We identified barriers and challenges to engagement andoutlined strategies used to identify clients, match them with peers, and providesupport to both peers and clients. We found that peers played a flexible,non-clinical role and were perceived as friends. Connections to communityresources helped when clients needed additional support. We also documentedcreative strategies used to maintain inter-personal connections during theCOVID-19 pandemic. This study fills a gap in understanding how a peer-supportprogram can be designed to address loneliness and social isolation, particularlyin low-income, urban settings.This paper describes the evaluation of a longitudinal peer-support programdeveloped to address loneliness and isolation among low-income, urbancommunity-dwelling older adults in San Francisco. Our objective was to determinebarriers, challenges, and successful strategies in implementation of theprogram. In-depth qualitative interviews with clients ( TheNatAddressing loneliness among older adults can be complicated by other intersectingneeds. Many at-risk older adults live alone, with disabilities, and below thefederal poverty level , all of Located in San Francisco’s Tenderloin neighborhood, Curry has been operating for over45 years, providing holistic care and services for low-income, diverse older adults.The peer-support program was developed iteratively with guidance and experience fromthe community and staff at the center. The guiding theory was that a peer-supportprogram may address complex, intersecting health and social needs by connectingindividuals with shared life experiences. Although the program was developed withouta specific theoretical underpinning, there is strong alignment in the academicliterature around the value of peer support for behavioral health and loneliness as well To evaluate the peer-support program, in 2019, Curry partnered with our research teambased at an academic medical center. Client outcomes are reported elsewhere . Usingdn = 74) were low-income,community-dwelling older adults (age 55 and older) of diverse racial and ethnicbackgrounds recruited over a 2-year period. Many reported histories ofhomelessness and substance use. Clients were enrolled through Curry and otherorganizations known to serve older adults in the community. Peers(n = 8) were also diverse in terms of gender, sexualorientation, and racial/ethnic backgrounds. Similar to the clients, peers wereolder adults (55 and older) who had shared experiences such as living withloneliness, having experienced homelessness, and having histories of accessingbehavioral health services.Program participants . Interviews wereconducted with 6 peers and 15 clients between March and June 2020 until thematicsaturation was reached. Client interviewees included 10 men and 5 women,including 2 transgender women. Race/ethnicity reported by clients included 5non-Hispanic White, 5 Latino/a, 2 African American, and 3 unknown. All clientswere housed in single-room occupancy (SRO) housing in the San FranciscoTenderloin neighborhood. Demographic information for the 6 peers was reported asfollows: 3 men and 3 women, including 1 transgender woman; and 2 non-HispanicWhite, 2 Asian, 1 Latino/a, 1 Black/African American. All peers who werecontacted consented to participate, and only one client declined due toscheduling conflicts. Participants had to be conversant in English or Spanishand willing and able to give informed consent. Clients received a gift cardincentive ($20).Interview guides were developed by the evaluators  for the peer andclient interviews. Program leaders  reviewed the interview guides toensure comprehensiveness and appropriateness. Interviews explored programexperiences and perceived core elements, areas of unmet need, perceived impactof the program, and recommendations for improvements. Each interview lastedapproximately 45 min. Interviews were audio-recorded and transcribed.Interviewers wrote field notes following each interview to summarize key pointsand capture emerging themes. This study was determined to be quality improvementby our university’s institutional review board.In addition to conducting qualitative interviews, evaluators observed informalmeetings of peers and supervisors and reviewed secondary documents such asprogress reports and service manuals that explained the history of the programand how it evolved. Evaluators  wrote memos to complement the datacollected through interviews and focused on documenting program design and othercontextual information . We condFor analysis, we first conducted thematic analysis using a template technique toidentify and refine themes in the interviews . Each trWe then used an implementation science (IS) approach to understand how thetopical areas of our analysis related to each other and could be used to informthe continuation and expansion of the program. Briefly, IS is the scientificstudy of methods to promote the systematic uptake of research findings and otherevidence-based practices into routine practice to improve the quality andeffectiveness of health services For a peer-support program to be effective, identifying and recruitingclients is the first critical step. Program staff learned that recruitingfrom places where seniors already gathered  was helpful, but this meant that many people who were sociallyisolated were “invisible,” and those with safety or mobility concerns weresimilarly missed. Recruitment by flyer similarly had limited success becauseof the stigma associated with loneliness. Peers noted that few clients usedthe terms loneliness or isolation, though they might ask for support in waysthat suggested they wanted companionship.To overcome recruitment challenges, the program manager gave presentationsabout the program at partner organizations. This facilitated clientreferrals from other organizations such as public health clinics andcommunity centers that may have identified at-risk clients. Peers andprogram staff also directed outreach to building managers of local housingunits in order to reach the “invisible.”The second recruitment step involved matching peers and clients. This wascentral to the program and occurred at two levels: matching based onbackground and shared interests. To accomplish this, the program needed torecruit a diverse group of peers with the capacity to match clients based onlanguage , shared interests, or sexualorientation and gender identity. However, issues around perceived safety inthe neighborhood presented difficulties recruiting peers, particularlywomen, so it was not always possible to match on all criteria. Matchingbased on shared interests was further facilitated by using open-endedquestions when recruiting clients to gauge interests.While demographic, cultural, or lifestyle concordance facilitated trust andbonding, it could also present challenges for maintaining boundaries.Additionally, occasionally shared experiences could bring up past trauma.Ongoing training and group meetings for the peers helped to address theseconcerns.I go and I introduce myself, and I tell them that I’m a peeroutreach specialist. And I might even say my job is to help toreduce isolation and loneliness at the initial meeting... We don’taddress it [loneliness and isolation] so much. It’s just understood.And then I tell them that we just have a friendly conversation. AndI might help you with a few things. Or help you to help yourself,really.—Peer 01Peers used a “soft approach” when initiating contact with potential clients. A“soft approach” meant that while discussions might briefly introduce programgoals to reduce loneliness and isolation, initial conversations typicallyfollowed a casual tone—it was simply an informal offer to visit and chat. A peerdescribed this process in the quote below:One of my clients I have is fairly new; he’s blind. I would visithim and take him to lunch and stuff… [At first] he didn’t trust meat all. And I understood why. He’s been blind, and people haveripped him off. So, he’s very suspicious of everyone…But then hestarted trusting me…I became the one that read his mail for him…. Webuilt trust now.—Peer 05When I first met him, I was a little hesitant. But I think that’snormal for first meetings. After that, it seems it’s been relaxedmore. [Interviewer: All it took was that first meeting and you feltcomfortable?] Yes. That’s always because for a blind person… or foranybody, you really have to feel each other out a little bit as faras what interests are and what you like doing.—Client 09Most peers and clients found that rapport developed quickly, as the initial visitset a friendly, non-judgmental tone. Timelines for building closeness would varyfrom client to client. For example, a client who was blind and had previousexperiences of people who took advantage of his disability required more time todevelop a trusting relationship with the peer. In the quotes below, both thepeer and client describe these initial hesitations: For me, spontaneously…within the firstmonth or so, within a few weeks. It just depends. I got ladies openup to me within the next week or so. Some it takes maybe a month …to warm up … [Interviewer: What makes you good at this work do youthink?] Because I care. I care and they sense that, you know, andbuilding care and trust, it builds rapport.”—Peer 06Nevertheless, a common theme was that clients could tell that the peers genuinelycared about them, which further promoted trust and bonding.I look for their interests. If they’re a music lover, I look forprograms that have music that they can enjoy or art. If they’rereally into art, then I make plans to see an art exhibit or takethem to a museum. Something that will interest them enough to get upin the morning or the afternoon and be looking forward to it. It’sjust basically looking for their interests and going withthat.—Peer 05I’ve been through my own trials and tribulations just like theyhave, like everybody has. It’s easier to communicate that and tobreak the ice and to get through. It’s like I can say, “I know whatyou feel like. I’ve been there. And I’m not a doctor talking down toyou, like, oh, you need this and that and here’s your problembecause I say so.”