In multiple stellar systems, interactions among the companion stars and their discs affect planet formation. In the circumstellar case, tidal truncation makes protoplanetary discs smaller, fainter and less long-lived than those evolving in isolation, thereby reducing the amount of material (gas and dust) available to assemble planetary embryos. On the contrary, in the circumbinary case the reduced accretion can increase the disc lifetime, with beneficial effects on planet formation. In this chapter we review the main observational results on discs in multiple stellar systems and discuss their possible explanations, focusing on recent numerical simulations, mainly dealing with dust dynamics and disc evolution. Finally, some open issues and future research directions are examined. Multiplicity is common among main sequence stars –5, and eRadial velocity and high-resolution imaging exoplanet surveys established that multiplicity has a substantial impact on the occurrence of circumstellar planets e.g. –20). A c. A c20])tainties .TESS data [Kepler eclipsing binaries, the occurrence rate of giant planets coplanar with their binary host is Instead, despite the recent improvements with ESS data , 23, theent}≈10% , 25. Thinsidered .Protostars and Planets VII chapter on multiplicity [The recently issued iplicity  thoroughOn observational grounds, there is general consensus on stellar multiplicity substantially influencing disc evolution. Infrared excess signatures showed that the fraction of stars with discs decreases in multiple systems with decreasing binary separation –30: in bng discs , 31. Using discs –34: in CUnresolved observation of discs in binary systems in the (sub-)mm, using single-dish telescopes, showed that multiplicity also affects continuum luminosities, with discs being fainter in closer binaries –37. The mentclass2pt{minimRecent ALMA surveys confirmed these results –47. HoweThe unprecedented angular resolution provided by ALMA allowed to resolve circumstellar discs in binary systems, showing that dust emission is more compact , 44–46 ant}≈4.2, ) than innt}≈2.8, , 51). Thparation . Finallyparation  or UX Taparation .As for accretion signatures, disc surveys in multiple systems are rare because of the high spectral and angular resolution required. In fact, disentangling the accretion signatures of each component remains challenging (e.g. ). HST anr masses . These rr masses , 33. Recr masses , 57. Whey tracks .The recent advent of new instruments like ALMA and the Spectro-Polarimetric High-contrast Exoplanet REsearch (SPHERE) at VLT has also been revolutionising our understanding of circumbinary discs. Despite being not as ubiquitous as S-type ones , there ato 0.44, ) and shoto 0.44, –67. In tto 0.44, , 65, 68,to 0.44, , 65), stto 0.44, , 68 and to 0.44, , 68, 69 to 0.44, –73.Nonetheless, circumbinary disc statistics are still limited, and it remains unclear whether or not their lifetimes are significantly different from single-star systems , 75. Ind≈20 Myr, , 76). A The interaction between a gaseous disc and an embedded satellite (e.g. a planet or a stellar companion) has been investigated since the late 1970s, either tidally , in the e is the binary eccentricity, The location where a disc is truncated depends on several parameters. In the case of circular coplanar tidally interacting binaries, truncation occurs when the viscous and tidal torques balance. Because both these terms scale linearly with viscosity, the truncation radius does not depend on viscosity . This ise radius , the minsults of . \documeadius of  in circulated in  for diffntersect –89. Thisntersect .Numerical studies of circumstellar protoplanetary discs in binary systems mainly focused on planetesimal evolution. Earlier phases were almost only considered to analyse the conditions for planet formation in very close . Later γ-Cephei  and [98,γ-Cephei  argued tγ-Cephei  showed tAs for dust, simulations of growth and transport have traditionally been challenging also in the case of single-star discs , 102. Baulation.  considerulation.  argued tTo sum up, these works paint a consistent picture that planet formation in binaries faces more challenges than in single systems. The observational evidence that planets in binary systems nevertheless exist implies that planet formation must then be a fast process, unless viscosity is low enough  and dustA population-oriented approach has also been sought, in order to systematically compare protoplanetary disc simulations and observations. In these works, circular coplanar binary discs are considered and tidal truncation is modelled impeding any exchange of material at the expected truncation radius.Evidence of systems where only one component shows IR excess , 107 motWhen discs are evolving viscously, the disc-clearing timescale is set by the truncation radius, because of the suppression of viscous spreading. So, for nditions . Howevers higher . This dis higher .When simulated populations of discs, with observationally motivated initial conditions, were compared with data, a good agreement was found, both with the disc fraction of Taurus binaries as a function of the companion separation, and with the relative lifetime of primary and secondary discs as a function of the binary separation and mass ratio . HoweverTo explore the effect of binarity on dust dynamics,  coupled ata, see ); for a hosts of .Fig. 1Thx of the dust flux, These models were post-processed, computing the surface brightness and the dust size (defined as the radius enclosing a faction nd 7) by . In the entclass1pt{minimar Taurus  and purpphiuchus ), whose f 2 to 7  smaller Following-up on previously published tests , we can ix F” in ).2 In thix F” in .Fig. 2LeThis outcome is intriguing provided that in the case of isolated discs substructures need to be invoked to explain the difference between the predicted and observationally inferred dust-to-gas size ratios . A possientclass1pt{minimaentclass1pt{minimaThe inference of a shorter accretion timescale in binary than in single-star discs  was receAll in all, these simple models can reproduce well the behaviour of the binary disc populations in young nearby star-forming regions, even though larger observational samples would be beneficial to get better constraints. Possible limitations are discussed in Sect. “Pure” circumbinary discs exist only around relatively close binaries . Intera}q>0.04, . Interes}q>0.04, . This is}q>0.04, , 126. Fo}q>0.04, , 127–130Models with circular binaries have the most eccentric cavities. Increasing the binary eccentricity, the cavity becomes less eccentric until a critical value outwards , 131, asoutwards . The disoutwards . Howeveroutwards , 133. Ploutwards ). Lower-Most recently, dust evolution in circumbinary discs was also studied. , 136 agrIn misaligned circumbinary discs, dust evolution shows interesting features. Solids with and dust . Analytiand dust . These pand dust . Dust piand dust .The problem of accretion in circumbinary discs has been studied in great detail due to its applicability in different contexts . In particular, in the case of black hole binaries, during the gas-driven migration phase, the accretion process influences the spin alignment process , determiFirst analytical studies predicted a suppression of the accretion when high mass ratio companions were present . Howevergle star .In the latter case, when the stars are at apocenter, and can efficiently interact with the disc, dense clumps of material are launched towards/swept by the binary , 147. OnSeveral works have argued that accretion takes place preferentially on the secondary star, because it orbits farther from the centre of mass of the binary/closer to the disc , 148–151nt}q≳0.2 , and cirt}e≈0.1, ).Also in hierarchical triple systems the highest accretor is generally the less-massive component. However, mass equalisation takes place one order of magnitude faster than in binary systems with the same parameters . This isIn the case of dust, accretion of solids can take place due to the disruption of the dust trap, co-located with the pressure maximum at the cavity edge, by binary interactions. Subdivision of material on each binary component is as in the gas . HoweverThe predictions of circumbinary accretion simulations discussed so far are difficult to test observationally. While streams of accreting material in multiple stellar systems have been detected , 157–159To sum up, the simulations of circumbinary accretion discussed so far depict a complicated process, quasi-periodic but intrinsically variable and dependent on a number of different parameters. Nonetheless, the pulsed accretion model qualitatively agrees with observations. Two main limitations complicate the interpretation of numerical prediction in the case of protoplanetary discs and need to be addressed in the future: (a) very high viscosities are employed (in between those expected in binary black hole and planet-forming discs); (b) magnetic fields are not included. The latter can reduce the size of circumstellar disc, potentially leading to interaction of the accretion streams and the stellar magnetospheres, increasing variability.Even though the evolution of a circumbinary disc requires 2/3D simulations to be studied accurately, computationally cheaper methods are necessary to explore the vast parameter space characteristic of this problem. Here we examine whether the population-oriented framework recently employed in the case of circumstellar discs , 110 canWe run 1D dusty simulations of viscously evolving circumbinary discs. The presence of a companion is modelled reducing the accretion rate by 90% compared to a single-star disc with the same parameters , 121. FoWhen dust can accrete without restrictions , after 2 Myr the dust-to-gas mass ratio in circumbinary and single-star discs (as in ) is the The dependence on entation  that repin situ or ex situ) formation in circumbinary discs on secular timescales, and how this depends on several disc and binary parameters. However, we need 2/3D-informed dust accretion rates to tailor our simulations to and provide more reliable results.Clearly both the case of fully open and fully closed dust inner boundary are extreme, and the behaviour of solids in circumbinary disc is “in between”. Notwithstanding, we showed that 1D models have the potential to inform us on the available material for planet  that arThe entirety of the published work we have summarised in the previous sections has considered discs evolving in the viscous framework. As recently reviewed by , an alteReference  is the oConsidering that the presence of a companion clearly breaks azimuthal symmetry, 1D models are forced to take the assumption that there is a well-defined truncation radius at the inner (circumbinary) or outer (circumstellar) boundary, and that accretion through the boundary happens at a prescribed rate (circumbinary) or not at all (circumstellar). As we showed in Sect. We reviewed the main literature results on disc evolution in binary systems with particular focus on the case of dust.Simulations of discs in binary systems agree that in these extreme environment planet formation is difficult. The short disc lifetime and the fast removal of material make challenging to explain planet formation in the context of core accretion and suggest that planetesimals must form fast (see Sect. Simple population-oriented models can explain well the behaviour of disc fraction with time and the relative primary/secondary disc lifetime as a function of the binary separation and mass ratio . When duIn the case of circumbinary discs the inner binary can extend the disc lifetime, making these system unique laboratories to study planet formation and the efficiency disc dispersal by thermal winds (see Sect. Observations of circumstellar binary discs agree that the presence of a companion affects their evolution. Discs in binary systems are less-long lived, fainter and smaller than single-star ones, particularly in the case of a close companions with extreme mass ratio. This qualitatively explains the small stellar companion fraction of planet hosts.We ran a new a set of simplified 1D models of viscous circumbinary discs inspired by the recent 2D dusty simulations of , 136. We


