Background and objectives: More and more children with severe-to-profound hearing loss are receiving cochlear implants (CIs) at an early age to improve their hearing and listening abilities, speech recognition, speech intelligibility, and other aspects of spoken language development. Despite this, the rehabilitation outcomes can be very heterogeneous in this population, not only because of issues related to surgery and fitting or the specific characteristics of the child with his/her additional disabilities but also because of huge differences in the quality of the support and rehabilitation offered by the therapist and the family. These quality standards for the rehabilitation of young deaf children receiving CIs are developed within the European KA202 Erasmus+ project “VOICE”—vocational education and training for speech and language therapists and parents for the rehabilitation of children with CIs, Ref. No.: 2020-1-RO01-KA202-080059. Material and methods: To develop these quality standards, we used the input from the face-to-face interviews of 11 local rehabilitation experts in CIs from the four partner countries of the project and the outcomes of the bibliographic analysis of 848 publications retrieved from six databases: Pub Med, Psych Info, CINAHL, Scopus, Eric, and Cochrane. Based on all this information, we created a first set of 32 quality standards over four domains: general, fitting, rehabilitation, and for professionals. Further on, the Delphi method was used by 18 international rehabilitation experts to discuss and agree on these standards. Results: The results from the literature analysis and the interviews show us that more than 90% of the consulted international experts agreed on 29 quality standards. They focus on different aspects of rehabilitation: the multidisciplinary team, their expertise and knowledge, important rehabilitation topics to focus on, and programming issues related to rehabilitation. Conclusions: These quality standards aim to optimize the activity of speech rehabilitation specialists so that they reach the optimal level of expertise. Also presented is the necessary equipment for the IC team to carry out the rehabilitation sessions in good conditions. This set of quality standards can be useful to ensure the appropriate postoperative care of these children. As a result, the rehabilitation process will be more relaxed, and therapists will have the opportunity to focus more on the specific needs of each child, with the provision of quality services, which will result in better results. This theme is particularly complex and dependent on multifactorial aspects of medicine, education, speech therapy, social work, and psychology that are very intricate and interdependent. The introduction of universal neonatal hearing screening made an earlier diagnosis of hearing loss in children possible. The benefits of early identification and intervention ,3,4,5,6 Nowadays, more and more deaf children are receiving CIs, which results in a positive impact on their auditory perception ,9 and laFurthermore, the WHO reports in the World Hearing Report  that timThe importance of the content of the rehabilitation program and family support was also confirmed by Percy-Smith and colleagues , who fouThere are many studies on the benefits of CIs and the factors that influence the rehabilitation of these children. The factor recognized as the most important to obtain significant results is early implantation ,21. HoweDue to the huge differences in the service delivery models and intervention between countries, and even within the same country, between CI teams , we haveThe main objective of our project is to train speech and language pathologists (SLPs) and parents to teach children with CIs to understand speech and to speak. In the scope of this project, we also identified quality standards for good practice to help service providers maintain and improve their standards and quality service provision for young deaf children receiving CIs.Rehabilitation, according to the WHO , represeTo develop the quality standards, the authors started by interviewing 12 local experts in rehabilitation of young CI children. Each of the 6 partners interviewed, in person or online, 2 local experts in the field of rehabilitation, resulting in 12 experts from 4 countries . For personal reasons, we could not make the interview with one expert from the Netherlands, so the final total number of experts was 11 . The met-What is your experience in rehabilitation of young deaf children with CI’s learning to speak and to develop spoken language?-Who  should be involved in the rehabilitation process after CI in young deaf children?-What should be the role for the CI-team and what should we expect from local professionals? So, who is doing what?-What are important domains to focus on during the rehabilitation of young CI-children?-Should we involve the parents in the rehabilitation process? If so, Why + How + How often?-Do you prefer a specific rehabilitation program or approach for therapy? Which resources  do you suggest for other therapists to become an expert too?-Do we have to monitor the listening, speech and spoken language development of these young CI-children? If so. Why and how often?-What frequency of therapy sessions do you suggest for these young CI-children and their families? How often? For how many minutes? For how many months/years?To have a standardized interview across the partners, we created 8 open questions to focus on during the interview :-What ishttps://voice-erasmus.eu (accessed on 12 January 2023)The content of all these interviews was analyzed and structured following the 8 open questions above. We focused especially on common answers between the local experts. All this was summarized in a report, which is available from the project website The topic itself is emergent because of the recent technological history, with few professionals involved and with procedures that are not consolidated yet.To have input from latest scientific research, we performed a review of literature on rehabilitation of young children receiving CIs. The present methodological framework is based on the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines to ensure replicability and transparency . All studies at all levels of evidence were included: best practice, case studies, prospective and retrospective studies, cross-sectional and longitudinal studies, and (non)randomized control studies (RCSs). The articles had to be published in peer-reviewed journals or books in the English language between 2000 and 31 May 2021. The articles had to focus on CI children under age of 6 with bilateral hearing loss.The literature search was conducted between 31 May 2021 and 31 August 2021 using a 4-word search (cochlear implant + children + rehabilitation + education) through