members with baseline and 12-month BP data over the analysis period was 1117 members, including 788 members with uncontrolled SBP (≥130 mm Hg) at baseline and 329 with controlled SBP (<130 mm Hg) at baseline . The meaP<.05; Approximately two-thirds  of members were classified as obese, and 77% (n=860) of them had Stage 1 or 2 hypertension based on baseline SBP or DBP measurements. Stratified by SBP control at baseline, those with uncontrolled SBP were significantly more likely to be male and had significantly higher mean weight, BMI, and DBP at baseline . With regard to BP engagement, members used their BP cuff or manually entered BP values an average of 13.4 (median 8.7) times per month over 12 months. For self-monitoring related app or website activities, members weighed in on average 4 times per week and tracked their physical activity on average 3.7 times per week.Overall, 55.5% (n=620) of members were classified as “highly engaged” with the program (mean weekly activities ≥4) versus 44.5% (n=497) as “less engaged” (weekly activities <4). Meal tracking accounted for 82% of the mean weekly engagement metric. There was no significant difference in program engagement by uncontrolled versus controlled SBP at baseline . In addition, members with uncontrolled SBP at baseline experienced clinically meaningful reductions in SBP and DBP from baseline to 12 months . Nearly all members  with uncontrolled DBP (≥80 mm Hg) at baseline also had uncontrolled SBP at baseline. Members with uncontrolled DBP experienced clinically meaningful unadjusted mean reductions in DBP from baseline to 12 months . Members with controlled SBP at baseline experienced mean increases in SBP and DBP from baseline to 12 months , but these increases were not clinically significant (As shown in nificant .P<.001), and among those with uncontrolled SBP at baseline, average marginal estimates of SBP significantly decreased by 8.0 mm Hg at 12 months . Among members with uncontrolled SBP at baseline, program engagement was significantly related to a 12-month change in SBP with highly engaged members experiencing greater mean reductions than less engaged members . Additionally, members with obesity had significantly greater reductions in SBP compared to those who did not have obesity (P=.02).The final multivariable regression models were consistent with unadjusted estimates (data not shown). Overall, in fully adjusted models, average marginal estimates of SBP significantly decreased by 4.8 mm Hg from baseline to 12 months . Overall, 13% (146/1117) of members shifted from Stage 1 to At Goal, 9% (103/1117) from Stage 2 to At Goal, and 15% (169/1117) from Stage 2 to Stage 1. Additionally, among those with uncontrolled BP at baseline, 17% (146/860) of members shifted from Stage 1 to At Goal, 12% (103/860) from Stage 2 to At Goal, and 19.7% (169/860) from Stage 2 to Stage 1.Both overall and among those with uncontrolled SBP or DBP at baseline, the percentage of members within each HBPM hypertension category  showed significant improvement from baseline to 12 months as shown in P<.001); furthermore, the mean DBP at 12 months moved to the At Goal category for those with Stage 1 DBP at baseline (The mean change in BP by HBPM stage among those with uncontrolled SBP and DBP at baseline is shown in baseline .P<.001) and approximately 2.6% weight loss. Both members with uncontrolled and controlled SBP at baseline experienced significant weight loss from baseline to 12 months ; the mean percent weight loss among those with uncontrolled versus controlled SBP at baseline were 2.7% and 2.4% at 12 months, respectively  of members with uncontrolled SBP or uncontrolled DBP at baseline experienced a large enough improvement in BP to shift down by 1 or more categories. Weight and BMI addressed in the program through diet, physical activity, and behavior change support also showed statistically significant reductions during the study period. Program engagement was also evident in this study, with over half of members being classified as “highly engaged” (mean weekly activities ≥4). These members experienced significantly greater reductions in SBP compared to those that were less engaged in the program, supporting current literature on the effectiveness of engagement on interventions for hypertension self-management ,33.Although members with SBP and DBP within the goal range at baseline experienced statistically significant increases in BP at 12 months, the magnitude of the changes was not clinically meaningful, and the mean of this group still fell within the At Goal HBPM category at 12 months. These increases may be due to regression to the mean, random variability in the data, or from disease progression as members’ age in the program. Moreover, these members also lost nearly as much percent body weight as members with uncontrolled BP at baseline, demonstrating that they also benefited