Objectives: Together with the COVID-19 pandemic, conspiracy theories have begun to spread. Evidence is lacking for religious conspiracy theories (RCT) related to COVID-19 in a non-religious environment. This study aimed to assess links between religiosity and spirituality (R/S) and RCT about COVID-19, and to examine their associations with mental health.Methods: A sample of Czech adults  participated in the survey. We measured R/S, RCT, negative religious coping (NRC), feelings impairment and mental health symptoms.Results: We found R/S were significantly associated with RCT with β 0.71  for the strongest association. Moreover, RCT and NRC were strongly associated with paranoia, anxiety and depression. The most frequent association was found for NRC and paranoid ideation, with β of 0.35 (95% CI 0.26–0.44).Conclusion: Our findings showed associations between religiosity/spirituality and beliefs in religious conspiracy theories about COVID-19. Moreover, these RCT and negative religious coping were linked to higher possibility of mental health problems. Understanding these associations may help prevent this negative impact and contribute to the effectiveness of psychotherapeutic help. When the World Health Organization (WHO) declared the coronavirus disease COVID-19 as a pandemic in March 2020 , 4. ThesIn a period of uncertainty, misinformation and feelings of powerlessness, people are likely to be attracted to conspiracy theories , 9, whicReligiosity and spirituality (R/S) represent important dimensions of the lives of many people and an important resource for health and well-being . A largeFurthermore, some studies have shown associations of R/S with conspiracy beliefs , 33. ConThe Czech Republic is characterized by a high degree of secularization, as most people do not report any religion affiliation or regular church attendance . Recent Therefore, the aim of this study is to assess the associations of religiosity/spirituality and negative religious coping with beliefs in religious conspiracy theories about COVID-19 and to examine the associations of such beliefs and coping on mental health by assessing their relationship with emotional impairment, paranoia, depression and anxiety during the first wave of the COVID-19 pandemic.For this study we used data from the Czech population aged 18 to 97. The data was collected during the first lockdown in April 2020 through an anonymous online survey aimed at depicting the actual situation through the most critical time of the first wave of the COVID-19 pandemic. The online survey was prepared at the researchers’ institution and a professional agency ensured its distribution in order to achieve a balanced sample regarding age and sex. Details on age and gender regarding the composition our sample vs. a Czech national representative sample can be found in the Appendix see .n = 13) the final sample consisted of 1,273 respondents .Consequently, in order to ensure the high quality of the data, the following data were excluded: 1) an extremely short time filling in the survey ; 2) a unified pattern of responses, i.e., responding to most of the items in the survey in the same way. After exclusion of the problematic subjects .Religious coping was assessed using the negative religious coping subscale (NRC) of the Brief RCOPE . The insReligious conspiracy theories were assessed using four statements capturing common religious opinions on the COVID-19 pandemic. The statements were generated from searching the Internet and social media during the first weeks of the pandemic. Although the approach may not be completely exhaustive, we tried to capture the most common theories involving religious themes. The assessed statements were: “The current coronavirus pandemic is God’s punishment”; “The current pandemic is a punishment for the moral decline of the Church and for the liberal attitudes of Pope Francis”; “The current pandemic has been foretold by some religious visionaries”; and “The current pandemic is only the beginning of the events described in the book of the Apocalypse.” Participants were asked to mark to what degree the information corresponds to the truth. Possible options ranged from “does not correspond at all” (0) to “definitely corresponds” . When anNegative feelings impairment was assessed by the question: “In connection with the pandemic, has anything changed in your life in the following areas?” These areas were: the feeling of loneliness, threat, fear and anxiety, helplessness, loss of hope. The possible answers were : “worsenParanoia was assessed using the Paranoid Ideation subscale of the Brief Symptom Inventory BSI-53) , 43. The3 , 43. TAnxiety was measured using the Overall Anxiety Severity and Impairment Scale (OASIS) . It is aTo assess depression, we used an abbreviated version the Overall Depression Severity and Impairment Scale (ODSIS) . This seSpirituality was measured using the Daily Spiritual Experience Scale (DSES). The scale measures the frequency of ordinary experiences of connection with transcendence in everyday life . The preReligiosity was measured using the following question: “At present, would you call yourself a believer?” with possible answers: “yes, I am a member of a church or religious society”; “yes, but I am not a member of a church or religious society”; “no”; “no, I am a convinced atheist”. For the purpose of further analysis, participants who reported “yes” were dichotomized as religious.Sociodemographic characteristics, such as sex, age, education level, marital status and economic activity, were obtained by means of the questionnaire.p-values of these univariate analyses were corrected for the family-wise error rate (FWER) using a Bonferroni approach. All multiple regression models were first assessed as crude and consequently adjusted for sex, age, and the highest level of education. The data have been adjusted to partial out variance of variables which might confound our results. This approach helped us to interpret the data for the given variable without the constraints of removed variables. Each of the independent variables was assessed in a separate model. All analyses were performed using the statistical software IBM SPSS version 25  and R .In the first step, the descriptive statistics of the key study variables were calculated. The differences in basic characteristics and in the observed categorical variables were assessed using the Chi-Squared test. In the further step, we conducted Principal Component Analyses (PCA) on items for each scale. In the next step, component scores were calculated from the first extracted component. These scores were used in the further analyses. Prior to further analysis, all continuous dependent and independent variables were standardized to Z-scores. We assessed the associations of spirituality, religiosity and NRC with the whole RCT using linear mixed model, i.e. multiple linear regression. Logistic regression was used only to asses changes in feelings associated with COVID-19 pandemic. In all regression models, we set a time needed for finishing the questionnaire as a random effect. In each regression analysis, we used a model with random intercept. If chi-square difference test suggested that a model with random slope has a better fit, we included a random slope into a model. Subsequently, the procedure was repeated for the associations of RCT and NRC with changes in life during the pandemic as well as with paranoia, anxiety and depression. The p < 0.05) only for the respondents believing in NRC. Moreover, the respondents differed significantly in levels of education , and a comparison showed significant difference among religious respondents within the group believing in RCT(p < 0.001) and within the group using NRC (p < 0.01).The sociodemographic characteristics of the sample are presented in p < 0.001) associated with RCT beliefs around COVID-19. The results are also visually depicted in The results of binary logistic regression assessing the RCT and NRC with paranoia and anxiety and depression frequency and intensity are presented in We assessed links between R/S and beliefs in RCT and examined the associations of such beliefs with mental health. RCT beliefs were found to be associated with both R/S and NRC. Although we found no associations of RCT and NRC with the impairment of negative feelings except associations of NRC with threat, fear and anxiety, both RCT and NRC were strongly associated with paranoia, anxiety and depression. The strongest association was observed between NRC and the beliefs in RCT about COVID-19.The findings of higher RCT belief in the group with a secondary vocational education without graduation vary from the study of Klosfad at al.  which foFurthermore, we confirmed an expected association between both R/S with each of the assessed RCT beliefs. This is in line with a number of other studies showing the associations of R/S with conspiracy theories , 33, altIn our study, we did not observe any significant associations of RCT beliefs with impaired feelings except feelings of threat, fear and anxiety. These findings are in contrast with the findings of other studies, which reported an increase of negative feelings during the pandemic in connection to conspiracy theories , 62 and Our further results showed strong associations of NRC with paranoia. This finding is in line with the study of McConnell . ParanoiMoreover, in our study, NRC was also associated with both anxiety and depression. These results correspond with the findings of studies that showed a relationship of NRC with depressive disorder , 37 and This study has several important strengths. The first one is its large sample, which is balanced and close to having a national characteristic regarding age and sex. It is also one of the few studies exploring the relationship between RCT, R/S and mental health during the COVID-19 pandemic and describing significant