the following 6 databases: PubMed, Eric, Cochrane, CINAHL, Scopus, and Psych Info.Three authors  performed independent systematic title and abstract screening based on the predefined inclusion criteria. A.M. and T.M. first performed the same literature search using PubMed. Their outcomes were compared to each other (inter-reliability) and checked independently by the main author (L.D.R.). As the inter-reliability score was very high (>90%), A.M. further performed the search on Cochrane and Scopus, and T.M., together with L.D.R., performed the literature search using Eric, CINAHL, and Psych Info. Separate from the search through the 6 databases, PubMed (339), Psych info (203), CINAHL (189), Scopus (95), Eric (14), and Cochrane (8), there was also the possibility to add additional records identified through other sources (39). In total, we retrieved 848 publications.A bibliographic analysis was performed after more than 150 papers were evaluated from the point of view of the level of evidence, as defined by Lebwohl and colleagues , i.e., iThe level of evidence from all full-text articles was scored by 5 coauthors . All scores were extra-checked by the main author L.D.R., and in case of a different score , they had a short discussion to come to a final score.The development of the quality standards involved a modified Delphi consensus process that was informed by outcome of the interviews of the local experts and the extensive analysis of the literature. Based on all this information, we created a list of 32 quality standards over 4 domains related to rehabilitation: (1) general, (2) fitting, (3) rehabilitation per se, and (4) standards for professionals.An international group of world-renowned clinical experts in the field of rehabilitation of young children with CIs and with significant experience joined a Delphi consensus panel. All 6 partners suggested 3 international experts on which they have based the rehabilitation in their center. The aim was to develop a series of quality standards for rehabilitation of children using CIs.The Delphi method was modified to include 2 rounds of email questionnaires. In the first round, we asked the 18 international experts  in the fThe proposed standards on rehabilitation of deaf children receiving CIs offer optimal level of expertise necessary for staff working in field of speech therapy and present the facilities CI teams should have. They cover different aspects of rehabilitation, such as multidisciplinary, the necessary knowledge, the domains to focus on, CI programming, and so on.The group of local experts consisted of 10 speech and language pathologists and 1 otolaryngologist, with an average experience of 13 years in the field of pediatric cochlear implantation. All mentioned that the CI team should be a multidisciplinary team, which consists of an otolaryngologist, audiologist, and speech and language pathologist as a minimum. Preferably, also a psychologist, social worker, teacher of the deaf, and a physical or occupational therapist should be included in the team. Parents should be seen as equal partners too, and nearly all the experts (8/11) suggested to use a family-centered approach.The local experts also suggested that the CI team should be the coordinator of the rehabilitation/aftercare and that there should be good liaison with the local support team. The most important domains to focus on during the rehabilitation process are audition/hearing/wearing devices; communication/speech/spoken language (11/11); parent (care) support/coaching (8/11); cognitive development (7/11); social–emotional development (6/11); reading/school performance (4/11); motor skills/planning (4/11); and self-advocacy/identity (3/11).Auditory verbal therapy (AVT) was mentioned by 7 out of 11 experts as the approach which fits best most children and their families, but on the other hand, the same experts stated there is not one approach that fits all.Most local experts (9/11) also mentioned that during the rehabilitation process, all steps in the development of the child should be monitored regularly, especially hearing and speech and language development. Concerning the frequency of therapy, there was huge variability between the experts, but ideally, most of the experts (6/11) suggested one session of 1 h on a weekly basis. But it was also mentioned that the frequency of rehabilitation will depend on the child, the family, the distance , and the availability of support services.In total, 848 individual publications were identified , but aftFinally, we could include 150 publications in the qualitative synthesis, and for this purpose, we only kept the 66 publications with an A or B level of evidence and excluded those that scored C, D, or E. Of these 66 publications, only 2 publications ,30 receiWithin the field of the rehabilitation of children with CIs, it is exceptional to find research based on double-blind studies. A good level of evidence is mostly shown by publications on prospective clinical trials on more than 20 subjects, lacking adequate peer group controls or another key facet of the design.There is still no consensus on the most appropriate methodology for approaching the rehabilitation of children with CIs ,32. A reBased on the comments of the international experts during the first round, especially focusing on the overlap between some quality standards, we updated the quality standards and came to a new list of 29 quality standards. During the second round, we asked the same international experts to agree or not agree on the proposed standards. Finally, more than 90% of the international experts agreed on 29 quality standards over four domains: (1) general standards, (2) fitting, (3) rehabilitation, and (4) quality standards for staff, of which most of them contain several subcategories.These standards for the rehabilitation of children with CIs can help health systems and, more specifically, CI teams and all those involved in the rehabilitation of children with CIs, to provide quality and State-of-the-Art care. We are absolutely convinced that by using these standards, they will improve the quality of their service delivery, and the result will be rehabilitation with better results.▪-Ideally there should also be a psychologist and social worker included in the team.-The multidisciplinary team should work inter professionally (not next to each other but together) and in close cooperation with the parents/carers.-The multidisciplinary team will liaise and work with the child’s local support team.Providing a Child with a Cochlear Implant Requires a Dedicated Multi-Disciplinary Team Consisting at Minimum of an Otolaryngologist, Audiologist and a SLT Specialist▪The CI-Team of the Hospital Should Coordinate the Selection, Surgery, Fitting, Rehabilitation and after Care ▪-Ideally in their language.