—Peer 03Shared experiences and common interests also fostered relationship-building and empathy.The clients that I’m working with are starting to build morefriendships with each other. Five ladies have a circle now. Beforethe pandemic, there was a restaurant that we - Curry has a tab with.And that was part of our goal too, was to like connect people,connect them. Let’s take them there for lunch, get them socializing,if it’s okay with them of course… From what I’ve seen, having a peercome in and kind of push them a little bit in a gentle way andencourage them like, yeah, it’s okay to socialize still, you know,and you got it. You can stop, you got it. You know how to socialize,you know? The encouragement helps.—Peer 06As the program developed, it became clear that clients experienced commonbarriers to socializing, including neighborhood safety and co-existing mentalhealth challenges. Over time, the program worked to address these barriers. Onestrategy involved adding group activities, including large groups (>10persons) and smaller groups (<5) for clients who preferred a more intimatesetting. These activities addressed the common barrier of maladaptive socialcognition by helping participants gain confidence in socializing and allowingconnection with people who shared similar interests. When asked about changesobserved among clients, one of the peers talked about the benefit of the group programs:I know that I really trust [Peer]. I really know him very well.And I felt safer for him be go with to different places. Like sovery happy – very secure.—Client 07 When safety was identified as a barrier, clients appreciated having peersavailable to accompany them on walks and errands. Notably, many clientsexperienced violence or aggression in their neighborhood and had concerns aboutleaving their homes, particularly those with physical or visual impairment.Another client—a transgender woman who had experienced several instances ofviolence—felt comforted by the peer’s company.There’s another one who was very isolated and didn't have muchoutside contact. We just started chatting on the phone and talkingabout different things. And we went over to [a community center] andwe took in a movie. It used to be I would call and he wouldn’tanswer the phone. But now he sees it's me and so he answers thephone. So I think seeing people kind of step out of depression alittle bit, that’s the effect that I can see, that this is allhappening.—Peer 03Crucially, peers recognized how symptoms of depression could cause clients towithdraw socially and that it may take extra time for them to engage in theprogram. Training in topics such as motivational interviewing and harm reductionhelped peers learn how to work with some of the clients who were relativelyharder to reach. In the quote below, a peer described the changes they had seenin one of their more isolated clients over time:When the program began, it was assumed that participants were not connected toservice providers and that the peers should focus on connecting clients toservices . In fact, this was one of the goals of the initial funding, to help“connect” isolated adults to services. However, peers discovered that manyclients had connections, so their role mostly involved referring participantsback to their providers by suggesting, reminding, or accompanying clients toappointments. Some clients experienced complex medical or functional needs thatexceeded what peers could address. In these cases, peers would often collaboratewith a home health aide or another caretaker if available to coordinate visitsor errands. Peers also leveraged their knowledge of community resources toconnect clients to additional services as needed. The program’s connection toCurry and its comprehensive array of services provided a valuable resource.I don’t think of him as a care provider, more as like as for as afriend…. Well, he just came over. We found we had lots in common.And one thing led to another and we just talked a lot and enjoy eachother’s sense of humor, I guess.—Client 02 The program’s flexibility and emphasis on avoiding a pre-determined agenda wasone of its hallmarks. This approach facilitated trust and gave clients a safespace to build skills and confidence. It also allowed clients to be supported inways that were most meaningful and impactful to them. For example, one clientwho had worked with two different peers (one who had since retired) describedhow they had gone so far as to help him set up an art show to display his workin a local café. When talking about how often he would see the peer, he said,“There’s no real strict formula that way for me with him – he’s just a friend.”Almost all participants used the word “friend” to describe the peer, and thisdynamic felt unique compared to other programs.I like [the peer] as my friend. I don’t think about him as - herewe got another counselor. I have already enough counselor. I need abreak…I never feel like he’s working for me as my therapist or mycounselor. I mean, I have therapists… Like I said, I look at [thepeer] as my friend. I don’t consider him another caseworker. I don’tneed no caseworker anymore. I have enough, I have enough of this. Ineed a friend.—Client 04 As another client explained, having the peer as a friend rather than as a serviceprovider was a welcome “break” and exactly what he needed:Last year, I had one client who passed away… I kind of saw thatcoming because he, you know, was not in good health. But after hepassed away, I felt really bad, you know. I had to talk to [mysupervisor]. And he asked me if you need to see a grief counselor,he can set up the appointment.—Peer 04As noted above, the non-clinical role of the peer was critical as wasflexibility. Yet, there were times where this flexibility could result inboundary crossing. Peers and clients also described challenges with emotionalattachment, including coping with grief and loss. Connections to griefcounseling and routine check-ins with the program supervisor helped, in additionto regular trainings and meetings with other peers.Well, what has happened now, since this virus…He’d give me a callevery day, check on me and see how I’m doing and just make sure I’mdoing okay. He’s very caring to people. And, you know, I’m glad hecalls. Because, you know, he’s part of my family,too.—Client 07 When shelter-in-place started, activities suddenly shifted from in-person tovirtual. Peers were able to maintain connections with most clients during thepandemic, but a large part of that may have been influenced by pre-pandemiclongstanding relationships and rapport. Peers described creative ways that theytried to maintain a connection with their clients, such as by watching the sametelevision shows and then talking about them over the phone or by dropping offcare packages. Even under the stressors introduced by the pandemic, the clientswe interviewed felt that contacts by telephone were meaningful. Below, a clientdescribed how she valued the frequent check-ins by phone:However, many clients also acknowledged that they were struggling with theadditional isolation. For example, one client described how the experience hasbeen difficult for her depression and recovery (“I’m not used to being in asmuch”)—but she appreciated how the peer recognized this challenge and validatedher feelings.Peer support has existed in a variety of behavioral health contexts . HoweverAdditional key lessons include the importance of understanding the populationserved—this involved understanding clients’ needs and how best to engage them—andhaving programmatic flexibility to meet needs as they arise. For example, theprogram reduced the age minimum from 60 to 55 years to account for the possibilityof premature aging among low-income, homeless populations in San Francisco .AlthougAdditionally, loneliness and social isolation are distinct yet related concepts andoften require different strategies and interventions . SeveralOur work adds to the growing body of literature on the mechanisms and potentialbenefits of peer-support programs . A recenMost peer programs that address mental health tend to be time-limited, haveformalized connections with medical professionals, and encourage clients to setspecific goals during the course of the intervention . This prOverall, our findings show that peer-support programs to reduce loneliness andisolation among low-income older adults can be feasible and acceptable. Our findingsalign with other implementation studies that have demonstrated the importance oforganizational culture, training, and role clarification when integratingpeer-support programs for mental health . We alsoAs this program existed prior to and during COVID-19, it is important to note theeffect of shelter-in-place on participants. Similar to other programs andorganizations, in-person contacts were severely restricted for months. This led tochanges in service delivery and posed new challenges with identifying and recruitingclients who may benefit from peer support.Despite these limitations, the program was successful in its continued outreachefforts. Since COVID restrictions went into effect, referrals continued, however,several clients were lost to follow-up, primarily due to lack of access totechnology and phones. This highlights the importance of recognizing the financialand digital divide that can further isolate those that are already vulnerable, whichhas also been noted in other recent studies .Our study has limitations. Due to the onset of the coronavirus pandemic, all datacollection activities were moved from in-person to virtual. This limited our sampleto those who had phones and sufficient minutes to participate in an interview. Weattempted to mitigate this by coordinating with caregivers who could let the clientborrow a phone for the interview. We also did not interview those who declined theprogram or dropped out, although we do have secondhand stories from the peers thatcan explain some of the reasons why some clients may have declined. Finally, thisprogram focused on an urban, diverse and low-income population, and as such, itsfindings may need to be adapted for rural settings or areas with differentdemographics. However, our findings do correspond with other studies ofpeer-delivered loneliness interventions and add to a growing body of literature ontheir value .This study demonstrates the feasibility and acceptability of a peer-support programto address loneliness and isolation and outlines several implementation challengesand strategies. Our findings can inform the design of future interventions toaddress loneliness and isolation, particularly among low-income older adults whoexperience complex and intersecting health and social needs.