from the program from a weight loss perspective.While there have been a number of studies examining different models of digital health solutions for the management of hypertension ,34, few In a review of the literature, 1 previous cohort study of a hypertension self-management program offered through an employer health plan also found that higher engagement with the app was associated with greater reductions in SBP . The proThere are limitations to this study. First, the study population was composed primarily of commercially insured and middle-aged adults, with a lower representation than the national average of members who identify as Hispanic. All members had access to internet connectivity, a smartphone app, a web OS platform, a computer or tablet, and sufficient technology literacy. These demographics limit the generalizability of our findings to other populations including Medicaid, Medicare, or uninsured populations, which currently have lower adoption of technology.Second, members were enrolled in the program based on a self-reported diagnosis of high BP or hypertension, and access to medical records was not available to further validate the diagnosis. An assessment of usual medical care and the presence of medication adherence issues and treatment inertia was also not possible due to the lack of longitudinal medication data. In addition, we accounted for normal variation in BP by calculating a mean BP using clinical best practices rather than relying upon a single BP measurement ; yet, thP<.001). Additionally, some members may have been engaged with the program even if they did not report BP data or chose to only report limited BP data at 12 months, thus not meeting the minimum criteria to be included in the study (per the protocol discussed in the measures section of the methods).Due to the real-world digital delivery of this program, about one-quarter of members with a baseline BP measurement also had a valid 12-month BP follow-up measurement. However, there were only a few differences between those with complete 12 months of data versus those without or excluded from the study; excluded members due to missing follow-up data were more likely to be Black and female .Future research should examine the implementation of similar digital health programs into the health care ecosystem including bidirectional data exchange and care coordination. More evidence for the applicability of digital programs to other populations  and how a digital solution might reduce the burden on the primary care team would further bolster the evidence for a widespread adoption of this approach to hypertension management.The cost-effectiveness and the long-term impact of a digital health program on the health economics of hypertension management were not directly assessed in this study. However, a recent study showed that patients with hypertension had a US $432 decrease in health care expenditures in the year following a decrease in 1 BMI unit inflated to 2022 dollars . Thus, fThe current management of hypertension in the United States is in need of innovative solutions that can scale to reverse the alarming trend of worsening disease and unsustainable costs related to hypertension in the health care system. Digital health solutions have shown promise in allowing more care to be shared by the patient in a self-management program and less time required by the physician to deliver lifestyle counseling and behavior change support. This study provides evidence that a digital solution, coupled with human-led health coaching, is associated with improved SBP control over a sustained period of time.


Decoy receptor 3 (DcR3), a soluble glycosylated protein in the tumor necrosis factor receptor superfamily, plays a role in tumor and inflammatory diseases. Sepsis is a life-threatening organ dysfunction caused by the dysregulation of the response to infection. Currently, no specific drug that can alleviate or even cure sepsis in a comprehensive and multi-level manner has been found. DcR3 is closely related to sepsis and considerably upregulated in the serum of those patients, and its upregulation is positively correlated with the severity of sepsis and can be a potential biomarker for diagnosis. DcR3 alone or in combination with other markers has shown promising results in the early diagnosis of sepsis. Furthermore, DcR3 is a multipotent immunomodulator that can bind FasL, LIGHT, and TL1A through decoy action, and block downstream apoptosis and inflammatory signaling. It also regulates T-cell and macrophage differentiation and modulates immune status through non-decoy action; therefore, DcR3 could be a potential drug for the treatment of sepsis. The application of DcR3 in the treatment of a mouse model of sepsis also achieved good efficacy. Here, we introduce and discuss the progress in, and suggest novel ideas for, research regarding DcR3 in the diagnosis