-Parents/educators/professionals should get appropriate counselling from the CI team and other professionals to have appropriate expectations from the cochlear implant, depending on several variables such as age at implantation or additional disabilities.-Parents/educators/professionals should have the opportunity to meet other families with CI children.-Parents/educators/professionals also need psychological support: taking care of their emotions and stress.Parents/Educators/Professionals Need Balanced and Unbiased Up-to-Date Information about CI’s and the Fitting/Rehabilitation Process▪Rehabilitation should Be Delivered by the CI-Team in Close Cooperation with A Local Expert (Team) in Listening and Spoken Language Development. ▪-In case of parents or legal guardians are not able to be actively engaged in the child’s rehabilitation due to very low Social Economical Status, mental health matters, or cognitive delays, other family members or carers should be involved.-Professionals should use a child/family cantered approach.Rehabilitation Is Not Possible without Parent/Family/Caregiver Involvement▪The Cochlear Implant Surgery Should Take Place as Soon as a Child Is Identified as a Candidate and Should Ideally Be Done by the Age of 12 Months or Sooner, Preferably under the Age of 36 Months, without Excluding Those Older Than 37 Months▪-We expect all countries to follow the principles and guidelines of the Joint Committee on Infant Hearing to have early hearing screening (before age 1 month), diagnosis (before 3 months) and start with rehabilitation (fitting hearing aids and early intervention) before 6 months of age.A Child with Bilateral Deafness Should Be Fitted Bilaterally with CI’s, Preferably before the Age of 18 Months▪-There should be a written policy regarding who is responsible in the event of loss/damage and what spares can be provided as a matter of routine.The CI-Team will Issue or Dispatch Replacements for Faulty External Equipment within Two Working Days▪Each Child’s Sound Processor Must Be up Graded Every 5 Years▪-The audits should become freely available to interested parties.The National CI Program should Conduct and Publish Annual Audits and Comply with the Requirements of the Responsible National Authorities. Audits should Cover All Aspects Related to CI: Clinical Activity, Staff Expertise, Child Outcomes, Surgical Complications, Device Failures, and Child and Family/Caregiver Feedback on the Service Provided▪The Fitting of the Sound Processor should Be Carried out by Qualified Paediatric Audiologist Preferably in Clinic, Face-to-Face Rather Than Remotely▪-It is recommended that local professionals receives writen reports on the child’s auditory function-It is recommended that local professionals received written reports on the child’s auditory performance.There should Be a Liaison between the Audiologist of the CI-Team and the Local Rehabilitation Expert/Local Support Team (and Vice Versa) to Exchange Information about the Progress of the Child’s Auditory Skills▪-This is within the role of the audiologist and the rehabilitation therapist.-Supporting materials on the handling, operating and care of the sound processor should be issued to the parent/carer.-The recommended use of assistive listening accessories  should be explained to the parent/carer by the CI team  before the CI surgery and the information reviewed after the activation.Instructions on the Use of the Sound Processor Must Be Given to the Parent/Caregiver on or before the Day of Activation and should Be Repeated at Least Twice within the Six Months Following Activation▪-It is recommended to assess speech perception with standardized tests and a functional hearing questionnaire. Ideally: every 6 months in the first 2 years after the cochlear implant activation and then every year minimum of once a year.-Measuring speech perception of soft speech and speech in noise should begin after two years of CI use.-The results should be shared with the child’s parents/educators and local professionals.Appropriate Audiological, Standardized Speech Perception Tests and Functional Hearing Assessment  should Be Performed at 6 Months Intervals to Enable Hearing to Be Monitored▪-Even if rehabilitation does not start until initial fitting, written material about the content of rehabilitation should be shared with the parent/carer well before initial fitting, so that they have a good idea of what is needed to promote an appropriate child’s listening and spoken language development.Rehabilitation should Begin before Implantation and at the Latest Immediately after Initial Fitting, According to the Individual Needs of the Child▪-Parents/educators/professionals must have equal access to information on CI in their preferred language.-CI companies should make their brochures available in the preferred language of the parents/caregivers.Parents/Educators/Professionals Are Considered and Valued as Equal Partners in the Rehabilitation Process of Their Child▪-Standardized assessments for typical hearing children should be used for comparisons.-Additional rehabilitation and/or referrals should take place where progress is slower than expected.Appropriate Measures should Be Performed Yearly  to Monitor Progress in Language, Communicational and Educational Outcomes the First 3 Years after Implantation▪-Additional needs should be identified as soon as possible, so rehabilitation and expectations can be adapted to the special needs. Additional specialists in other fields can be incorporated into the team to share their expertise.A Diagnostic Coaching Approach to CI Rehabilitation Yields the Most Efficient and Best Benefit, Both to Children and to Parents/Educators/Professionals▪The Audiologist and Speech and Language Therapist Together with the Parents should Decide on the Frequency of Specialist Contact Sessions for Fitting and for Rehabilitation Based on the Individual Needs of the Child and Their Family▪As the Recommended Approach of Services Is Family-Centered, It Is Understood That Rehabilitation Therapy Sessions can Take Place Weekly or Fortnightly, Considering That Most Listening and Spoken Language Experience Will Occur at Home between the Sessions▪Children with CI’s should have Annually the Opportunity to Trial and Assess Assistive Listening Devices ▪-Listening skills/functional listening/speech perception.-Speech intelligibility, voice quality and prosody.-Communication skills including repair strategies.-All aspects of language development.-Theory of Mind development.-Ability to troubleshoot and maintain external equipment.-Using assistive listening devices.-Music.-Literacy (reading).-Cognitive skills (Executive Functions).-Mainstream education (inclusion).