associations in this area. Further, with its focus on specific area of religious conspiracies it contributes to other studies that found connections of COVID-19 conspiracy beliefs with anxiety and depression.However, this study also has some limitations. The first is the cross-sectional design, which does not enable us to make decisive conclusions on the direction of causality. Thus, the present study should be confirmed by studies with a longitudinal design. Moreover, there could be a methodological limitation to our study as we assesses beliefs in RCT among all respondents, whereas NRC was assessed only among religious respondents. Thus, our design did not allow us to explore another possible model, i. e. to treat NRC as a dependent variable. Another limitation concerns the relatively modest number of religious respondents who reported NRC, which decreased the power of the study. However, this subsample still included 131 respondents. A further limitation can be the use of a self-report methodology, which can cause information bias and may be influenced by a social desirability. Nevertheless, in the area of assessing conspiracy theory beliefs, an online anonymous survey seems to be an applicable means of lowering the unwillingness of respondents to admit their true beliefs . In addiOur results show that RCT beliefs concerning COVID-19 are related to an individual’s R/S and maladaptive NRC strategies. These findings may help to understand the factors influencing the dynamics of development of RCT and their associations with R/S areas of human lives. We also found that both RCT and NRC were negatively associated with mental health. This points out that some aspects of R/S may have a relevant impact on mental health and adjustment during the pandemic. This can be helpful for health care workers, as well as for workers in helping professions, such as psychotherapy, psychosomatic medicine, social work or pastoral care.Further research should focus on the causal effects of the RCT beliefs dynamic and on the mutual interaction between R/S and conspiracies in general. It could also focus on a more specific categorization of the respondent groups according to their religiosity or spirituality and test for potential confounders between RCT, NRC and mental health.The impact of the COVID-19 pandemic is not only related to physical health but also involves psychological issues. Our findings emphasize the associations of religious conspiracy theories about the pandemic with R/S and NRC. The negative effect of RCT beliefs and of NRC was revealed by significantly higher levels of paranoia, depression and anxiety in those who reported such beliefs or/and a way of coping. Thus, this study offers a deeper understanding of the factors that might influence the development of religious conspiracy theories and contribute to studies on conspiracy theories and the extent to which these beliefs may affect mental health. Furthermore, it stresses the importance of addressing spiritual issues in order to minimize maladaptive coping strategies associated with RCT beliefs.


Research about using physical activity (PA) to improve health, quality of life, and participation after moderate-to-severe traumatic brain injury (TBI) is receiving growing attention. However, best-practices for maintaining PA participation after TBI have yet to be defined. In this context, a team of researchers and stakeholders with a moderate-to-severe TBI (including program participants and peer mentors) participated in a co-creation process to optimize a 9-month, 3-phased, community-based, adapted PA program named TBI-Health.The study aimed to provide a detailed account of the participation in and co-creation of a new TBI-Health Program to enhance sport and exercise participation for adults with moderate-to-severe TBI. Specifically, we carried out an in-depth exploration of the perceived experiences and outcomes of users over one cycle of the program to assist the co-creation process.n = 10; peer mentors n = 4) were involved in audio-recorded focus groups after each program phase. Reflexive thematic analyses within and across the phases identified three higher-order themes.An interpretive case study approach was used to explore the experiences and outcomes of the participatory co-creation within and across phases of the TBI-Health program. A purposeful sample of fourteen adults with moderate-to-severe TBI (program participants Program Participation included barriers, facilitators, sources of motivation and suggested modifications to optimize the program; Biopsychosocial Changes highlighted perceived physical, psychological, and social outcomes, by self and others, that resulted from program participation; PA Autonomy emphasized transitions in knowledge, sex- and gender-related beliefs, and abilities related to exercise and sport participation.Study findings suggest the TBI-Health program can increase autonomy for and reduce barriers to PA for adults with moderate-to-severe TBI, which results in increased PA participation and important physical, psychological, and social benefits. More research is needed about the TBI-Health program with larger samples. Research about using physical activity (PA) to improve long-term problems  after moderate-to-severe traumatic brain injury (TBI) has received growing attention –3 and suTaking a participatory approach to modifying a PA- and nutrition-based program for the TBI community has been documented in previous research. For instance, consulting with an advisory committee of key stakeholders helped specifically tailor the content and delivery of an evidence-based diabetes prevention program for adults with moderate-to-severe TBI . A 10-meTBI-Health program to enhance sport and exercise participation for adults with moderate-to-severe TBI. Specifically, we carried out an in-depth exploration of the perceived experiences and outcomes of program users and peer mentors over one 9-month cycle of the program and co-creation process.In a similar participatory context, a team of researchers, community stakeholders, and persons with moderate-to-severe TBI (including program participants and peer mentors) collaborated for the purpose of optimizing a 9-month, 3-phased, community-based PA program named TBI-Health. The grass-roots initiative was first established in response to a need for PA support in the community after moderate-to-severe TBI  and was safely in a smaller machine-based section of the gym, (2) independently in the larger free-weight and machine-based section of the gym, and (3) for a sport challenge on an outdoor walking trail near the gym.The third iteration of the TBI-Health program discussed here See  was firsGroup-based exercises and instruction during TBI-Health were delivered by the PI, a certified personal trainer at the YMCA. In phase one (weeks 1–12), group programs took a generic approach to prescribing 10–15 min of warming up on cardiovascular machines, before completing 8–10 resistance training exercises (2–3 sets of 12–15 repetitions) on major muscle groups of the body for 45–60 min in a smaller gym located on the second floor of the YMCA Center. The sessions always finished with body-weight exercises for the core muscle groups and stretching to cool down in a studio for 20–30 min.Phase two (weeks 13–24) followed the same approach but took place in a larger gym with more equipment, located on the third floor of the YMCA Center. Similar programs were provided to the participants through mobile fitness applications, which they accessed on their personal mobile devices. In phase three (weeks 25–36), participants continued their individual programs on the third floor in addition to following a progressive run/walk program to prepare for a community organized, 5-kilometer (k) sport challenge on an outdoor walking trail near the YMCA. Exercises across phases were modified for participants with mobility limitations from an ability perspective . Participants were also encouraged to exercise at the center outside program hours, but adherence was measured by program attendance. Motivational strategies were regularly provided in the form of positive encouragement by the PI and peer mentors (past participants from the program).The starting level for cardiovascular and resistance training exercise was established by the participants, while supervised by the PI, based on their perceived rate of exertion. Subsequent progressions were guided by incremental increases in time and intensity of approximately 10% per week. There was no home program component, but non-exercise components included social activities organized between members and a social media page that facilitated discussions between past/present participants in the program. The PI kept a written log about participants' involvement, fidelity, and attendance during sessions, in addition to any adverse events.Supplementary File S1; The study was guided by participatory and interpretive case study methods to provide a multi-faceted exploration of a particular case over time through an in-depth collection of multiple sources of evidence in a real-life context , 16. TheTBI-Health program. Eligible participants (1) were at least 18 years of age, (2) lived with a moderate-to-severe TBI, (3) and were able to speak English or French. Exclusion criteria were (1) not being able to safely participate in general forms of PA, (2) having a heart, blood, or respiratory conditioning that could be worsened through PA, and (3) not being an in-or out-patient in a rehabilitation hospital center. Recruitment was facilitated by the Montreal-based Quebec TBI Association, based on their members’ medical records, which were kept on file. Program participants included six new  and four returning members , in addition to four peer mentors . One participant was partially hemiplegic, two participants used a walking cane, and another wore an ankle brace. All participants could communicate effectively and had sufficient cognitive ability to understand program instructions and travel independently to and from the YMCA. Peer mentors were past participants onboarded as YMCA volunteers to help run the program as expert members and positive role models for the others. Demographic characteristics of the 17 participants are included  were recruited to participate and contribute to the new uded See . Study pThe process of co-creation (involving capturing participant experiences) was conducted over 9-months of program delivery through participatory work groups, focus groups, and field note observations. Whereas the nine monthly participatory workgroups tailored the content and delivery of each phase as it was being delivered, the focus groups at the end of each 3-month phase reflected the perceived experiences of all the participants involved See .In addition to their leadership roles with the program, the four peer mentors collaborated with the research team through nine work groups, lasting approximately 60 min each, in a private office at the YMCA with the PI and a senior member of the research team (BS/SW). Work groups were