Strong legs and good balance increase mobility and prevent falls in old age. Gym exercise is an effective way to improve muscle strength in old age, particularly when organized in a progressive training program. Current challenge is to recognize and motivate older people to join muscle-strengthening exercise groups. The national “Strength in Old Age Program” (2005-) aims to launch guided strength and balance exercises for independently living older adults with decreased functional capacity. One core activity is to find and motivate old people to participate in a progressive 8-12-week muscle strengthening exercise program. We aimed to increase participation in the organized activity and support participation after the progressive program had ended, to improve the exercise facilities at local level, and to study the perceived benefits from the participants in the Program. Setting was real-life setting, i.e. no case-control trials were set. Good practices were developed to recognize and recruit participants for the program: perform functional capacity tests in locations where old people go as part of their routines, such as free flu vaccination events, use screening questionnaires systematically for all, and activate/guide health care professionals to refer the high-risk patients to gym training. Further, as many municipalities were limited in their gym facilities, the program developed the following solutions: collaborate with private sector service providers, purchase only the essential leg-strengthening devices and use cheap solutions, improve the quality of training by increasing training frequency and combine nutritional advice. The program aimed to improve sustainability of training, where several approaches were found successful: educate peers who instruct gym groups in future, develop the chain of professional exercise counselling from health care to sport sector, and provide free-of-charge gym training sessions to continue after their progressive program. The participants  of the progressive gym training program perceived mostly good or strong benefits from their participation in the program. Participants who attended gym training felt the highest impact on muscle strength, fitness and activities of daily living, when compared to other types of training groups  in the program.Conclusion suggests that gym exercise is a feasible good practice that should be encouraged in real-life setting.


Older Americans Act (OAA) programs and services are strongly linked to social determinants of health (SDOH) and integral to addressing social needs among older adults and individuals with disabilities and their families. Supported by the Administration for Community Living, researchers examined the intersection of OAA-funded programs and services under Titles III, VI, and VII and their impacts on SDOH. This study used an integration of extant literature; secondary data; and interviews with ACL office leadership, AAAs, Title VI program staff, and other local service providers to examine existing social needs among older adults, equity prioritization within OAA-funded program development, and impacts of OAA-funded programs and services. Study findings highlighted relationships between ACL and Aging Network entities, best practices for and process challenges of transforming grant funding into recipient services, and OAA-funded program areas for possible future development.


BCR::ABL1. The development of tyrosine kinase inhibitors (TKIs) highly specific to p210BCRABL1-, the constitutively active tyrosine kinase encoded by BCR::ABL1, has greatly improved the prognosis for CML patients. Now, the survival rate of CML nearly parallels that of age matched controls. However, therapy resistance remains a persistent problem in the pursuit of a cure. TKI resistance can be attributed to both BCR::ABL1 dependent and independent mechanisms. Recently, the role of non-coding RNAs (ncRNAs) has been increasingly explored due to their frequent dysregulation in a variety of malignancies. Specifically, microRNAs (miRNAs), circular RNAs (circRNAs), and long non-coding RNAs (lncRNAs) have been shown to contribute to the development and progression of therapy resistance in CML. Since each ncRNA exhibits multiple functions and is capable of controlling gene expression, they exert their effect on CML resistance through a diverse set of mechanisms and pathways. In most cases ncRNAs with tumor suppressing functions are silenced in CML, while those with oncogenic properties are overexpressed. Here, we discuss the relevance of many aberrantly expressed ncRNAs and their effect on therapy resistance in CML.Chronic myeloid leukemia (CML) is a myeloproliferative neoplasm initiated by the presence of the fusion gene  Breakpoint Cluster Region (BCR) and Abelson Tyrosine-Protein Kinase 1 (ABL1) genes resulting from the translocation generates the chimeric oncogene BCR::ABL1 that is both necessary and sufficient for the development of CML . Tht of CML ,6,7,8,9.c stress ,11,12. WBCR-ABL1 ,14. In aia (AML) ,16. p210 (B-ALL) ,16. A th (CML-N) .BCR::ABL1 expression is the transformation of the hematopoietic stem cell (HSC) into the leukemic stem cell (LSC) which initiates and propagates CML [BCR::ABL1 is sufficient to cause the transformation of the HSC to the LSC and initiate CML, many other events contribute to the development and persistence of this disease.The result of ates CML . AlthougThe generation of CML is not a one-step process. The progression of the disease occurs in three phases: the chronic phase (CP), the accelerated phase (AP), and the blast phase (BP). Each phase is classified by the percentage of blasts in the bone marrow or blood. As the disease progresses it becomes more resistant to therapy and associates with poor survival. Patients who are diagnosed with CP-CML are more manageable and are very responsive to current targeted therapies, while patients diagnosed with BP-CML have most aggressive disease, equivalent to acute leukemia. If left untreated, CML will progress to the BP in just a period of three to eight years .The presBCRABL1-, as well as other BCR::ABL1 variants, although less effectively [The current first-line standard of care for CML patients is treatment with tyrosine kinase inhibitors (TKIs) that competitively or allosterically inhibit p210ectively ,21,22. Cectively .Patients treated in the chronic phase of CML have a life expectancy approaching those of age matched controls . BecauseBCR::ABL1 amplification is also common and can overtake the inhibitory capacity of TKIs by simply out numbering the drug [BCR::ABL1 independent mechanisms contribute to therapy resistance by increasing genomic instability, modifying drug transporters, changing the bone marrow microenvironment (BMM), supporting LSCs, and activating signaling pathways which promote survival [However, despite the undisputed success of TKIs in treating many CML patients, there are a few downsides to this therapy. Some patients are inherently unresponsive to first line TKI therapy or develop resistance during treatment. Of those patients, 40–60% possessed at least one mutation in the kinase domain which is responsible for the drug resistance ,29,30. Wthe drug . Additiosurvival ,33,34. Isurvival ,36. Unfosurvival ,42,43,44BCR::ABL1 for survival and therefore cause relapse after treatment discontinuation [BCR::ABL1, therapy resistance, and CML LSCs must be better understood and targeted to achieve a cure for CML.CML LSCs also provide a therapeutic challenge as they are not dependent on inuation . Furtherinuation ,47. BCR:Recently, many studies have focused on the role of ncRNAs in CML. ncRNAs contribute to therapy resistance and disease progression through a variety of mechanisms because they can exhibit multiple different functions and regulate gene expression responsible for many biological processes. In this review we explore the most studied ncRNAs in CML and their role in contributing to therapy resistance: miRNAs, circRNAs, and lncRNAs.BCR::ABL1 activity. The aberrantly expressed miRNAs then exert their effect by targeting BCR::ABL1, CML LSCs, pathways implicit in therapy resistance, and drug transporters.miRNAs are small RNA molecules with a length between 18–22 nucleotides that regulate gene expression by mainly preventing translation of transcribed messenger RNA (mRNA). miRNAs accomplish this generally by binding to the 3′ untranslated region (UTR) of mRNA and associating with RNA-induced silencing complex (RISC) to degrade its complementary target mRNA. Their