-Advocacy.Rehabilitation of Young CI-Children should Involve Collaboration between the CI Centre, Local Professionals, and Parents/Educators to Cover the Following Areas:▪-Among all auditory-based early intervention approaches for children receiving CI, evidence-based practice has proven that an approach focusing on listening and spoken language has the most impact on the child’s speech perception skills and expressive spoken language development.-The decision to add signed support or sign language in the rehabilitation therapy will be discussed among parents and professionals so parents can make an informed decision.It Is Recommended That All Children to Receive, Based on Their Need, Listening and Spoken Language Therapy after Implantation, Even Those Who Benefit Little from CI and Who Are Anticipated to Still Be Sign Reliant▪Rehabilitation Therapists and Parents/Educators will Collaboratively Generate Measurable and Appropriate Goals in All Areas of the Child’s Development , and Identify Ways to Integrate the Goals and Strategies to Achieve them in a Nurturing and Rich Language▪Music should Be Integrated in the Rehabilitation of Young Children Using CI’s, Particularly as a Home-Based Fun Activity Rather Than in a Formal Setting▪Every Country should Have Training Opportunities for Professionals in the Various Communication Approaches  to Become An Expert in the Field of Rehabilitation and Education of CI-Children▪-Some very complex children may need a very specialized service.The Staff of the CI Team in the Hospital and Local Rehabilitation Therapists should Have the Knowledge and Expertise That Enables Them to Work Effectively with Children Wearing CI’s, Including Those with Additional Needs Than Their Hearing Loss▪-The therapist should also have expertise in coaching and counselling parents.-The therapist should also have expertise in a family-centered approach.Rehabilitation of Young CI-Children should Be Carried out by An Expert in Promoting Listening, Speech and Spoken Language Development, in Managing the Technology and the Environment▪-Expertise and skills working with infants and very young children (for pediatric services).-Expertise in auditory development and listening skills.-Knowledge on how to manage the technology.-Knowledge on how to manage the acoustics of the environment and on how to address challenging listening situations .-Gain insight into the impact of hearing loss on a child’s overall development  and how to support these skills.-Knowledge of communication support teams, i.e., speech to text or sign language interpreters.-Knowledge of audiology and assistive listening technology.-To get to know the culture and language of the deaf community.-Knowledge on how to coach/guide families.-Knowledge on inclusion of a CI-child .The Expertise of the Rehabilitation Therapist/Rehabilitation Team should Include the Following Skills:https://voice-erasmus.eu (accessed on 12 January 2023)These standards for the rehabilitation of deaf children receiving CIs can be downloaded as a pdf file from the project website Over the past two decades, there has been a great deal of research into the benefits of CIs and the search for the best way to support young CI children and their families. It is important to note that the overall level of evidence in the studies included in our literature analysis is low. Only two studies had a high level of evidence. Therefore, the level of available evidence does not seem to be sufficient to support the existence of differences in auditory and speech and language development between different rehabilitation approaches. This observation is consistent with the findings of recent systematic reviews, which concluded that more data are needed to be able to guide professionals and parents in their decision-making process ,32,33.The studies selected for the bibliographic analysis present some methodological limitations with the impact of the level of evidence. Due to the methodological design used in most studies, it is difficult to identify the rehabilitation factor and state that the approach led to an observed difference between groups.Meanwhile, good prospective clinical trials with 20 or more subjects focusing on variables that predict good outcomes are needed. Ideally, but difficult from an ethical point of view, longitudinal prospective studies are needed, which include many subjects and a control group, in order to find the best rehabilitation techniques for the desired results. Parameters, such as the frequency and duration of the sessions, the content of the rehabilitation sessions, different neurobiological processes, sequential vs. simultaneous cochlear implantation, monaural versus binaural implantation, and various materials and listening conditions, must be evaluated.There is an urgent need for quality standards on the rehabilitation of young children receiving CIs. To our knowledge, this is the first international consensus study to be published on quality standards for the rehabilitation of young CI children. Twenty-nine quality standards were developed and endorsed by the Delphi consensus panel. These quality standards will function best with an experienced team with knowledge and expertise in early implantation, fitting, rehabilitation, parent coaching, monitoring children, and the maintenance of the device and aftercare.In addition, there is the challenge of ensuring the appropriate rehabilitation methods for each child with their individual needs. The results of recent and future neuroscience research on developmental critical periods, synaptic plasticity, auditory cortex changes after cochlear implantation, and auditory processing will help to better design the rehabilitation procedures after implantation. Better evaluations of therapy methods, applying the new developed tests that assess the progress of the implanted child  as well as an increased availability of auditory support programs might help to deliver them more readily and widely in a variety of languages. These challenges reside amongst all professionals and parents dealing with implanted children on a daily basis.The most discussed topics during our Delphi consensus panel were those related to standards of rehabilitation per se. For instance, one standard that was removed after heated debates was that “The paediatric CI may be only carried out if the parents are able to take responsibility for the child’s rehabilitation”. At a certain point, the standard became “Paediatric CI may be only carried out if there is rehabilitation available after CI”, and finally, the standard was eliminated. Another standard that incited discussions was related to the recommendation to use sign language by the SLTs during the rehabilitation sessions. The majority of experts emphasized that “Rehabilitation approach that do not include signs language appear more frequent associated with a better auditory speech and language development”. But there were voices who said that “For some children a