structured with five guiding questions about how (1) the program was running, (2) the group was responding, (3) program components should be modified, (4) the mentors’ responsibilities should be defined, and (5) they would self-rate their contribution to the development of the program in each meeting on a scale from 1 to 10 . Individual responses to the questions in the work groups were recorded in written text, with a pen, on paperback journals assigned to each one of the mentors. Data from these sessions were not analyzed, but rather integrated within the modules and delivery of the program as it was being offered .Program participants and peer mentors were involved in audio-recorded 60–90-minute semi-structured focus groups at three time points across the 9-month program, approximately three months apart, after each respective phase of the program. Focus groups took place in a private studio at the YMCA and were divided in two sections to accommodate the number of people and provide the opportunity to discuss individual and shared experiences . They were led by the PI, who had previous experience interviewing adults with moderate-to-severe TBI , and a sThe semi-structured question guide and probes for the focus groups were based on a question guide developed with the multidisciplinary team's expertise and piloted with past participants for optimal length and prompts. The questions focused on gathering perceptions about (a) experiences, including program impacts and sex and gender considerations; (b) positive/negative aspects of each phase of the program, including what was successful, challenging, and required modification; and (c) any personal changes that had occurred in that phase, in relation to their capabilities, opportunities, and motivations. Interview questions across the three time points were the same to achieve conceptual depth about the peer mentors and program participants’ experiences and outcomes in the participatory co-creation process.The PI supervised the TBI-Health program two days per week over a period of nine months for a total of 72 of the 75 program sessions (∼108 h). He was involved as a program coordinator to onboard, guide, and monitor the participants throughout the different phases of the program, but also maintained the role of participant observer throughout the 90-minute program sessions. As an observer, he walked around and spoke with participants to note his perceptions of their behaviors and gain entry to their everyday program experiences. During and after program sessions, the PI typed these observation and field note entries in a personal journal on his laptop computer, along with preliminary interpretations about his perceptions. The PI maintained similar field notes before and after each one of the participatory work groups and audio-recorded focus groups, to document contextual information about the meetings and his possible influence on participants in his dual role as PI and program coordinator.Braun and Clarke's  reflexivwithin phases, before developing inter-analysis themes across phases. The first step of this analysis involved becoming familiar with the data by reading and re-reading transcripts, while taking notes about initial ideas. In the second step, a codebook was generated using the qualitative analysis software (NVivo 12). Once all segments were coded, the RA met with the PI to carefully discuss and revise the codes, and ensure they accurately represented the semantic content. In third step, the RA began collating the codes into potential sub-themes within each phase, while maintaining consistent language to help identify similarities and differences across cases.To capture the perceived changes about the participants’ perceptions over time, the analysis team determined that pooling the data and systematically coding by phase of the program would facilitate the interpretive goal of generating intra-analysis themes fourth step, the RA, PI, and Co-Is worked closely through an iterative process of critically reviewing the sub-themes to ensure they accurately represented the coded extracts within each phase and the larger data set, in addition to discussing the direction of analysis, and guiding research question. The fifth step involved refining the similarities and differences of sub-themes, within and then across the phases, which revealed the types of changes that were occurring over time. Sub-themes identified from the intra-analyses within each phase were reviewed and defined before themes were identified from the inter-analyses across phases.For the sixth step involved producing a graphic report of the intra- and inter-analysis process (Supplementary File S2), as well as compiling vivid and compelling extracts relating back to the research question. In this final step, the analysis team critically reviewed every step of the process, ensuring that each intra-phase sub-theme did not belong to a different inter-phase theme, by asking whether the sub-theme itself was problematic or needed to be re-named. The analysis was finalized by reviewing the final themes in relation to the data set and the research question to ensure that the overall story of analysis was reflected within the report. Included quotes were translated by a professional translator , with no prior connection to the participants.The final Ongoing methods were upheld to ensure the qualitative rigor of this study , 22, sucProgram Participation, Biopsychosocial Changes, and PA Autonomy) were generated from the inter-analyses across the program phases, representing 10 sub-themes developed from the intra-analyses within each program phase, and 123 initial codes identified from the exploration . Program attendance varied per participant over the 9-months and 75 sessions . Three participants  stopped attending for personal reasons after three, four, and six months of the program respectively, but the 14 others were involved in the 9-month project until the end. No adverse (undesirable) events were reported throughout the program. Eleven individuals (79%) participated in the 5k sport challenge, indicating the success with which the program was carried out as planned. Stemming from the six, semi-structured focus groups, three higher-order themes  there with big muscles, and a little voice inside you says that’s putting the bar high.” Similarly, in phase two, M3 explained how “it’s not written in our forehead that we have a TBI, you know. You can only see it because sometimes we have difficulties, or we get tired very fast – chronic fatigue.” Communication difficulties were mentioned again in phase three, so M1 emphasized that “when there is an important message, maybe you can translate it to me because most of them (participants) speak French, but I don’t.”The “I love the machines on the third floor, but it seems that the people there are just interested in their own thing, because they don’t talk, they’re … uh, concentrated.” Whereas M3 further explained that building connections (with other members) just required a little more time, “It will be three years that I’m on the third (floor), since the beginning of the program, and it took ages before I could engage in a conversation with those people.” No external barriers were identified in phase three.In phase one, external barriers included difficulties getting to the YMCA . P7, who lived in the suburbs, explained that “it’s getting here that’s complicated … As my mobility is more reduced than for the rest of you. It’s accessibility. Finding a parking place, then getting to the gym, for me is the greatest barrier.” Participants also experienced difficulties when the smaller gym area was overcrowded because they felt that space was limited. In contrast, the external barrier experienced by some participants in phase two related to fewer opportunities for social interaction. P12 shared, Program Facilitators sub-theme. In phase one, the participants discussed external facilitators related to receiving support and guidance from the mentors, as well as the YMCA staff and research team. P13 explained how, “the major success of phase one was the structure, like say putting a frame around a picture, which was provided by you and the whole team to facilitate things for us.”Throughout the 9-month program, participants discussed the external factors that affect program participation, in addition to the structure  and technology aids that make the program easier to follow and affect program experiences, as highlighted in the Participants appreciated the program aids in phase one, like having the training program written on a visible whiteboard. M4 remarked: “it just makes things easier and … well that’s it. And with all those little reminders about the major muscle groups, or the rules, things like that.” But in phase two, the external facilitators related more to the progression of the program and technology aids, which were both specific to the transition to the larger gym area and use of an online software to facilitate the use of digital programs on the participants' smart devices. M4 explained, “the visual aspect, and that it's well explained  …  each rhythm is explained, then each muscle it activates is shown … Then you can also see the training progress over time, which is also interesting.” P2 added that having access to a mobile training application “gave us more autonomy.” External facilitators were not identified in phase three.Program Motivation sub-theme. Participants' motivation in phase one was related to biopsychosocial outcomes, the structure the program provided in the week, being an example for others with TBI, and contributing to the research project. For instance, P13 explained the way he felt: “participating in the research is truly motivating … the altruistic part of me and that part that wants to help the brain injured also comes in when considering the possibility of developing a post-rehabilitation reference that may be recognized and publicized.” Motivation in phase two related again to the perceived biopsychosocial outcomes and structure in the week, but was extended by accountability and an increased interest in PA. For example, P4 discussed how: “everyone is more motivated in phase two. In phase one, you knew it was good for you, so you went. But ahhh … by phase two, people are happy to be there!”The sources of motivation for participating in the program varied considerably and in relation to the changing focus of the phases in the Participants also expressed how being around others from the group helped maintain their motivation to participate in PA. P10 shared, “if it’s me who is deciding on my own, it won’t work. I can’t get there. Someone must help me … push me to go forward. That encourages me .” P4 also shared, “Simply put, it’s the ripple effect. When we see people like us training, it pulls you into the wave.” In phase three, however, the motivation for participating in the program was more related to having a training routine, pushing personal limits, and the 5k sport challenge. P6 explained: “it motivates me more because it means the