complementary pairing with mRNAs can also prevent their localization and association with ribosomes, even in the absence of the RISC complex. Because they can regulate gene expression, miRNAs control a vast array of biological processes including differentiation, proliferation, and apoptosis which explains why a variety of miRNAs have been implicated in many different malignancies. CML is no exception, as a variety of miRNAs are shown to be dysregulated, contributing to the disease. The development of miRNA mimics, which can be used to restore miRNA expression in cases in which it was downregulated, and antagomirs, which may be used to mitigate overexpression of mRNAs, demonstrate that miRNA dysregulation is a targetable aberration. Currently, the primary methods of delivery of these treatments are viral or lipid nanoparticles but each method has limitations regarding its translation into the clinic. Despite this, further characterization of the functions of miRNAs in CML is crucial, so that once delivery methods are improved, miRNA therapies can be readily deployed. Furthermore, although miRNAs are small, single-stranded RNAs, it is reported that they are relatively stable and may be useful as potential biomarkers for a variety of diseases . Here, wBCR::ABL1, miRNAs which directly target these transcripts before they can be translated into the oncoprotein are obvious therapeutic candidates and were the focus of early studies of non-coding RNAs in CML. Several miRNAs targeting BCR::ABL1 transcripts have been identified and characterized. Since miR-29b is downregulated in CML patients, it was selected for further investigation showing that overexpression of miR-29b in the K562 CML cell line leads to a decrease of BCR::ABL1 expression. The 3′ UTR of BCR::ABL1 was confirmed as the target site for miR-29b using a luciferase assay and overexpression of miR-29b induced apoptosis and slowed proliferation in vitro [BCR::ABL1 expression, and their down-regulation contributes to IM resistance. Therefore, reestablishing homeostatic levels of miR-424 and miR-30a via introduction of miRNA mimics may be an effective strategy to mitigate BCR::ABL1 overexpression that contributes to disease severity and therapy resistance [Because the development of CML is a direct result of the fusion protein transcribed from in vitro . Similarin vitro ,51. Howein vitro . These msistance .BCR::ABL1 and was decreased in CML mesenchymal stromal cells (MSCs) [BCR::ABL1, which reduces growth and survival of CML and has been shown to sensitize CML LSCs to IM [Since we know that the BMM and niches play a significant role in contributing to therapy resistance, it is likely that miRNAs are dysregulated there as well. Indeed, like the previously discussed miRNAs, miR-320a regulates s (MSCs) . Low miRs (MSCs) . RestoriCs to IM ,54. DeliBCR::ABL1 and HOXA9 oncogenes as targets of miR-196b and further in vitro experiments confirmed miR-196b could suppress them, diminishing proliferation and cell cycling [BCR::ABL1 and overexpression of miR-23a decreased BCR::ABL1 inducing apoptosis [BCR::ABL1. Introducing hypomethylating agents could potentially restore their functions, reducing disease progression and resistance. Indeed, the use of hypomethylating agents to treat CML has been documented, with recent data indicating a synergistic effect of an oral demethylating agent (OR-2100) with TKIs on CML growth in vitro [Since current miRNA mimic delivery methods have limitations, other therapies to address aberrant expression of miRNAs should be explored. In fact, multiple studies have elucidated epigenetic modifications which contribute to the silencing of tumor suppressing miRNAs. Methylation of CpG islands, specifically, is a useful tool for cancer progression, as it allows tumor suppressors to be efficiently silenced. miR-196b was shown to be heavily methylated in CML patients, explaining its limited expression in CML patients when compared to healthy controls . Lucifer cycling . Similar cycling . Expresspoptosis . These rin vitro . Anotherin vitro . It was in vitro .BCR::ABL1 and ABL1, however, the suppression of miR-96 is closely associated with the transition from CP to BP [BCR::ABL1 products, progressing the disease [Like previously discussed miRNAs, miR-96 directly targets the 3′ UTR of CP to BP . The dow disease . The utiBCR::ABL1 make them a particularly challenging target [LSCs not only initiate but also contribute to disease progression, persistence, and relapse in CML patients. However, LSC quiescence and independency of g target ,46,47. TBCR::ABL1, adenosine deaminase acting on RNA1 (ADAR1) is stimulated. The newly activated ADAR1 modifies the early precursor pri-let-7 preventing the biosynthesis of let-7. This blocks its ability to give rise to mature miRNAs and promotes an increase in LIN28B, a transcription factor promoting pluripotency, known to contribute to cancer progression [c-MYC, limiting its translation and exerting a pro-apoptotic effect that is independent of BCR::ABL1 [BCR::ABL1, but also one of the most important BCR::ABL1 independent mechanisms of therapy resistance and relapse: the survival and self-renewal of the LSC.Let-7, an miRNA precursor, is implicated as a tumor suppressor in a variety of solid tumors including lung, ovarian, breast, and colorectal cancer . Recent gression . The decgression . Downreggression . Survivigression ,66. By igression . FurtherCR::ABL1 . Since tConversely to Let-7, miR-203, and miR-494, many miRNAs exhibit oncogenic properties and so they are often upregulated in CML. Up-regulated in many human cancers, miR-21 has been shown to contribute to oncogenesis and targeting miR-21 has led to an increase in efficacy of a variety of therapies . In CML,TET2 by binding to its 3′ UTR. TET2 contributes to the apoptotic response in response to TKI treatment and has been shown to act as a tumor suppressor, particularly for malignancies of the myeloid descent [TET2 transcript translation, and apoptosis in response to TKI administration [EPAS1), mitigating its function in regulating cellular responses to hypoxic environments [miR-29a-3p, which is also upregulated in CML LSCs, suppresses  descent . Therefostration . Similarronments . miR-378ronments . Previouronments ,73. Reseronments . Taken tmiR-126-3p (miR-126) contributes to disease persistence by regulating LSC dormancy and engraftment potential. Although miR-126 is downregulated in the LSC compared to healthy long-term HSCs, it is upregulated in the leukemic niche, particularly in endothelial cells which secrete miR-126 to the LSCs . In addiBCR::ABL1 transcripts are generated, an increase in MAPK activation yields more hnRNP E2, ultimately causing a block in differentiation by binding to CEBPA and preventing its translation [BCR::ABL1 dependent pathway [CEBPA protein, as under normal conditions, miR-328 competes with CEBPA mRNA for binding to hnRNP E2, releasing CEBPA transcripts for translation [CEBPA translation [PIM1, a molecule essential for the survival of CML [Aside from the treatment challenges presented by LSCs, impaired differentiation is an established obstacle in both AML and BP CML ,76. Whilnslation . Interes pathway . It was nslation . Expectenslation . Althougl of CML . miR-328Yet, another type of clinically relevant miRNAs to CML is that which is directly linked to TKI resistance since those miRNAs dictate treatment strategies, predict outcomes, and offer promise for novel therapeutics. Each miRNA discussed here targets a different mRNA in different pathways, giving each a unique mechanism for therapy resistance.Data shows that AKR1C3 is highly up-regulated in the resistant CML BMM, and when ectopically expressed, it decreased the efficacy of IM treatment in vitro . IncreasAlternatively, miR-577, which is downregulated in mononucleated cells in peripheral blood of CML patients, targets NUP160, which encodes part of a nuclear pore complex . PreviouBCR::ABL1 transcripts indirectly [BCR::ABL1 and CCND1 combatting therapy resistance.Researchers also determined miR-342-5p to be suppressed in CML patients while CCND1 expression levels were particularly high . A lucifdirectly . TreatmeYet, another mechanism for drug resistance that plays an important role in CML is regulated by miRNAs: drug transporters. Efflux transporters allow cells to evade therapy by pumping the molecule out of the cytosol. The mononuclear cells of peripheral blood of IM resistant CML patients compared to responsive patients showed a decrease in miR-214 . InteresBCR::ABL1 transcripts, modulating