signed supported approach to CI therapy yields the most benefit, both for children, parents and teacher”. The standard was eliminated by itself but has been added to Standard 4.3.9. as a possible support method. The last eliminated standard was a reference to the “continuously diagnostic coaching approach to CI therapy yields the most benefit, both for children and to parents and teachers”; the idea of closely monitoring the progress of children has already been mentioned in Standard 4.3.3.But there were some interesting talks related to some other standards; for instance, the reference to the frequency and quality of the therapy gave rise to numerous comments: “the frequency…of sessions for rehabilitation must be based on the individual need of the child”, “it also depends on the needs of the local service professionals”, “it is not frequency or the number of hours important but the quality of the therapy”, “I think that it can depend on the number and the level of expertise of the local service professionals than on their (child’s) needs”, “I think both frequency and quality of the therapy are very important after paediatric CI”, and so on. The result of this topic is illustrated by Standards 4.3.5. and 4.3.6.A strength of this study on the quality standards for the rehabilitation of deaf children is that they were developed based on good practice from local experts, the evidence identified in a robust analysis of the medical literature on the topic of rehabilitation, and the expert opinion of an international Delphi consensus panel with experience in the rehabilitation of young children receiving CIs. This approach is in line with the American Academy of Otolaryngology–Head and Neck Surgery Foundation methods  for the A limitation of the study is the minimal representation of Asia, Africa, and South America on the Delphi consensus panel and the preponderance of local experts from one country (Romania). However, the presence of two international experts from a Spanish speaking country and the fact that in most American Latin countries, the official language is Spanish, we expect that the standards may apply there too. The same applies for Afrikaans, a language that has its origin in German and Dutch languages, as long as we have international experts from Germany and Holland. We cannot tell if the consensus is true for SLTs from Asia, but we expect it is.Another limit lies in the diversity of tests used to quantify the auditory and speech and language outcomes, which makes it difficult to compare results directly from the included studies. Furthermore, most studies did not clearly define the approach used or the intervention setting  that children were involved in.Future research should try to avoid these limitations to bring more robust data to the field of rehabilitation. As many studies were based on retrospective data or cross-sectional designs, an important element that should be considered by future researchers is using a study design that has fewer methodological limits. Focusing on prospective and longitudinal data and using a bigger sample size would allow better control of the studied variables, enhance the level of evidence, and allow researchers to match the groups on key variables to reduce their influence on the results.To develop quality standards for the rehabilitation of deaf children receiving CIs, we used the input from the interviews of 11 local rehabilitation experts on CIs from the four partner countries involved in the VOICE project and the outcome of the analysis of 848 publications related to the theme and retrieved from six databases. The Delphi method approach was used by 18 international rehabilitation specialists in CI intervention to discuss and agree on these quality standards. Finally, >90% of the international experts agreed on 29 quality standards, of which most of them contain some subcategories.Further research is needed to address the issue of the rehabilitation of young deaf children receiving CIs. Studies involving larger samples, matched groups, and well-controlled interventions are essential to isolate the intervention factor and be able to generalize findings.Meanwhile, we have to focus on good practice which takes into consideration the specific needs of the child, their family, and the contact they are evolving in .We believe that the guidelines for good practices presented here can act as a lever for the necessary studies, as they already indicate the conceptual field where future studies should take place and, therefore, help in the creation of evidence-informed approaches.


Androgen signalling, through the transcription factor androgen receptor (AR), is vital to all stages of prostate development and most prostate cancer progression. AR signalling controls differentiation, morphogenesis, and function of the prostate. It also drives proliferation and survival in prostate cancer cells as the tumour progresses; given this importance, it is the main therapeutic target for disseminated disease. AR is also essential in the surrounding stroma, for the embryonic development of the prostate and controlling epithelial glandular development. Stromal AR is also important in cancer initiation, regulating paracrine factors that excite cancer cell proliferation, but lower stromal AR expression correlates with shorter time to progression/worse outcomes. The profile of AR target genes is different between benign and cancerous epithelial cells, between castrate-resistant prostate cancer cells and treatment-naïve cancer cells, between metastatic and primary cancer cells, and between epithelial cells and fibroblasts. This is also true of AR DNA-binding profiles. Potentially regulating the cellular specificity of AR binding and action are pioneer factors and coregulators, which control and influence the ability of AR to bind to chromatin and regulate gene expression. The expression of these factors differs between benign and cancerous cells, as well as throughout disease progression. The expression profile is also different between fibroblast and mesenchymal cell types. The functional importance of coregulators and pioneer factors in androgen signalling makes them attractive therapeutic targets, but given the contextual expression of these factors, it is essential to understand their roles in different cancerous and cell-lineage states. The prostate is an androgen-dependent organ comprised of two main compartments, which both transform with cancer progression. The normal prostate is composed of tubes of columnar epithelial cells and basal cells, which are embedded in a surrounding stromal compartment comprised of smooth muscle cells, fibroblasts, vasculature, and immune cells . Cancer When the cancer metastasises, it forms new microenvironments composed of cells of the organ it has invaded. In both primary and metastatic