moment approaches when we leave the YMCA. The fact of going out to the mountain, with no machines. You run or you walk … you are with nature.” Similarly, M1 added: “I enjoy it because … it’s challenging. I never did that  before and then … you started to join with a group and meeting a lot of people.”Program Modifications sub-theme. A variety of recommendations for improving phase one of the program were provided, such as maintaining the program's structure while encouraging more freedom of discovery, including personal training goals and group activities, in addition to advertising the program externally, and clearly defining the mentors' roles and responsibilities. Confusion about the mentors' roles and responsibilities was discussed on several occasions, in addition to the mentors' desire for more responsibility. M4 explained, “I’d rather have a framework with precise objectives to respect, so I have a title and suitable role as a mentor.” On several occasions, mentors also expressed their desire to proudly represent the group through TBI-Health logos on their clothing, in addition to a desire to give back to the community. M2 shared, “it’s like we’ve become … we want people to become aware, for example, of the accident we’ve had, and everything to do with TBI.”Suggestions from participants about improving the program structure across the three phases of the program are grouped in the Further suggestions during the focus groups about improving program structure in phase two included maintaining the existing progression across phases, including progressions within phases, adding a nutritional component, scheduling group classes once a week, and adapting the walks outside the center by walking speed and ability. M3 shared, “I would love if it would be possible just to go up the mountain at your own speed, and to have a breakpoint … somewhere where we all meet together no matter what.” Suggestions about improving program structure in phase three included providing access to YMCA trainers and classes, in addition to maintaining the program's 9-month length and clearly defined phases. M3 offered his impression of why this approach works: “I feel that basically, the program is like a cooking recipe and basically if you carefully list how to add all the ingredients, well everyone will make a success of the recipe.”Biopsychosocial Changes theme reflected the perceived changes, by self and others, related to the physical, cognitive, psychological, and social outcomes from the program. The Physical Outcomes sub-theme in phase one reflected the participants' perceptions about their improved physical endurance and management of TBI impairments related to sleep, energy, and recovery as well as the perceptions of others. Some were not aware of these potential benefits. For instance, P2 explained: “I never thought … that physical activity would make me progress that well. I have so much more energy than before.” Perceptions about physical outcomes in phase two had more to do with strength and endurance, in addition to the management of TBI-related impairments with balance, mobility, and migraines. This was the first time that participants spoke about these kinds of changes, which they related specifically to the program. P8 shared, “the workout that you developed for us unblocked something in my back. So that now, I can walk straight. I no longer need a brace, no longer need a cane, so for me it’s just like, wow!” In phase three, perceptions about improvements in physical abilities were extended with cardio and endurance in addition to the management of TBI related impairments with balance, movement, mobility aids, and migraines. P5, who is partially hemiplegic explained “when I walk, I have more confidence in myself because I am more stable. I lose my balance less often … I like that better.” In addition, P3 no longer used a cane following the program, and P12 no longer required her orthotics (ankle brace).The Cognitive Outcomes sub-theme. M1, explained that in phase two “I’ve started memorizing, I feel like my brain is working now. Before, like every second … I always checked in the paper that you gave me what’s next … But now, I know what I need to do once I get inside, I know what I need to do.” Similar examples were shared in phase three by P6:In addition to physical outcomes, and beginning in the second phase, participants spoke about their perceived improvements with concentration and memory within the We're not less intelligent than other people. Personally, I tend to forget things. It doesn't make me less capable of understanding. But the fact of training upstairs, more than on the second floor, gives us more opportunities to use our memory and remember the exercises.M3 further emphasized, “the more important muscle is up there (the head). And that’s why we’re training. And that’s why we’re doing this study as well … I think the concentration and I think that the memory is working hard as well as we’re training.” Findings about cognitive outcomes, which surfaced in phases two and three, were not identified in phase one of the program.Psychological Outcomes sub-theme, participants expressed perceptions by self and others about positive changes to their mood states related to self-confidence, feelings of enjoyment, pride, and privilege, as well as feeling valued and validated as someone with a TBI in phase one. M3 shared his sentiments:Within the It makes me proud to take part as mentor in a research study about the subject that has been the most terrible experience of my life, the accident that nearly killed me … and to have saved myself and to have gotten where I am today and the people around me, my family, are so proud of that, and when I tell them about it, and how we participate, you know, we're here! I hold that close to my heart.These positive feelings were mirrored by the impressions of others too, as seen with P2’s personal example: “I started the program in April, and my daughter, two or three weeks ago said to me: mom, you’ve changed so much. You’re so much better, she says. You’re starting to be more … she thinks I’m slowly becoming as happy as I was before.”In phase two, the positive perceptions about the participants’ mood states were extended to feelings of capability, empowerment, motivation, physical improvements, and having a positive role in the program. Participants shared how they felt accomplished and empowered to carry out more daily activities, which would have otherwise been restricted by fatigue. They were energized and motivated about their perceived physical improvements and felt positive about helping others in the program. P4 said, “it brings me, well, a lot of pleasure, but it also brings me a satisfaction, like a feeling of duty accomplished.” Phase three included positive changes to mood states related to self-care, pride, and capability of completing the outdoor 5k sport challenge. P7 explained, “me personally, I felt surprised, I never thought I’d do so well …” The mentor M2 added, “as for the (sport) challenge, it was really awesome. Outdoing yourself … a great success, and why not do a bigger challenge (in the future)?”Social Outcomes sub-theme was identified the most frequently within the Biopsychosocial Changes theme. In the first phase of the program, participants discussed examples related to their program participation together, indicating an area that was relevant to their lives. They recalled experiencing positive social time with non-program participants, as well as with program-peers, in addition to feeling equal to other members at the YMCA. M3 explained, “People from the Y here, we’re quite different from them, as we’ve seen. They do not look down on us, nor do they look up to us. We’re equal with everyone, we have our place here … this is where I discovered it, in fact.” They also compared their tight-knit group to a family, due to the inclusive nature of the program. In phase one for instance, they discussed the self-improvements that resulted from their shared experiences together. M1, who was encouraged by her peers to become a mentor explained, “yes … I did improve a lot. Before like M2 said, I’m just always shy, hiding … I don’t talk to anyone that I don’t know, but now I’m starting to talk to someone (in reference to the young man she is in a relationship with).” In phase one, the mentors asked to join the participants in future focus groups. M4 explained, “I don’t feel my title makes me any better than the others. I’m … lucky enough to be a mentor because I’ve been here since the first cohort … but I don’t feel less or better than anyone else. I think we’re all on the same level.”The In the second phase, social outcomes remained similar. Participants continued speaking about how the strength of TBI-Health was related to the inclusive nature of the program for people with all ranges of abilities, in addition exchanging socially with members outside of the program. M2 shared his perception about, “establishing a contact with them (other YMCA members), many of us even made some good friends, chatting with people who don’t belong to our group, I’ve noticed …” Then, in phase three, the participants discussed how the program brought them together in solidarity. P2 explained, “We help each other a lot. Because, with TBI … you become, how can I say, a little less confident maybe … So being together makes you feel a little more solid.” By this final phase, participants were discussing increased confidence to expand their social circle through their program participation and the outdoor 5k sport challenge. P5 spoke about a member who started assisting her by running arm-in-arm on the YMCA track, “as for me … I found someone to help me out every session, and he’s almost always there … he’s a member of the YMCA but from another group … we’d like to do something outside of the gym, but it hasn’t happened yet. This way I have a friend though, that I can meet outside.”PA Autonomy theme highlighted the perceived transitions that occurred in knowledge, abilities, and sex- and gender-related beliefs relating to exercise and sport participation within and outside of the gym, which provided the participants with the confidence and independence to be more autonomous in their PA participation. Participants discussed the evolution in their sex- and gender-related beliefs and confidence about PA participation, as captured in the Sex and Gender sub-theme. For instance, in phase one, preconceived sex- and gender-related beliefs about preferences for type and intensity of PA were identified. Participants commented about their sex- or gender-based observations. M1, a female mentor, remarked that “I think some of the men are always working hard training, and women sometimes just do more social.” Others discussed sex- or gender-based observations about exercise preferences. P12 added, “it seems normal to me that guys prefer certain exercises, but not women. Even in (fitness) classes, it’s like that.”The Interestingly, in phase two, participants began challenging their own preconceived sex- and gender-related