the CML LSC, activating or suppressing pathways implicit in CML, and regulating drug transporters. The implementation of strategies to restore homeostatic expression of miRNAs, such as treatment with mimics or antagomiRs is needed in combination with highly specific tyrosine kinase inhibition to fully eliminate disease progression and relapse. Below in An abundance of data indicates that miRNAs are dysregulated in CML, with a variety of mechanisms responsible for such dysregulation, including remodeled leukemic niches, epigenetic silencing, and activation or suppression of a variety of pathways. Once dysregulated, these miRNAs exhibit their effect on CML using diverse functions, including regulating Like miRNAs, circRNAs are ncRNAs which regulate a vast array of pathways and are frequently dysregulated in cancer and many other diseases. These single stranded RNA molecules are covalently linked at their 3′ and 5′ ends, generating a circular structure . circRNABCR::ABL1 fusion gene, there is a clear potential for novel circRNAs to be generated by the fusion, as circRNAs are often found in coding regions of genes [BCR::ABL1 remained steady [BCR::ABL1 [BCR::ABL1, exerts an oncogenic effect by sponging miR-148-3p, which is responsible for limiting the expression of its target CDC25B thus regulating cell cycle progression [BCR::ABL1 mRNA transcripts. Importantly, data indicates that F-circBA1 was more easily detectable than BCR::ABL1 transcripts following RNase R treatment, suggesting that F-circBA1 may serve as a more robust diagnostic marker than BCR::ABL1 transcripts [Given that CML is the result of the chromosomal translocation which gives rise to the of genes ,100. So d steady . The autCR::ABL1 . PreviouCR::ABL1 ,103. Howgression . When migression ,106,107.gression . Silencigression . Since tnscripts .Most circRNAs involved in CML therapy resistance are not generated from the classical translocation, but rather are dysregulated in CML. Circ_0009910 was shown to be consistently upregulated in IM resistant patients and was correlated with poor outcomes . It was Similarly, hsa_circ_0058493 is deregulated in the mononucleated cells of peripheral blood of IM resistant CML patients and is associated with a worse prognosis . DownregBCR::ABL1 transcripts. One study showed that circ_0051886 and circ_0080145 are upregulated in K562 IM resistant cells and that they target miRNAs responsible for regulating the transcription of ABL1 [BCR::ABL1 protein expression while overexpression of the circRNAs upregulated BCR::ABL1 [BCR::ABL1; however, luciferase assay reported miR-29b as the target instead of miR-203 [BCR::ABL1 mRNA transcripts and decreases proliferation while promoting apoptosis [Unsurprisingly, some circRNAs contribute to therapy resistance in CML by exhibiting an effect on  of ABL1 . KnockdoCR::ABL1 . Thus, tCR::ABL1 . Another miR-203 . As mentpoptosis . Yet, anpoptosis .Clearly, circRNAs are dysregulated in CML but their roles in contributing to therapy resistance need to be studied further. The functions of circRNAs are complex, as they may act as competitive endogenous RNAs (ceRNA) against multiple miRNAs, each of which could potentially target multiple mRNA transcripts. Because of this, it is difficult to determine the exact mechanism of therapy resistance stemming from dysregulated circRNAs. Although many of these circRNAs may appear to possess therapeutic potential, due to their robust circular structure, they are highly stable and difficult to degrade. Instead, current application of circRNAs should be for biomarkers to predict outcomes and dictate treatment plans. Below in Any single stranded RNA which does not encode proteins and exceeds a length of 200 nucleotides is considered a lncRNA . Like miTKI resistance presents a clinical challenge in the treatment of CML patients, necessitating further understanding of the processes which drive it. Due to the wide range of functions, they perform, lncRNAs can be upregulated or downregulated in CML. Maternally expressed 3 (MEG3) is a lncRNA which is downregulated in advanced stages of CML and was shown to be heavily methylated in IM resistant cells ,117. WhiAs one of the functions of MEG3 is to suppress a miRNA involved with the efflux of drugs, many other lncRNAs share the same function. For instance, the lncRNA SNHG5 and the drug efflux transporter ABCC2 were both dysregulated in CML, and their expression was correlated . FunctioJust as increased HOTAIR expression is associated with disease severity of CML, so is the lncRNA HULC. Knockdown of HULC led to an increase in the apoptosis inducing caspase-3 while lowering the expression of c-Myc and Bcl-2 . It was BCR::ABL1 and binds to its promoter, explaining why NEAT1 is suppressed in CML [BCR::ABL1 inhibition restores NEAT1 expression, conferring with IM resistance. NEAT1 is associated with IM sensitivity due to its ability to bind paraspeckle protein splicing factor proline/glutamine-rich (SFPQ), which is involved in apoptotic pathways [Some lncRNAs are clearly dysregulated in CML, but either no or conflicting reports on their functions in CML exist. For instance, lncRNA nuclear-enriched abundant transcript 1 (NEAT1), which plays a role in nuclear structure and scaffolding, is downregulated in CML . NEAT1 id in CML . Thus, Bpathways . Howeverpathways . Althougpathways .Due to the complex function of lncRNAs, it is difficult to fully elucidate the mechanisms in which they regulate CML therapy resistance. Further efforts are needed to establish lncRNAs as biomarkers and therapeutic targets, but here we have established that the dysregulation of lncRNAs in CML resistance warrants further study. Below in BCR::ABL1 expression, and modulate the CML LSC to contribute to therapy resistance in CML. The various classes of ncRNAs offer promise as potential biomarkers or therapeutic targets. Further research is clearly necessary before the potential of these ncRNAs can be fully realized, but this review has established that ncRNAs play an important role in the development of CML therapy resistance and warrant further study. Below in The development of TKIs drastically changed the treatment and prognosis of CML for countless patients. However, IM resistance and TKI resistance in general, remains an obstacle to curing CML. Because of this, the role of ncRNAs in therapy resistance has been explored and offers promise both as biomarkers and therapeutic targets. Remodeling of the BMM, gene fusions, epigenetic modifications, pathway amplifications, and many other mechanisms are responsible for the dysregulation of ncRNAs in CML. Aberrantly expressed ncRNAs then activate or suppress molecular pathways implicit in therapy resistance, upregulate drug transporters, regulate


A Fitness and Lifestyle Intervention Programme (FLIP IT) is a healthy lifestyle programme, developed for patients identified by their multi-disciplinary team that focusses on helping patients improve their understanding of the benefits of living a healthier life and supporting them to live a healthier life. We evaluate the effectiveness of the FLIP IT programme in tackling obesity and managing the weight of inpatients in a medium secure mental health unit.Patients requiring support in managing their physical health from different secure wards were enrolled into the FLIP IT programme following identification by the Multidisciplinary team. Each cycle of the programme was completed over an eleven-week period. Data were collected for a total of seven cohorts of the FLIP IT program. Descriptive analysis was conducted with SPSS. Descriptive statistics, including means, frequencies and proportions were generated. Comparison was done between participants measurements at the start and end of the programme.A total of 55 participant records from seven cohorts of the FLIP IT program were analysed; 33 (60%) male and 22 (40%) female. Ten participants did not complete the program; discontinuation rate of 18.2%, 7(70%) of which were females and 3(30%) of which were males. There was not much changes in BMI category from start to end (34.10 to 34.14) and in Waist to hip ratio only (0.951 to 0.949) subsequently.Although, it showed only marginal number of improvement in some categories and no improvement in BMI category, also some patient did withdraw from the project. However, this does not mean that project FLIP IT was not useful at all, as it encouraged some participants to make small everyday changes in secure unit to gain understanding into the importance of their physical health.