lesions, the microenvironment is largely composed of activated fibroblasts (termed cancer-associated fibroblasts (CAFs)); immune cells are also recruited, endothelial cells are usurped to feed the tumour, and organ-specific cells are also present . There iIn advanced and metastatic disease, the principal treatment involves systemically targeting the action of the androgen receptor (AR) using androgen deprivation or anti-androgens. While initially effective in reducing tumour burden, the disease can re-emerge in a therapy-resistant state termed castrate-resistant prostate cancer (CRPC). This stage of the disease is less responsive to androgens/anti-androgens, but AR signalling still remains active. There are several hypotheses as to how tumours become CRPCs ; this rAR regulation of gene transcription is a highly co-ordinated process . Upon acAR is expressed throughout the body and heterogeneously within PCa microenvironment . AR chroRecombinant mouse models have shown that epithelial AR expression is not required for embryonic prostate development  identified that at every stage of prostate cancer, there is a distinct binding pattern for AR  is the most investigated pioneer factor in PCa as it has a prominent role in AR signalling. Before binding to chromatin, FOXA1 reads the epigenetic state of histones, such as the methylation status of histone H3 lysine 4, which then regulates the recruitment of AR to DNA  is the second most well-characterised pioneer factor in PCa and often co-localises with FOXA1 . GATA2 hin vitro and in vivo  and c-FOS (FOS). JUN and FOS act to enhance AR activity in transactivation promoter assays  or inhibit (co-repress) the transcriptional capacity of nuclear receptors. It is now becoming apparent that coregulator action can be gene-specific, i.e. whether it acts on AR as a co-activator, a co-repressor, or has no effect, is dependent on the target gene  family protein NCoA1 expression, there is reduced androgen-driven growth/mass of the prostate gland  resistance identified coregulators included in the gene expression changes associated with insensitivity to flutamide, with NCOA2 and NCOA4 increasing and co-repressor NCOR1 decreasing  and CAFs . There hInterestingly, in fibroblasts, there appears to be a relationship between proteins involved in cell movement and AR. Filamin A (FLNA) is a protein involved in linking the cytoskeleton and the plasma membrane and is most highly expressed in the stroma. The FLNA–AR axis mediates CAF movement, which in turn influences cancer invasiveness , 2007. IIn some aspects, the metastatic microenvironment is composed of similar cell types as the primary microenvironment, in that there are fibroblasts, endothelial cells, and immune cells. Whether AR action is distinct in these cell types based on their resident organ is unclear. Furthermore, specialised cells of the metastasised organs can express AR, but the role of coregulators in these cell types is largely unknown.In the bone microenvironment, there are AR-positive osteoblasts  and NIHR Imperial Biomedical Research Centrehttp://dx.doi.org/10.13039/501100013342-funding.The authors acknowledge funding from the


Infertility is a global health concern inflicting a considerable burden on the global economy and a severe socio-psychological impact. Approximately 15% of couples suffer from infertility globally, with a male factor contribution of approximately 50%. However, male infertility remains largely unexplored, as the burden of infertility is mostly assigned to female people. Endocrine-disrupting chemicals (EDCs) have been proposed as one of the factors causing male infertility. Pyrethroids represent an important class of EDCs, and numerous studies have associated pyrethroid exposure with impaired male reproductive function and development. Therefore, the present study investigated the potentially toxic effects of two common pyrethroids, cypermethrin and deltamethrin, on androgen receptor (AR) signaling. The structural binding characterization of cypermethrin and deltamethrin against the AR ligand-binding pocket was performed using Schrodinger’s induced fit docking (IFD) approach. Various parameters were estimated, such as binding interactions, binding energy, docking score, and IFD score. Furthermore, the AR native ligand, testosterone, was subjected to similar experiments against the AR ligand-binding pocket. The results revealed commonality in the amino acid-binding interactions and overlap in other structural parameters between the AR native ligand, testosterone, and the ligands, cypermethrin and deltamethrin. The estimated binding energy values of cypermethrin and deltamethrin were very high and close to those calculated for AR native ligand, testosterone. Taken together, the results of this study suggested potential disruption of AR signaling by cypermethrin and deltamethrin, which may result in androgen dysfunction and subsequent male infertility. Male infertility is a global health issue, with nearly 30 million male people suffering from this condition, contributing approximately 40%–50% to the overall couple infertility cases . InfertiA thorough review of available epidemiological studies indicated an association between pyrethroid exposure and male infertility . For exaAll pyrethroids are categorized into two groups based on their physical properties and toxicity. The compounds included in these two groups are represented as class I and class II . Our preThe commonly used class II pyrethroids—cypermethrin and deltamethrin—exhibited successful docking in the AR ligand-binding pocket. Both ligands cypermethrin and deltamethrin were placed stably in the AR ligand-binding pocket, following induced fit docking (IFD), indicating their firm binding. The IFD approach generated several docking poses for each ligand. However, only the best poses were chosen and carried forward for structural characterization. In addition, the AR native ligand, testosterone, was also placed stably in the AR ligand-binding pocket. Here, the best-ranking pose was also chosen for further analysis. All the chosen poses for both ligands exhibiting molecular interactions of amino acid residues with respective ligands are presented . CypermeThe cypermethrin–AR docking complex displayed several interactions with AR amino acid residues. Overall, 25 amino acid residues of the AR displayed various molecular interactions, such as hydrophobic, hydrogen bonding, and van der Waals interactions, with the ligand cypermethrin. The amino acid residues involved in various interactions were Leu-701, Leu-704, Asn-705, Leu-707, Gly-708, Gln-711, Trp-741, Met-742, Met-745, Val-746, Met-749, Phe-764, Phe-770, Ser-778, Met-780, Gln-783, Cys-784, Met-787, Leu-873, Phe-876, Thr-877, Leu-880, Phe-891, Met-895, and Ile-899. Moreover, the pi–pi interaction was displayed by Phe-764 . In addiSimilarly, the molecular interaction of the AR native ligand, testosterone, with AR amino acid residues is also presented . AltogetThe other parameters, such as IFD, Dock score, and Glide score, essential for structural binding analysis and characterization of cypermethrin and the AR native ligand, testosterone, are also presented . In addiThe docking display pose of deltamethrin exhibited 24 amino acid residues engaged in various molecular interactions with the AR . FurtherThis study aimed to characterize the structural binding parameters, including the molecular interactions of commonly used class II pyrethroids—cypermethrin and deltamethrin—in the AR ligand-binding pocket. This study was performed to advance our understanding of the potential AR signaling disruption by the aforementioned ligands, which could have subsequent male infertility consequences. The in-depth result analysis of this study indicated the stable binding of both ligands (cypermethrin and deltamethrin) into the AR ligand-binding pocket. Furthermore, the stability and good quality of AR–ligand complexes were indicated by the estimated values of structural binding parameters, such as the IFD score, Glide score, Dock score, and binding energy. The several molecular interactions displayed in the AR–ligand complexes, such as hydrogen bond, pi–pi interactions, and salt bridge, contribute significantly to the stability of these complexes. The critical analysis of the comparison of the AR native ligand’s (testosterone) docking pose with the best-chosen docking pose of cypermethrin and deltamethrin indicated 80%–90% commonality in the interacting amino acid residue lining the AR ligand-binding pocket. Furthermore, the binding energy values calculated for cypermethrin and deltamethrin were also similar to the AR native ligand, testosterone. The values calculated for cypermethrin and deltamethrin were close to the values calculated for the AR native ligand, testosterone. Therefore, the results of this study suggest the potential for these ligands to disrupt the AR signaling, which might subsequently have an adverse impact on male reproductive development and fertility.in silico studies on the structural binding characterization of cypermethrin and deltamethrin against the AR are unavailable. However, we recently reported the potential AR signaling disruption by one of the commonly used pyrethroid compounds, which is permethrin , thus forming a stable and successful docking complex. In addition, the results also revealed high binding energy for both pyrethroids against the AR ligand-binding pocket, which was similar to the values calculated for the AR native ligand, testosterone. Overall, the results of the present study suggested that both the indicated ligands (cypermethrin and deltamethrin) have the potential to disrupt the AR signaling function and might subsequently affect the male reproductive functions, causing infertility.https://pubchem.ncbi.nlm.nih.gov/). It was followed by structural binding characterization of these ligands using the Schrodinger 2017 suite with Maestro 11.4 as a graphical user interface . The detailed methodology is described in our previous study  were retrieved from Protein Data Bank (PDB) (http://www.rcsb.org/). The retrieved coordinates were imported to Glide docking software, and the protein crystal complex was subjected to further processing and prepared for docking studies using the protein preparation wizard workflow of Schrodinger Glide , as described in our previous study . The PubChem compound identity for the ligand cypermethrin is 2912, whereas the PubChem compound identity for deltamethrin is 40585. These ligands were processed and prepared for simulation studies using the LigPrep module of Schrodinger . The two-dimensional structures of cypermethrin and deltamethrin are presented in The three-dimensional structural coordinates for the commonly used class II pyrethroids (cypermethrin and deltamethrin) were downloaded from the PubChem compound database  function in the Prime module of Schrodinger 2017, as described previously .


After COVID-19, there was an outbreak of a new infectious disease caused by monkeypox virus. So far, no specific drug has been found to treat it. Xuanbai Chengqi decoction (XBCQD) has shown effects against a variety of viruses in China.We searched for the active compounds and potential targets for XBCQD from multiple open databases and literature. Monkeypox related targets were searched out from the OMIM and GeneCards databases. After determining the assumed targets of XBCQD for monkeypox treatment, we built the PPI network and used R for GO enrichment and KEGG pathway analysis. The interactions between the active compounds and the hub targets were investigated by molecular docking and molecular dynamics (MD) simulations.In total, 5 active compounds and 10 hub targets of XBCQD were screened out. GO enrichment and KEGG analysis demonstrated that XBCQD plays a therapeutic role in monkeypox mainly by regulating signaling pathways related to viral infection and inflammatory response. The main active compound estrone binding to target AR was confirmed to be the best therapy choice for monkeypox.This study systematically explored the interactions between the bioactive compounds of XBCQD and the monkeypox-specific XBCQD targets using network pharmacological methods, bioinformatics analyses and molecular simulations, suggesting that XBCQD could have a beneficial therapeutic effect on monkeypox by reducing the inflammatory damage and viral replication via multiple pathways. The use of XBCQD on monkeypox disease was confirmed to be best worked through the estrone-target AR interaction. Our work could provide evidence and guidance for further research on the treatment of monkeypox disease. In JuneMonkeypox disease is a rare zoonotic disease caused by the monkeypox virus . It is eThe monkeypox virus is a double-stranded DNA virus that is related to the variola virus . The cliXuanbai Chengqi decoction (XBCQD) is a TCM consisting of four Chinese herbs, including mineral-based gypsum, herbal rhubarb, bitter almond, and trichosanthes . It was In fact, XBCQD is a representative Chinese medicine prescription in the Differentiation of Febrile Disease written by Wu Jutong in Qing dynasty. It has been widely used in China for the treatment of lung injury, pulmonary fibrosis, chronic obstructive pulmonary and other common respiratory diseases. It can effectively reduce phlegm, heat, cough, wheezing, chest tightness, and has less adverse reactions . With thin vivo binding patterns of ligand-receptor  of the targets.2.3.The targets of monkeypox disease were searched by using OMIM2.4.Using the Venny online database,2.5.The String2.6.Homo sapiens” in “List.” The target, the minimum overlap, the p-value and the minimum concentration