and treatment of sepsis. Decoy receptor 3 (DcR3) is a soluble glycosylated protein, primarily circulating as a secreted protein and is highly expressed in tumors and inflammatory diseases . DcR3 caDcR3 is closely related to sepsis. Significant upregulation of DcR3 levels in the serum of patients with sepsis is positively correlated with its severity and could therefore be used as a biomarker for its diagnosis . DcR3 alRattus norvegicus) and mice (Mus musculus). The human (Homo sapiens) DcR3 gene is located at the telomeric end of chromosome 20 (20q13.3) and encodes 300 amino acids, of which the first 29 amino acid residues are signal peptide sequences with a mature product size of approximately 33 kilodalton (kDa) [DcR3, alternatively referred to as tumor necrosis factor receptor superfamily member 6b (TNFRSF6B), TR6, or M68, belongs to the decoy receptor family within the tumor necrosis factor receptor superfamily. It is a soluble receptor that lacks a structural transmembrane domain and is chemically a glycosylated protein . As a meon (kDa) .DcR3 is not expressed or is less expressed under normal physiological conditions, but is highly expressed in patients with gastric  or pancrThe physiological role of DcR3 is not fully understood, but as a soluble receptor in the decoy receptor family, DcR3 can neutralize the biological effects of FasL, LIGHT, and TL1A through its decoy function . As showFasL, TL1A, and LIGHT can activate downstream signaling pathways by binding to specific receptors on the cell membrane, leading to cellular inflammation and apoptosis. FasL is predominantly synthesized by activated T-lymphocytes, specifically cytotoxic T-lymphocytes (CTL), as well as natural killer (NK) cells. The binding of FasL to its receptor Fas (CD95) triggers apoptosis in target cells ,30. The LIGHT is expressed in lymphoid tissues and can bind to three receptors: herpesvirus entry mediator (HVEM), lymphotoxin β receptor (LTβR), and DcR3 ,34. The TL1A was originally found in endothelial cells and is a ligand for death receptor 3 (DR3) . ActivatBesides exercising a decoy function, DcR3 can also perform a non-decoy function, i.e., DcR3 acts as an effector molecule that directly regulates the activity of many cell types . SolubleIn recent years, DcR3 has been reported to be closely associated with HSPG, and through it may exert a non-deceptive function . The DcRBased on the decoy and non-decoy functions, DcR3 can maintain the homeostasis of the internal environment in inflammatory diseases by reducing the apoptosis of immune cells and decreasing the level of inflammatory factors. Therefore, the administration of DcR3 by increasing its autologous expression or its expression in vitro could be a research direction in the treatment of inflammatory diseases .Sepsis is a critical condition characterized by the dysfunction of vital organs, resulting from an infection-triggered dysregulation of the patient’s immune response. No specific drug has yet been found that can alleviate or even cure sepsis in a comprehensive and multi-level manner . Sepsis σήψη, meaning putrefaction. The term has been used since the time of Hippocrates, but the definition has been ambiguous in the medical community, leading to numerous difficulties in clinical diagnosis and medication prescription [The word sepsis is derived from the Greek word cription ,59. To ocription ,61. Sepscription . Sepsis The pathophysiological mechanisms of sepsis are complex—it is a syndrome with high heterogeneity. This is reflected primarily in the different clinical manifestations, as patients of different ages exhibit different physiological characteristics, and this heterogeneity is considered a major factor in the failure of immunomodulatory tests in patients with sepsis. Hyperinflammation and immunosuppression are intertwined in the course of the disease. As shown in According to the definition offered by sepsis 3.0, sepsis is a disease caused by an overreaction of the host to infection. The occurrence of sepsis originates from various infections, including pathogenic microbial infections and various traumas, the former being more common in clinical practice. As shown in The damage caused by sepsis to the organism worsens with delayed intervention and therefore requires early recognition and standardized treatment . MortaliSeverity and prognosis evaluation can help design an early and effective clinical treatment plan . Sepsis Several drugs have been developed to treat sepsis, but no satisfactory results have yet been achieved. Only early prevention, detection, and treatment can reduce the incidence and improve the survival rate of patients with sepsis. Treatment options for sepsis have focused on fluid resuscitation, antibiotic therapy, and immunotherapy ,87. AlthThe aim of immunotherapy is to restore or strengthen the body’s immunity. Abnormalities such as dysregulation of cytokine