Given that high levels of stress during adolescence are associated with negative consequences, it is important that adolescents with psychological needs are supported at an early stage, for instance with interventions at school. However, knowledge about the potential of school-based programs targeting adolescents with psychological needs, aimed at reducing school or social stress, is lacking.The current study aimed to investigate the effectiveness of two targeted school-based skills-training programs, addressing either skills to deal with performance anxiety or social skills.N = 361 adolescents  from various educational levels and ethnic identity backgrounds. The performance anxiety program included N = 196 participants , while the social skills program included N = 165 participants . MANCOVA’s were performed.Two randomized controlled trials were performed with participants who self-selected to one of the programs. The sample comprised of The performance anxiety program had a small effect on reducing adolescents’ test anxiety. Furthermore, for adolescents who attended more than half of the sessions, the program had small effects on reducing test anxiety and fear of failure. The program did not improve adolescents’ coping skills or mental health. The social skills program was not effective in improving social skills, social anxiety, and mental health.A relatively short, targeted program addressing skills to deal with performance anxiety can have the potential to reduce adolescents’ performance anxiety.International Clinical Trials Registry Platform . Registered 12 December 2018. Study protocol van Loon et al., .The online version contains supplementary material available at 10.1007/s10566-023-09736-x. Adolescence is a period of physical, psychological, and social developments , the school , the self , and peers , romantic relationships, and peer pressure  and behavioral problems : a three-tiered approach with universal, targeted, and intensive interventions  received written information about the skills-training programs that were offered and received an information letter about the corresponding study (on paper and via email). Effort was put into promoting the skills-training programs to students (and parents), including motivating mentors and school staff, giving presentations (about the programs and study) during classes, sending a promotion video (by trainers of the programs), and telephoning parents. Students and parents provided active informed consent for the students’ participation in the study. Participants were randomly allocated by the first author  into the experimental (for which the training started immediately) or the waitlist control group. Before the start of the skills-training programs (T1) and immediately after completion of the intervention programs (T2), program targets , direct program outcomes , and mental health outcomes  were assessed in both groups. Participants filled in the questionnaires individually in small groups , under supervision of one or multiple researchers. Filling out the questionnaires took approximately 45 min. The current study is registered in the International Clinical Trials Registry Platform  and the Ethical Committee Psychology of Leiden University approved the design of the study (number CEP19-1210/577)  for each school-based skills-training program to ensure there was enough power for the analyses , a track preparing students for vocational training , a track preparing students to study at universities of applied sciences  and a track preparing students for university education . As it is essential that various groups are represented in study samples, especially socially disadvantaged groups  , while the other participants registered for the social skills program . Some participants were excluded from the sample because they were not targeted as intended (N = 68)n = 15 in performance anxiety program and n = 3 in the social skills program) were lost to follow-up . For the performance anxiety program, dropouts were more often participants from the lowest educational level at T1 . For the social skills program, dropouts had higher levels of well-being at T1 . There were no other differences at T1 between participants and dropouts regarding demographics  and study variables. Dropouts were excluded from the analyses . Table In total, 379 participants registered for the skills-training programs . The second cohort started in the school year 2019/2020 at nine  schools. Two schools finished the skills-training programs before the COVID-19 pandemic and school closings (N = 55 participants). Due to the COVID-19 pandemic and the abrupt closing of the schools , the skills-training programs that had started in February 2020 at five schools were cancelled after 2–4 sessions. At four of these schools, the programs restarted in September 2020 when the schools reopened . Furthermore, two schools had not yet started with the skills-training programs in February 2020. Programs at these schools were postponed to September 2020 . Unfortunately, having to restart or postpone the programs in these six schools resulted in drop-out from the intervention (not the assessments): half of the participants at these schools did not attend any session of the performance anxiety program (N = 30 of 62 participants) and a quarter did not attend any session of the social skills program (N = 11 of 48 participants).Our sample contained three cohorts that were differently affected by the COVID-19 pandemic. The first cohort of data collection started and finished in the school year 2018/2019 at three schools . All trainers had at least higher vocational education  and had at least one year experience as a trainer (M = 5 years). The programs were adjusted from existing performance anxiety and social skills programs offered by the participating youth care organizations. Program duration was shortened to fit the schedule of schools. Each skills-training program consisted of seven 45-min small-group sessions during consecutive weeks. The groups consisted of approximately eight students (range of 3–16 participants), with one or two professional trainers per group.The skills-training programs were provided at the schools by trained professionals from three youth care organizations , cognitive coping strategies , dealing with (school) pressure , and relaxation techniques . With regard to program integrity, on average, 90% of the program assignments were correctly implemented . In the remainder, program assignments could not be completed within the time frame.The program targeting social skills consisted of social skill building  and cognitive coping strategies . Regarding program integrity, on average, 89% of the program assignments were correctly implemented. Again, the other assignments could not be completed due to time constraints.The waitlist control group did not receive any training during the implementation of the intervention program in the experimental group. The control group received the skills-training program after completion of the postintervention measurement (T2), approximately eight weeks later than the experimental group.ethnic identity by asking which identity the participants felt most connected to  and distinguished three groups: Western , mix Western-non-Western  or non-Western . Educational level of participants was assessed by the class they were in . Three groups were distinguished: practical-prevocational education students , prevocational/senior general education students, and senior general-preuniversity education students . Living situation was assessed by asking participants about their living situation . Two groups were distinguished: living with both parents (adolescents who lived with both their parents in the same house) versus living in a non-nuclear family (adolescents who reported something else). Financial problems were assessed by asking participants about financial problems in their family.Characteristics of adolescents were collected at baseline (T1), including gender, age, number of siblings, country of birth, ethnic identity, educational level (and school year), living situation, and financial problems. We assessed Skills to deal with performance anxiety were assessed with the Dutch version of the Cognitive Emotional Regulation Questionnaire, short form (CERQ-short)  to 5 . The questionnaire consists of nine subscales, divided into maladaptive and adaptive coping   to 5 . The questionnaire consists of four subscales that refer to specific social situations: (1) display negative feelings , (2) express personal limitations , (3) initiate assertiveness , and (4) display positive feelings . Sum scores were computed per subscale, with a higher score reflecting more display of negative feelings (α = 0.83 at T1 and α = 0.87 at T2), expression of personal limitations (α = 0.84 at T1 and α = 0.88 at T2), assertiveness (α = 0.84 at T1 and α = 0.87 at T2), and display of positive feelings (α = 0.81 at T1 and α = 0.85 at T2).Performance anxiety was assessed with two questionnaires, measuring fear of failure and test anxiety . The Dutch short form of the Performance Failure Appraisal Inventory (PFAI short form)  to 2 (believe 100% of the time). A mean-item score was calculated. The TAI is a 20-item self-report questionnaire , measured on a 4-point scale ranging from 1  to 4 . Sum scores were computed. Higher (positive) scores reflect more fear of failure  and test anxiety (α = 0.93 at T1 and α = 0.88 at T2).Social anxiety was assessed with the social phobia scale of the Revised Child Anxiety and Depression Scale (RCADS)  to 3 . Sum scores were computed, with a higher score reflecting more social anxiety (α = 0.89 at T1 and α = 0.90 at T2).Stress levels of participants were assessed with the Chronic Stress Questionnaire for Children and Adolescents (CSQ-CA)  to 4 (completely true for me). Sum scores were computed, with a higher score reflecting more stress (α = 0.83 at T1 and T2).Internalizing and externalizing problems were assessed with the Dutch version of the Youth Outcome Questionnaire (Y-OQ-30.1)  to 5 . It consists of six subscales:somatic complaints, social isolation, aggression, conduct problems, hyperactivity/distractibility, and depression/anxiety. Internalizing problems were assessed with the subscale depression/anxiety . Externalizing problems were assessed with the subscales aggression and conduct problems . Sum scores were computed for both subscales, with higher scores reflecting more internalizing problems (α = 0.83 at T1 and α = 0.85 at T2) and externalizing problems (α = 0.88 at T1 and α = 0.90 at T2).Self-esteem was measured with the Dutch version of the Rosenberg Self-Esteem Scale (RSES)  to 4 (strongly disagree). Sum