beliefs through a newfound appreciation for different PA modalities, incentives, and preferences. M3 asserted, “there’s no gender! [Everyone laughing]. Gender wise! I mean, there’s like something here that brings the group together. And my preference is to come here to the YMCA to see you guys.” However, M1, the mentor, still felt that “they  just like to always say like they don’t want to do something because they’re busy talking. They’re not even exercising.” And while P12 first remarked that “I was always under the impression that guys were more about strength training, and girls it’s more cardio.” she further added, “finally discovered that I loved weight training. It’s fun! I neglected that … but no, it sure helps because I no longer need orthotics.”By phase three, the participants did not speak about as many differences and continued to challenge what they perceived to be others’ preconceived sex- and gender-related beliefs about personal exercise preferences in the gym. Apparently, the groups’ sex- and gender-related beliefs had changed. For instance, P11 concluded that “if you look carefully at the clientele up there, you’ll see that there are many women, and women who train. Some are even body building. It’s crazy … you’ll see all sorts” P12 shared a personal example,Exercises like barbell lifting, all those exercises I had, there were just guys doing them. And the guys, it seemed, were staring at me … (imagining them saying) “What do you think you’re doing? You shouldn’t be here.” - I'm doing my workout, that's all. So basically, you could say there is a zone for women and a zone for men (in the gym), but for me, I like to be able to do all the exercises …P3 further added, “girls … guys, it’s all the same,” thereby demonstrating, once again, how their previous impressions about the sex- and gender-related beliefs about exercise had changed.PA Autonomy theme, participants also discussed their capability as a gym-goer and knowledge of PA benefits after a TBI that supported independent PA, as highlighted in the PA Capability sub-theme. P8 shared how following and remembering a PA program, “it makes you realize you can do it.” Then P13 added, “for sure, differently, but nevertheless, you can do it.” Participants felt that others should be informed about the PA benefits after TBI too. P12 explained, “when you’ve been in the hospital for a few months because you’re not able to function, they (doctors) should be the ones to tell us: you should be moving. It will help you with your concentration, it will help you.” Then, in phase two, participants noted how the self-discipline of coming to the gym twice a week, as well as their increased PA knowledge, confidence, autonomy, and freedom contributed to their overall ability to participate in PA. P2 explained, “I think we all realized that we were able to do our activities on our own, well it gives you, it gives confidence.” Participants also discussed how their newfound confidence made them curious to try out new forms of PA, in different places, like the larger gym on the third floor or the walking trail. For example, P6 shared: “in phase two, I find there is greater freedom, you train all by yourself, you look for the machines you’re more …” P11 added “at ease with,” and P6 continued: “more successful with.”Within the PA Capability sub-theme. Notably, they discussed how they began enjoying the run/walk activities in preparation for the 5k sport challenge. M3 shared, “It’s a good idea to integrate that (outdoor outings) in the program … I think it’s super important to get fresh air outside … makes your worries go away, as they say.” The participants also discussed how their increased autonomy and freedom allowed them to experience more pleasure from doing PA. P12 explained, “now we’re a lot more familiar with the YMCA and we all know that we’re good at doing what we’ve learnt to do. So, it’s just more exciting, and we’re just able to go and have fun.” There was even an interest to start something of their own, “I was asking myself if it is possible, next year for example, to have a group within our group, like in a special team, like basketball for example, and they play against another group that has difficulties too” (M2). Based on their examples, it was evident participants wanted to continue their PA participation in and outside the program.In phase three, participants began identifying the increased capability and freedom associated with their independent exercise, in addition to an appreciation for outdoor PA, and a desire to explore new PA avenues (such as creating a sports team), as captured in the Suggested modifications from the focus groups were incorporated in the final version of the program. For instance, the existing program schedule, reminders, and supports  were maintained. However, newly integrated items in the program manual included providing French and English versions, clearly outlining the objectives and step-by-step progressions within each program phase, as well as defining the mentors’ and participants’ roles and responsibilities with a code of conduct. To further promote participation, the mentors began visiting group classes provided at the YMCA  with participants outside program hours, and the run/walk outings in preparation for the sport challenge were divided into walking speed groups depending on the participants’ abilities. To advertise the program externally, TBI-Health was showcased at provincial and national conferences, with support from the mentors as spokespersons.The purpose of this interpretive case study was to provide an in-depth account of the experiences and outcomes of the participation in and co-creation of a new community-based TBI-Health program to enhance sport and exercise participation for adults with moderate-to-severe TBI. The results identified themes, which will help enhance the program, and can inform future research and practice that promotes participation after moderate-to-severe TBI.The program participants discussed feeling anxious about participating correctly in PA, by comparing themselves physically to other members in the gym-based environment and commenting about invisible difficulties with fatigue after TBI. This finding is relevant because participation and long-term recovery after TBI may be influenced by social comparisons with peers, caregivers, and others after injury. For example, comparing oneself to an individual who is functioning well (upward comparison) can be positive if it is inspiring, but it can also be negative if the situation highlights one's deficits . The latPonsford and colleagues  suggest Study participants emphasized the types of external facilitators that enabled their program participation, such as the structured framework in place that afforded support and guidance from the program peer mentors, YMCA staff, and research team. In this way, having structure and routines to follow facilitated their involvement in PA. An appreciation for structure may be linked to the types of sequelae with which people with TBI live, including difficulties with social cognition and dysexecutive behavior, which are both shown to be significant predictors of vocational and social participation after moderate-to-severe TBI .Program aids, like clear instructions and visual reminders were emphasized by participants to facilitate their involvement and execution of program exercises. Having access to technology aids resonated with participants as an extra tool to help them understand how to carry out exercises and what muscles were being used in the process. These findings are important for PA participation after moderate-to-severe TBI in the long-term/chronic period because frequently reported problems include memory difficulties, and problems related to cognitive aspects of executive functioning . Thus, iMotivation after TBI is a multi-dimensional problem because studies have consistently shown that injuries to the brain commonly lead to apathy, or a decrease in the cognitive and psychological processes involved with goal-directed activity . HoweverInterestingly, our participants' motivation to participate in the adapted PA program evolved over the course of the intervention, as revealed by the similarities and differences across the three time points. The support and accountability afforded by the group-based activities stood out, because participants discussed overcoming motivational difficulties thanks to the positive influence of training with peers. This suggests that motivational problems rooted in psychological mechanisms may be attenuated through peer-assisted activities. Similar outcomes about the ways in which community-based peer-support programs can have a positive impact on recovery after TBI through acceptance and encouragement have been identified . Our finIn the community-based context, tailoring a PA-based health promotion program for adults with moderate-to-severe TBI through stakeholder input is relevant to its overall success . Based oOur participants discussed perceived improvements with their cognitive functions beginning in the second phase of the program, with examples about how training programs engaged their concentration and memory. Studies that investigate the potential impact of cardiovascular exercise on memory consistently show promise , althougBased on the findings about the perceived social outcomes, it was apparent that participants felt comfortable in their social environment. This is important because community-based programs have been proposed as the logical transition from the rehabilitation continuum for people living with disabilities  and few The transitions in sex- and gender-related beliefs about PA participation are noteworthy because sex- and gender-based stereotypes may present barriers to recommended amounts of PA  guidelines, the reflexive thematic analysis undertaken here fully embraces the subjective skills researchers bring to the interpretive process. The open coding and inductive theme development did not seek to ensure the accuracy and reliability of the process through coder agreement, but rather through a reflexive, critical, and iterative process informed by the team of authors. Therefore, codes and themes may be different for other analysts.This study identified three themes across the participatory co-creation experience of a 9-month 3-phased adapted PA program for adults with moderate-to-severe TBI, which highlighted the participants' Program Participation, Biopsychosocial Changes, and PA Autonomy. Findings from this study were integral to the design and implementation of the new and enhanced TBI-Health program and provide evidence-based recommendations for promoting continued PA participation after neurotrauma. We hope that future research and practice related to the design and implementation of community-based PA interventions will undertake similar methodological approaches to partnering with key stakeholders, based on the associated benefits with mood, quality of life and participation that may be obtained throughout the collaborative process.