secretion, decreased APC function, and apoptosis and depletion of lymphocytes occur during sepsis. Immunotherapeutic agents targeting sepsis include cytokine classes, such as interferon γ (IFN-γ) and thymidine α1, and cell surface co-inhibitory molecules, such as anti-programmed cell death receptor 1 (PD-1) antibodies, and anti-programmed cell death receptor ligand 1 (PD-L1) antibodies . Anti-PDEarly diagnosis and prompt treatment of patients with sepsis can improve the survival rate and reduce the abuse of antibiotics, thereby postponing the emergence of drug-resistant bacteria. Blood culture is the gold standard for sepsis detection, but this test is time consuming (48–72 h), has a low positive rate and an inability to diagnose sepsis caused by non-bacterial infections, therefore, there is an urgent need to find some efficient and sensitive testing methods for use in clinics . The disDcR3 is highly expressed in inflammatory diseases, but the exact role of highly expressed DcR3 in the inflammatory process remains to be elucidated ,95,96. CAlthough DcR3 is an emerging marker of sepsis, it is rarely used alone and, therefore, the use of DcR3 combined with other substances has become an emerging trend in the prediction of sepsis. The combination of serum DcR3 levels and the neutrophil-to-lymphocyte ratios in the blood can effectively assess the prognosis of patients with sepsis. The incorporation of the triple combination, comprising DcR3, the soluble urokinase-type fibrinogen activator receptor, and procalcitonin (PCT), enhances the accuracy and precision of sepsis detection .With an enhanced understanding of the pathogenesis of sepsis, immunotherapeutic agents are receiving increasing attention. The progression of sepsis can be broadly categorized into two distinct phases: hyperinflammation in the early stages, and immunosuppression in the late stages ,100,101.Endogenous DcR3 is likely unable to improve sepsis as it is induced in low amounts and cannot establish an overwhelming advantage. The in vitro expressed DcR3–Fc recombinant protein was injected intravenously into a mouse model of cecum ligation and puncture-induced sepsis, and significantly improved survival, decreased inflammatory factor levels, improved organ lesions, inhibited lymphocyte apoptosis, and increased lymphocyte numbers were observed . The recAlthough thousands of experimental animals have been rescued from sepsis in several preclinical studies over the past decades, no specific drug has yet emerged that can significantly improve the prognosis of human patients . DcR3 isFuture research on DcR3 should focus on elaborating the mechanism of action of DcR3 in ameliorating sepsis, as well as promoting the clinical application of DcR3. Because the DcR3 gene does not exist in the rat and mouse genome, it is not possible to directly construct DcR3 knockout mice. Additionally, although the therapeutic effects of DcR3 in septic mice can be investigated by constructing DcR3-expressing mice or by administering DcR3 in vitro, this is a more demanding experimental technique for the operator and is both time-consuming and expensive, making the application of DcR3 in the murine model somewhat limited. DcR3–Fc is a recombinant fusion protein formed by linking the DcR3 sequence to a human IgG1 Fc fragment, and DcR3–Fc can better mimic the biological effects of DcR3. The intrathecal administration of recombinant DcR3–Fc fusion proteins demonstrates a potential therapeutic effect in experimental autoimmune encephalomyelitis, suppresses macrophage activation induced by influenza virus, and mitigates pulmonary inflammation and mortality. Consequently, DcR3–Fc exhibits promise as a valuable tool for further investigation and facilitates comprehensive studies on DcR3 .DcR3 can be used as a biomarker for sepsis and can be used alone for early diagnosis or in combination with markers such as C-reactive protein (CRP), PCT, butyrylcholinesterase, presepsin, and pro-adrenomedullin. Although good results have been achieved by combining DcR3 with other sepsis markers, its application as a biomarker is partially limited because gram-positive, gram-negative, and fungal infections can all cause the upregulation of serum DcR3 levels in patients, making it impossible to effectively and specifically distinguish the type of infectious agent. The effective combination of DcR3 with other markers still needs to be explored further.The two stages of the disease in patients with sepsis—excessive inflammation and immunosuppression—are dynamically transformed and both can exist simultaneously ; therefoSepsis is a highly heterogeneous syndrome, and the diversity of patients at the individual level, including different clinical presentations and physiological characteristics at different ages, will affect the diagnosis, treatment standardization protocols, implementation, and development of sepsis . With th