scores were computed, with a higher score reflecting more self-esteem (α = 0.87 at T1 and α = 0.86 at T2).Well-being was measured with the WHO-Five Well-Being Index  to 5 . The sum score was multiplied by four to create the final score , with higher scores reflecting more positive well-being (α = 0.85 at T1 and α = 0.89 at T2).dex WHO, , Dutch vdex WHO, . ParticiStatistical analyses were performed using SPSS version 25. Descriptive analyses were performed for all study variables. We followed an intention-to-treat approach, and included all participants in the analyses (including participants who did not start the intervention or attended only a few sessions) to reduce motivation as a potential confounding effect and to examine the effectiveness of the assigned program , based on standardized means and errors. A positive Cohen’s d reflects improvements favoring the experimental group compared to the control group. Small effect sizes were considered d = 0.20, moderate effect sizes d = 0.50 and large effect sizes d = 0.80 , we pursued with multivariate analyses of covariance (MANCOVA’s) for the three outcome domains . The posttest outcome measures  were included as dependent variables and condition  was included as a fixed factor. The pretest outcome measures  and potential differences between the experimental and control group at T1 were included as covariates in the analyses. MANCOVA’s that were (trend-)significant were followed by tests of between-subjects effects, to investigate whether there was a statistically significant difference between the groups in terms of each dependent variable. Cohen’s 0 Cohen, .N = 144). The other participants enrolled during the pandemic . Of Cohort 2 participants, most  registered before postponement of the programs (before March 2020), while some  registered at a later opportunity, shortly before the postponed programs were to start. We performed a MANCOVA (as mentioned in the previous paragraph), with cohort as a covariate , adding the interaction of condition versus cohort . Second, we repeated the MANCOVA’s in the subsamples of adolescents who attended more than four sessions  in the performance anxiety program and 62 participants (71.3%) in the social skills program). Before the analyses, we examined differences at T1 between participants who attended more than four sessions and the control group. Materials, datasets, and analysis codes for this study are available from the corresponding author upon request.As the COVID-19 pandemic affected this project, we performed some additional (sensitivity) analyses to determine its impact on the results of this study. First, we investigated whether cohort influenced the results. Almost half of the participants enrolled in the skills-training programs before the COVID-19 pandemic  = 2.733, p = 0.068, ηp2 = 0.028; Table F  = 5.199, p = 0.024, d = 0.32), indicating that participants in the intervention group showed a significant reduction in test anxiety compared to participants in the control group. For the social skills program, there was no significant effect on social anxiety  Tables , 3.t = 2.750, p = 0.007) and stress  in the experimental subgroup relative to the control group of the performance anxiety program, these experimental subgroups did not differ from the control groups on any of the T1 assessments . The MANCOVA’s yielded similar results for the social skills program , whereas the aforementioned significant results for the performance anxiety program were slightly stronger. That is, a significant effect was found for the performance anxiety program  = 3.824, p = 0.024, ηp2 = 0.051) and between-subject results demonstrated that the program effectively reduced test anxiety  = 5.777, p = 0.018, d = 0.41) and fear of failure  = 4.710, p = 0.032, d = 0.38). This indicates that participants who attended more than four sessions of the performance anxiety program showed significant reductions in test anxiety and fear of failure compared to participants in the control group. All other results remained unchanged.For both skills-training programs, there were no significant condition*cohort effects for any of the outcomes, suggesting that program effectiveness was not affected by COVID-19-related postponement of the programs. Next, for both programs, the MANCOVA’s were repeated with the subgroup of the experimental group consisting of participants who attended at least four program sessions compared to the control group. Apart from higher levels of fear of failure  or ability to relax (from relaxation techniques). Previous research, for example, demonstrated that relaxation exercises reduced test anxiety in children and adolescents Gregor, . AnotherWith regard to mental health outcomes, the current study showed that the performance anxiety program did not improve adolescents’ mental health , which is inconsistent with most previous literature  and/or educational levels , which might have disrupted the dynamics of the group and complicated the teaching process. Second, it is possible that the target group experienced relatively mild social deficits, which makes it more challenging to demonstrate program effects. Third, the social skills program consisted of teaching different social skills . Possibly, this broad rather than in-depth focus did not allow for significant improvements. Lastly, in order to generate positive changes, it may be necessary to practice and apply the learned social skills in everyday life, as previous research demonstrated that prevention programs with homework assignments yielded larger effects than programs without  were aggravated by the COVID-19 pandemic. As the schools had to close (suddenly), the skills-training programs at six schools were postponed and restarted, and most participants had to complete the T1 assessments again. Consequently, a subgroup of participants had to fill in the questionnaires more often than  two times to control for time effects and some had to restart the intervention program at least six months later than planned. Postponement of the programs may have resulted in a lower program attendance (particularly for the performance anxiety program), for instance because adolescents felt they did not need the extra support anymore , they did not want to miss any classes , or because of lack of motivation in general. In sum, implementation challenges due to the COVID-19 pandemic , might have influenced program effectiveness. Future research should include focus groups with students, as this may provide valuable information about experienced barriers to program attendance that should be considered in the development and implementation of school-based intervention programs. Nevertheless, program enrollment before or after the COVID-19 pandemic did not yield different program effects, suggesting that the COVID-19 pandemic-induced challenges had little impact on program effectiveness.Additionally, despite the COVID-19 pandemic and difficulties of recruiting hard-to-reach participants, such as ethnic minority groups and groups of lower socioeconomic status  components and sessions Below is the link to the electronic supplementary material.


In the days to weeks following an earthquake, landslides can display specific post-seismic motions, including delayed initiations and post-seismic relaxations. These motions have an uncertain origin, sometimes attributed to specificities of the landslide basal interface or to fluid transports in the landslide basal shear zone. Here we address this question, by documenting the co- and post-seismic motions of slow-moving landslides accelerated by the Gorkha earthquake . We detect 11 slow-moving landslides over an area of 750 km Both the dynamic loading2 and grain crushing at the landslide basal surface3 can explain the co-seismic triggering of numerous landslides. In addition, different studies also report post-seismic activity of landslides, including (i) delayed landslide triggering after earthquakes from several hours to several days4, (ii) post-seismic accelerations of slow-moving landslides5, and (iii) increased landslide rates in the months to years following the main shaking8. These observations are not consistent with a landslide triggering caused by the dynamic loading or grain crushing at the interface, and show that the risk associated with earthquake-triggered-landslides is not limited to the brief moment around the earthquake shaking, but can last for years.Landslides are the main secondary effects of earthquakes in mountainous environments, often claiming more than a third of the casualties during the shaking9 dynamics in seismic environments has been undertaken11. These studies show a co- and a post-seismic acceleration of the landslides over several weeks, and material damage (i.e. cracking or changes of the void space in the bulk) over several months. This bulk damage is found to ease the water infiltration during the subsequent rainfall events over the months after major earthquakes11, and can therefore explain the increased landslide rates observed at the regional scales in the months to years after the earthquake7. However, the physical processes of the post-seismic motion of landslides in the weeks following the shaking, observed on different slow-moving landslides13, even without precipitation, are still uncertain.To infer the complex mechanics of post-seismic landslide movements, multi-parameter monitoring of slow-moving landslides13, whereas the Mela-Kabod landslide, situated in the near field of the same earthquake, displays at least 5 mm of post-seismic motion in the 3 weeks following the shaking , where seismic shaking has limited groundwater effects18. All these uncertain conclusions show the need for more observations of post-seismic landslide motions to better infer the underpinning mechanisms.Other hypothesis related to effects of fluid migration during the shakingIn this study, in order to understand the mechanisms of this post-seismic motion at a weekly/monthly scale, we document the kinematics of slow-moving landslides accelerated by the Gorkha earthquake . We provide unique observations of landslide kinematics in the near field of an earthquake that we analyze in regards with previous observations.19. The main shock was followed on 12 May 2015 by an aftershock (Dolakha earthquake) of Mw 7.3 on the eastern side of the main rupture. The seismic sequence triggered at least 25000 landslides21. These landslides are mainly attributed to a co-seismic triggering due to the dynamic loading of the steep slopes of the high Himalayas in fractured rockmass22 and weakened regolith21.The Gorkha earthquake of Mw 7.8 (25 April 2015) struck the central part of Nepal  of 6 deep seated landslides