Although a number of mood-stabilising atypical antipsychotics and antidepressants modulate serotonin type 7 receptor (5-HT7), the detailed contributions of 5-HT7 function to clinical efficacy and pathophysiology have not been fully understood. The mood-stabilising antipsychotic agent, lurasidone, and the serotonin partial agonist reuptake inhibitor, vortioxetine, exhibit higher binding affinity to 5-HT7 than other conventional antipsychotics and antidepressants. To date, the initially expected rapid onset of antidepressant effects—in comparison with conventional antidepressants or mood-stabilising antipsychotics—due to 5-HT7 inhibition has not been observed with lurasidone and vortioxetine; however, several clinical studies suggest that 5-HT7 inhibition likely contributes to quality of life of patients with schizophrenia and mood disorders via the improvement of cognition. Furthermore, recent preclinical studies reported that 5-HT7 inhibition might mitigate antipsychotic-induced weight gain and metabolic complication by blocking other monoamine receptors. Further preclinical studies for the development of 5-HT7 modulation against neurodevelopmental disorders and neurodegenerative diseases have been ongoing. To date, various findings from various preclinical studies indicate the possibility that 5-HT7 modifications can provide two independent strategies. The first is that 5-HT7 inhibition ameliorates the dysfunction of inter-neuronal transmission in mature networks. The other is that activation of 5-HT7 can improve transmission dysfunction due to microstructure abnormality in the neurotransmission network—which could be unaffected by conventional therapeutic agents—via modulating intracellular signalling during the neurodevelopmental stage or via loss of neural networks with aging. This review attempts to describe the current and novel clinical applications of 5-HT7 modulation based on preclinical findings. Serotonin 5-HT) receptor type 7 (5-HT7) is one of the most recently 1993) identified members of the 5-HT receptor family 993 ident,3,4,5. I-HT recepA number of preclinical studies have reported that 5-HT7 plays important roles in the regulation of mood, memory processing, cognition and emotional perception by following various experiments using selective 5-HT7 modulators and 5-HT7 knockout mice models ,24,25,26Recent pharmacodynamic studies demonstrated that 5-HT7 modulation possibly contributes to a part of the characteristics of the clinical effects of both lurasidone and vortioxetine via inter-neuronal transmission ,41,42,43The earliest identified physiological function of 5-HT7 was regulation of circadian rhythms . In thisThe 5-HT7 knockout mice displayed a reduction of immobility times in both a forced swim test and a tail suspension test, common pharmacological behaviour tests for the screening of antidepressants (decreasing immobility time is considered to correlate to antidepressant action in humans) ,55. BaseThe potential function of 5-HT7 on anxiety demonstrated the inconsistent results between pharmacological and molecular biological studies, similar to the case of depression. Expression of 5-HT7 mRNA increased by acute restraint stress but not by chronic variable stress in the rat hippocampus, indicating that 5-HT7 contributes to the regulation of response to stress ; howeverA number of pharmacological studies reported the therapeutic potential in components of positive and negative symptoms and cognitive dysfunction of schizophrenia using chemical-induced schizophrenia models. Compared with wild-type mice, 5-HT7 knockout mice were less susceptible to prepulse inhibition deficits of phencyclidine . SB-2699On the other hand, the effects of 5-HT7 inhibition on neurocognitive dysfunction (procognitive effects) demonstrated its promise. SB269970 attenuates amnesia in short-term memory induced by ketamine and MK801 ,73, and Vortioxetine is an antidepressant belonging to the family of monoamine transporter-inhibiting antidepressants; its antidepressant effect is thought to arise from not only its monoamine transporter inhibition but also 5-HT7 inhibition. The binding affinity of vortioxetine to 5-HT7 is relatively low compared to serotonin transporter, 5-HT1A and 5-HT3 , but theThe delay of the onset of the antidepressive effects of conventional monoaminergic antidepressant medication has been established as one of the major drawbacks of current treatments for depressive disorder, since all conventional monoamine transporter-inhibiting antidepressants require more than several weeks for the onset of beneficial antidepressive effects ,77. BaseIt has been recognized that comorbidity with anxiety (disorder) is the most significant factor affecting poor prognostic outcomes, such as increasing risk of recurrence, chronic course and suicidal behaviour ,85. SeveIn three placebo-controlled studies in adults with recurrent major depressive disorder, vortioxetine displayed clinically meaningful improvements in performance on two objective measures  that together cover a broad range of cognitive domains, including executive function, attention, processing speed, learning and memory ,93,94. IIn particular, enhancement of cognition with vortioxetine, in both subjective and objective functioning measures, was more pronounced in working patients, particularly in those whose job placed higher demands on executive functioning . Indeed,A mood-stabilising antipsychotic agent, lurasidone possesses the highest binding affinity to 5-HT7 among antipsychotics  Table 1Table 1. Several randomised control studies demonstrated that lurasidone improved comorbid anxiety symptom in schizophrenia, bipolar I and major depressive disorders. Lurasidone monotherapy (20~60 mg/day) improved depressive mood and concomitant anxiety in patients with bipolar I disorder . LurasidConsidering the clinical findings regarding vortioxetine, both lurasidone and vortioxetine, at the minimum, might be classified in a distinct category of treatments that can be promised to improve cognitive function compared to conventional mood-stabilising antipsychotics and antidepressants. In contrast, the anxiolytic effects of lurasidone and vortioxetine displayed discrepancy, since vortioxetine has been evaluated to possess one of the lowest anxiolytic effects among monoamine transporter-inhibiting antidepressants , whereas2+/calmodulin-dependent and Gs-independent signalling [Four splice variants of 5-HT7 were identified. These were distinct in their carboxyl terminals due to introns in the 5-HT7 gene, including 5-HT7a, 5-HT7b and 5-HT7c in rodents, and 5-HT7a, 5-HT7b and 5-HT7d in humans ,116,117.gnalling .Activation of 5-HT7 enhances synthesis of cyclic adenosine monophosphate (cAMP) via activation of adenylyl cyclase . IncreasTwo other types of signalling associated with 5-HT7 were also identified: Gα12  and metaIt has been established that the serotonergic system plays crucial roles in the organisation of the neural system, such as generation of neurogenesis, cell migration, axon guidance, dendritogenesis, synaptogenesis and brain wiring during the development of the mature brain . During Behavioural study demonstrated that 5-HT7 knockout mice displayed impairments of contextual learning, seeking behaviour and allocentric spatial memory . ElectroActivation of 5-HT7 during adolescence induced persistent upregulation of 5-HT7 . ChronicAlthough activation of hippocampal 5-HT7 contributes to the formation of learning and memory, suppression of 5-HT7, conversely, improved other cognitive components, such as executive function, which play important roles in quality of life. Traditionally, enhanced mesocortical dopaminergic transmission or dopamine release in the frontal cortex induced by blockade of D2 in the ventral tegmental area are considered to be key players in the improvement of positive and negative symptoms of schizophrenia . AdditioTonic hyperactivation of thalamocortical glutamatergic transmission was observed in schizophrenia, ADHD and autism ,164,165.Fragile X syndrome, which is caused by mutation of Fragile X mental retardation 1 (FMR1) gene, is a common neurodevelopmental disorder characterized by intellectual disability with autism . FragileActivation of 5-HT7 was a potential candidate target for relieving symptoms in patients with Rett syndrome. Rett syndrome is the second most common cause of mental retardation in females and plays a role in severe neurodevelopmental disorders such as breathing dysfunction, loss of coordination, abnormal eye and hand movements, epilepsy, aberrant sleeping behaviour and cognitive impairment . The priAssociation between 5-HT receptor gene polymorphism and autism spectrum disorder could not be detected by a transmission disequilibrium study , whereasNon-selectively activation of 5-HT receptors using 5-HT transporter inhibitors has shown little clinical benefit in neurodegenerative disorders ,191; howVarious studies have reported on antiseizure activities—using audiogenic seizures in DBA/2J mice, or the absence of seizures in WAG/Rij rats—following the administration of selective and non-selective antagonists ,199. TheThere are some findings indicating that 5-HT7 modulation may be therapeutic targets for the treatment of cancer. Notably, it has been anticipated that 5-HT7 antagonists would be useful for the treatment of hepatocellular cancer and small-intestinal neuroendocrine neoplasms, since 5-HT7 contributes to hepatocyte proliferation ,19,20. SThe mortality gap between patients with schizophrenia and the general population has been growing . Indeed,The detailed mechanisms of the suppression of AMPK signalling induced by 5-HT7 inhibition remained to be clarified, but decreased EPAC signalling is predicted to be one of the key players. Considering the binding profile of clozapine, which also posssesses relatively high affinity to 5-HT7, 5-HT7 inhibition cannot fully suppress the weight gain induced by H1 inhibition, but, at the minimum, it may suppress the activation of AMPK activity induced by 5-HT2A inhibition.The present review introduced the neuropharmacological findings of 5-HT7 modulation demonstrated by preclinical and clinical studies. The expected clinical effects of 5-HT7 inhibition on schizophrenia, mood and anxiety disorders by preclinical studies probably have not been able to contribute to the improvement of the core symptoms of these disorders; however, 5-HT7 inhibition possibly improves cognitive impairments in patients with schizophrenia and mood disorders compared to predictions from preclinical studies. Furthermore, it is suggested that 5-HT7 inhibition seems to have a mitigating effect on antipsychotic-induced weight gain and metabolic complication. Preclinical studies for the clinical application of 5-HT7 agonists for neurodevelopmental disorders and neurodegenerative diseases are currently underway. Until recently, several findings of these preclinical studies suggest that 5-HT7 modifications can serve two independent targets. The first is that 5-HT7 inhibition ameliorates the dysfunction of inter-neuronal transmission in mature networks. The other is that activation of 5-HT7 can improve transmission dysfunction due to microstructure abnormality in the neurotransmission network, which could not be affected by conventional therapeutic agents, via modulating intracellular signalling during the neurodevelopmental stage or through the loss of neural networks with aging. Therefore, the 5-HT7-modulating medications may be able to acquire a more practical treatment option via selectively using enhancement and suppression in an age- or pathological condition-dependent manner, rather than a binary choice.


N = 116), (2) English-speaking male veterans (N = 95), (3) English-speaking male and female adolescents (N = 155), and (4) Spanish-speaking male and female adults (N = 285). The QUIC-5 demonstrated substantial variance in distributions in each of the cohorts and is correlated on average 0.84 (r’s = 0.81–0.87) with the full 38-item version. Furthermore, the QUIC-5 predicted internalizing symptoms (anxiety and depression) in all cohorts with similar effect sizes  to the full versions . In sum, the QUIC-5 exhibits good psychometric properties and is a valid alternative to the full QUIC. These findings support the future use of the QUIC-5 in clinical and research settings as a concise way to measure unpredictability, identify risk of psychopathology, and intervene accordingly.Unpredictability is increasingly recognized as a primary dimension of early life adversity affecting lifespan mental health trajectories; screening for these experiences is therefore vital. The Questionnaire of Unpredictability in Childhood (QUIC) is a 38-item tool that measures unpredictability in childhood in social, emotional and physical domains. The available evidence indicates that exposure to unpredictable experiences measured with the QUIC predicts internalizing symptoms including depression and anxiety. The purpose of the present study was to validate English and Spanish brief versions (QUIC-5) suitable for administration in time-limited settings . Five representative items were identified from the QUIC and their psychometric properties examined. The predictive validity of the QUIC-5 was then compared to the QUIC by examining mental health in four cohorts: (1) English-speaking adult women assessed at 6-months postpartum ( There is little dispute that early life experience imparts a lasting imprint on trajectories of health and development across the lifespan. A rapidly accumulating body of evidence has shown poverty, neglect and abuse as well as other adverse experiences in childhood influence morbidity and mortality, including increased risk for psychopathology . UnfortuAlthough childhood adversity has been widely studied, much of this work has focused on a canonical set of adverse childhood experiences or ACEs  and emplThere are studies that have characterized unpredictability in a number of ways including parental behaviors , 2019, pGrowing evidence also demonstrates the predictive validity of the QUIC as a tool to measure the associations between unpredictability and mental health risk. In our initial validation paper, the QUIC predicted anxiety and depression in three independent cohorts: adult females, male veterans and male and female adolescents . ImportaWhile the QUIC is emerging as a comprehensive and valid tool to measure unpredictability in early life, a measure of this length may not be feasible in time-limited research and clinical contexts. Therefore, this study aimed to validate a brief version of the QUIC and QUIC-SP for use in these settings (QUIC-5 and QUIC-SP-5). We did this by examining the psychometric properties of these measures in four independent cohorts.The Questionnaire of Unpredictability in Childhood, which is validated in English QUIC;  and SpanThe utility and predictive validity of the QUIC-5 was assessed in four independent cohorts: (1) adult females, (2) male military veterans, (3) adolescents, and (4) Spanish-speaking adults. See Cohort 1 consisted of 116 adult females (age: 18–44 years) participating in an ongoing longitudinal study on maternal and child health. These participants completed the QUIC and the 10-item Edinburgh Postnatal Depression Scale (EPDS), which is a widely used and validated measure of depressive symptoms . The EPDCohort 2 consisted of 95 male veterans (age: 24–70 years) participating in either a follow-up assessment from a prospective, longitudinal study of deployment trauma or the Center of Excellence for Stress and Mental Health TBI/PTSD biorepository data archives. Participants completed the QUIC and Patient Health Questionnaire-9 (PHQ-9), which is a well validated 9-item questionnaire assessing severity of depressive symptoms .Cohort 3 comprised 226 adolescents  participating in a longitudinal study of maternal and child health. Adolescent participants completed the QUIC, the 12-item Children’s Depression Inventory CDI; , and theCohort 4 consisted of 285 Spanish-speaking adults  recruited for an online validation study of the QUIC-SP. In addition to the QUIC-SP, these participants completed the Beck Depression Inventory BDI; , which iThe distribution of QUIC-5 scores were first compared to examine variability in scores among the four cohorts. Next, Pearson correlations were used to determine the strength of the associations between the full and brief versions within each cohort. Last, the predictive validity of the QUIC-5 was compared to that of the full QUIC by examining bivariate correlations between the two versions of the QUIC and measures of anxiety and depressive symptoms.The distributions, means, medians, and standard deviations of QUIC-5 scores for each cohort are shown in r’s > 0.81; all p’s < 0.001). Among the adult females, the QUIC-5 was correlated 0.82  with the QUIC, 0.85  among male veterans, and 0.81  among adolescents. Among Cohort 4 (Spanish-speaking adults), the QUIC-SP-5 and QUIC-SP were correlated 0.87 .For each cohort, QUIC-5 scores were strongly correlated with full-length QUIC scores . Critically, the effect sizes were not substantively different from the association between the full-length QUIC and these same mental health indicators  in each of the four cohorts (Here we show that both the English and Spanish language versions of the QUIC-5 demonstrate excellent promise as brief assessments of unpredictability in childhood. These 5-item versions are associated on average 0.84 with the full-length version across four independent cohorts that span sex/gender, socioeconomic, and cultural groups and range in age from adolescence through 70 years. This high correlation is especially promising given that the full version was validated against prospective assessments of early life unpredictability and exhibits strong content and discriminant validity . PerhapsProgress has been made in documenting the role of adversity in shaping health and development. However, a significant barrier that remains is the relative lack of neurobiological models testing biologically plausible mechanistic processes linking early life adversity to developmental and mental health outcomes  – a gap Given that unpredictability is emerging as a core dimension in multiple conceptual models of childhood adversity , the breResearch thus far indicates that the effect sizes for the associations between unpredictability with mental health outcomes are similar to those of previously established adverse childhood experiences such as poverty and abuse , underscThe data presented in the study are available upon request to the corresponding author.The studies involving human participants were reviewed and approved by University of California, Irvine IRB; San Diego, VA IRB. Written informed consent to participate in this study was provided by all adult study participants. Written informed consent for minors to participate in this study was provided by the participants’ legal guardian/next of kin. Additionally, children provided assent to participate in this study.LG, TB, and HS developed the QUIC-5. LG and NL conducted the statistical analyses. LG, NL, MM, and SL drafted the manuscript. LG, EP, TB, HS, VR, DB, and CN participated in study conception and design and contributed funding. All authors provided editorial feedback and approved the submitted version.