before and after the Gorkha earthquake have been evidenced using InSAR techniques29. However, because of high noise during the monsoons, the behaviour during the co-seismic phase and the months that followed it can not be documented. Therefore, in this study, we propose to detect and monitor slow-moving landslides affected by the seismic sequence and the subsequent monsoons from image correlation techniques, in an area characterized by a high density of co-seismic disrupted landslides, evidences of shattered ridge30 and the previous description of numerous dormant large landslides28.In contrast to the catastrophic impact of the Gorkha eathquake on disrupted landslides triggering, which has been widely documented, very few studies have focused on its impact on slow-moving landslides and their possible reactivation or acceleration. The central Himalaya, however, has been described as hosting many dormant or slow-moving landslides21, and is struck by intense monsoons of more than 2.5 m per year, as estimated by the monthly rainfall GPCC-v2018 dataset31 or measured on a daily basis by a rain-gauge of the DHM  located at Bahrabise, Our area of interest is chosen around the Bhote Koshi valley, at the termination of the Gorkha earthquake rupture and in the area affected by the Dolakha earthquake Fig. . This reea Figs. . The areIn this study, the strategy developed to detect and monitor slow-moving landslides over an area of 750 kmges Fig. : (1) 6 o20 (50 ± 13°), showing a different type of landslide. We visited 8 of these landslides during two fieldtrips in May 2016 and January 2019. All the landslides exhibited clear signs of instability with fresh head- or lateral- scarp motions up to several meters  Fig. D, E, F t33.Pléiades data allows us to monitor the landslide motions over 3.5 years , responded to the earthquake solicitations, with an acceleration that lasted at least several months and not limited to the time of the earthquake. This is a fairly common behaviour for slow-moving landslides as pointed out previously . The simulated seismic ground motion for the two earthquakes clearly shows a lower shaking for the Dolakha earthquake than for the Gorkha earthquake, despite its proximity to the study area. For instance the recorded highest Peak Ground Acceleration (PGA) close by our area reaches 1.3 g for Gorkha (Chautara station), and around 0.3 g for the Dolakha earthquake in our area of study . This difference in ground motions can explain, on a first order, the lower effect of the Dolakha earthquake on the landslide kinematics.Furthermore, the shape of the post-seismic motion  or a time-dependent fracture process of the landslide shear zone (like progressive failure and maturation of the sliding surface37). This last hypothesis is hardly plausible due to the sharp increase of velocity at the landslide initiation, and due to the geomorphology of all the detected landslides, that are mostly reactivations of ancient thick slides with many pre-existing signs of instability. This shows indeed that the landslide failure surface should be already well developed before the earthquake.No anthropogenic forcing, like road construction, could explain the initiation of this landslide motion in the first few days after the earthquake. The time-dependent behavior, in particular the observed time-delay of large movement initiation after the main shock, suggests either a fluid effect , we conjecture that the landslide kinematics observed here has a similar origin.Many observations show co- or post-seismic variations of groundwater levels in wells18. Therefore, our observations and comparison with the existing database of slow-moving landslides accelerated by earthquakes, suggest that abrupt water increase might originate from the material consolidations in the near-field of earthquakes and provoke the landslide post-seismic motion.This hypothesis is also supported by the above inter-comparison of all the existing case-studies of post-seismic motions of landslides, which suggests that post-seismic motions only take place in the near-fields of earthquakes, where abrupt and transient water level changes occurred Fig. B. This h43, no groundwater level measurements are available in the vicinity of the Gorkha earthquake main rupture zone, that could be used to substantiate this hypothesis. Some water level changes were observed in the far-field of the Gorkha earthquake45, but data is missing in the near-field. Therefore, the origin of this potential excess pore-water pressure remains a main question.Unfortunately, with the exception of a spring that appeared following the earthquake sequence in Kodari area46 allows the subvertical draining of water and subsequently the recharge of deep aquifers16. The subvertical draining can be caused by the co-seismic shaking and fracturing of the bedrock. This hypothesis is also emphasized by the location of the studied area in the northern part of the Gorkha rupture area, in a zone where co-seismic deformation produced an increase of the North-South tensile stress, favouring an opening of the East-West oriented fractures. The deep aquifers would feed the sources in the lower parts of the massif16, where all the observed slow-moving landslides are situated . On the Tapgaon landslide, whose kinematics is the best resolved in time, all time-series show a synchronous pattern of displacement  or externally from the landslide area. In this latter case, this excess of water can be transported by subvertical cracks formed during the shaking, feeding a deep aquifer that emerges at the slope toes Fig. , where t4, with direct consequences on the hazard associated with earthquake-induced landslides. These new observations therefore emphasize the complex mechanics of landslide triggering by earthquakes: Following the co-seismic phase caused by the dynamic loading, a post-seismic phase of few days or weeks can lead to additional landslides in the near field caused by diffusion of groundwater excess from material contraction. Then, the material damage caused by the shaking, produces a phase of instability of several months to years where rainfalls can easily infiltrates and trigger landslides11. These different post-seismic phases highlight the hydrologic sensitivity of landslides, showing the need to improve our understanding of the groundwater processes on landslides.This late landslide initiation has also been reported following other major earthquakes, leading sometimes to catastrophic failuresThe data acquisitions are presented in Fig. 33 applied on the Pléiades images: (1) DEM construction from the December 2015 stereo acquisitions using Ames Stereo Pipeline v2.5.3 (https://ti.arc.nasa.gov/tech/asr/groups/intelligent-robotics/ngt/stereo/)24, (2) Orthorectification of the December 2015 images using the Rational Polynomial Coefficients (RPC), (3) Orthorectification of the other images using the December 2015 DEM and a rigorous sensor model refined from RPC using Ground Control Points (GCPs) extracted from tie-points with the December 2015 orthorectified image using the Cosi-Corr software50 , (4) Image correlation between all pairs of images from the same season (summer or winter) using the Mic-Mac software51 (https://micmac.ensg.eu/index.php/Accueil), that is best suited for small objects like landslides. (5) Filtering of the displacement fields with low correlation coefficient values. (6) Time inversion of the displacement fields per pixel using the TIO software (https://sourcesup.renater.fr/www/tio/), separately for the East/West (EW) and North/South (NS) components33. This process leads to a time-series of cumulative ground motion displacement along EW and NS. The steps 4, 5 and 6 are applied separately on winter (Nov/Dec 2014 - Dec 2015/Jan 2016 (stereo) - 09/12/2017) and summer (13/06/2014 - 04/05/2015 - 31/05/2015) images, due to large differences of illumination and vegetation that lead to correlations of low quality in between them. A constant bias per pixel in between the summer and winter time-series therefore remains. We fixed this bias by defining a zero-motion during the pre-earthquake time period (13/06/2014 - Nov/Dec 2014 ). This hypothesis is verified a posteriori by comparing with the time-series from SAR images and by checking the consistency of the landslide motion with time (monotonic increase of the cumulative motion).Time-series of ground displacements over the whole area of study are obtained by a classical schemeAt each time-step, the uncertainty on the ground motion is calculated with the standard deviation of the ground motion outside the landslide areas. The uncertainties are larger for summer images than winter images, mostly due to a higher vegetation cover. We therefore decided to visually detect slow-moving landslides in the winter displacement fields, by catching patches of motion compatible with slope processes . We estimate that all slow-moving landslides larger than 10000 m29, but is usually restricted to low displacement rates and for large landslides correctly oriented respect to the SAR orientation. Here, all the detected landslides display displacement rates of several meters in less than 1 year in Pléiades images. These velocities are too high to be detected by C-band InSAR. Therefore, correlation of SAR image amplitudes is used here. Two Sentinel-1 descending tracks (D121 and D019), as well as one ascending track (A085) cover the area of interest. Track A085 is not used here due to the bad geometric configuration of the landslides relatively to the track orientation that greatly limits the visibility of the detected landslides in this track. We limited our analysis with C-band radar to the 2015 period, as the major landslides, large enough to be detected by medium resolution imagery like Sentinel-1, are found to be mostly active at that time and not after . This method allows us to differentiate the size of the master correlation window in range and azimuth, which is key to measure the ground displacement of small objects in radar images57. We test different combinations of range and azimuth window sizes. The optimum sizes are found by maximizing the signal to noise ratio of the displacement field obtained by correlating two images encompassing an active slow-moving landslide, previously detected . A weight between pairs, function of their time-separations is used in the inversion process. This process leads to a time-series of ground displacement for the two tracks D121 and D019. Uncertainty of these time-series are estimated by the standard deviation of the ground motion outside the landslide areas.The images of the same track are all correlated two by two, and inverted using a time-inversionSupplementary Information 1.