were set to “human,” 3, 0.05 and 1.5, respectively. Then we ran the gene ontology function and KEGG pathway on the target genes. We screened and preserved the results of the most important BP, CC, MF, and KEGG pathways. Finally, the corresponding bubble diagram was derived.GO function and KEGG path enrichment were analyzed using Bioconductor2.7.To reveal the binding patterns between the active compounds and the targets, AutoDock Vina software, Discovery Studio 4.5 Client and PyMOL software were used. The 3D structures of the central targets (receptors) were obtained from the RCSB PDB2.8.The long-range electrostatic interactions were calculated using the particle mesh Ewald (PME) method. The target was placed in the center of simulation box filled with water TIP3P molecules with distance of 1.2 nm from the box boundary. There were 33 Na+ ions introduced in the water box to neutralize the charge of the whole system. The system was firstly balanced with energy minimization process which ran up to 100,000 steps using the steepest descent algorithm. Then the system was equilibrated to 310 K with v-rescale  method and backbone restrained. Subsequently, the system was further equilibrated at constant pressure (1 bar) and constant temperature (310 K). Finally, 200 ns MD test was conducted after all the restraints released. The simulation results were analyzed by Gromacs 5.1.2 built-in tools and our in-house scripts.3.3.1.In total, 285 compounds were screened out by the TCMSP database, among which 16, 19 and 11 compounds were from herbal rhubarb, bitter almond, and trichosanthes, respectively. And 43 active compounds met the OB ≥ 30% and DL ≥ 0.18 standards, which were selected for further analysis after removal of the duplicates. The TCMSP database was used to obtain the corresponding targets. All targets were then entered into the Uniprot database and normalized by removing the repeated ones. Finally, 116 potential targets were obtained.3.2.The GeneCards database  and the 3.3.According to the PPI network analysis , the 36 The ranking of the nodes of the most important active compounds in XBCQD was summarized in 3.4.p value of the BP item.The 36 XBCQD-monkey pox virus intersection targets were imported into the Metascape platform. GO functional enrichment analysis was performed on the targets of the active ingredients in the treatment of monkey pox virus from the levels of BP, CC, and MF . The topp value in p value of the path.It can be found that BP was related to rhythmic process, positive regulation of cell cycle, response to drug, epithelial cell proliferation, DNA-templated transcription, initiation, response to steroid hormone, regulation of epithelial cell proliferation, negative regulation of protein phosphorylation, regulation of epithelial cell proliferation, and transcription initiation from RNA polymerase II promoter. There were 155 items in the CC analysis , and thep values from the KEGG enrichment analysis and related targets were used to construct the KEGG key pathway network , Stigmasterol (MOL003035), Gamma-Aminobutyric Acid (MOL000388), Phytol (MOL001442) and estrone (MOL008204). The protein structures of hub targets were acquired online from RCSB PDB, including AR (PDB ID: 2QPY), CASP3 (PDB ID: 6BDV), CCNB1 (PDB ID: 2B9R), CDKN1A (PDB ID: 3TS8), ESR1 (PDB ID: 1A52), IL1B (PDB ID: 4DEP), JUN (PDB ID: 1FOS), MYC (PDB ID: 7C36), TP53 (PDB ID: 4MZI) and TNF (PDB ID: 1TNF). The values of affinity energy were obtained by docking analyses . Notably3.6.The two best dockings between the compounds and the targets (estrone-AR and estrone-ESR1) were selected to perform the MD simulations. After 200 ns of MD simulations, the dynamic evolutions of estrone-AR and estrone-ESR1 complexes were studied. The conformations of estrone-AR and estrone-ESR1 complexes as well as their contact residues were shown in As shown in From 4.TCM has accumulated a long history of clinical experience and efficacious prescriptions in preventing and treating diseases . It has The PPI analysis of the 36 targets showed that the top 10 hub targets, including ESR1, TP53, CASP3, JUN, TNF, MYC, CDKN1A, 1L1B, CCNB1, and AR may be the key targets of the treatment of monkeypox virus. The top 5 beta-sitosterol, Stigmasterol, Gamma-Aminobutyric Acid, Phytol, estrone and the top 10 targets were selected in this study. These bioactive compounds were found to effectively bind to the 10 targets according to the results of molecular docking. We further performed GO enrichment analysis on the 36 selected targets to better understand the multiple effects of XBCQD against monkeypox virus from a systematic perspective. The top 10 GO functional categories indicated that XBCQD may exert its effects through the involvement in the BP, MF, and CC. Among these targets, TP53 and ESR1 ranked highest. It was reported that TP53 could be one of the key enzymes in prostaglandin biosynthesis, which had an association with inflammation and mitosis . In addivia these pathways.The concentration of GO terms in hub targets showed that XBCQD treatment of monkeypox was mainly involved the rhythmic process, positive regulation of cell cycle, response to drug, epithelial cell proliferation and DNA-templated transcription, etc. KEGG pathway enrichment analysis of these targets indicated that they were involved in Hepatitis B, AGE-RAGE signal pathway of diabetes complications, Breast cancer, Proteoglycans in cancer, Human cytomegalovirus infection, etc. The AGE-RAGE signaling pathway was reported to have a regulatory role in diabetes . Some stThe results of network pharmacology were validated by molecular docking of the top 10 targets and 5 active compounds. The two complexes with lowest binding energy scores were found to be estrone-AR and estrone-ESR1. Furthermore, MD simulations showed that the average value of interaction energy of estrone-AR was −186 kcal/mol , while was lower than the value of −157 kcal/mol  of the estrone-ESR1 complex. Therefore, the interaction of estrone-AR complex was more stable comparing to estrone-ESR1 complex.via multiple pathways. In addition, the use of XBCQD on monkeypox disease was confirmed to be best worked through the estrone-target AR interaction. By using a series of computational approaches, our study established the drug screening of XBCQD on monkeypox disease for the first time, hopefully could provide some guidance for future drug development.In summary, this study systematically explored the interactions between the bioactive compounds of XBCQD and the monkeypox-specific XBCQD targets using network pharmacological methods, bioinformatics analyses and molecular simulations, suggesting that XBCQD could have a beneficial therapeutic effect on monkeypox by reducing the inflammatory damage and viral replication 5.By combining network pharmacology, molecular docking and MD simulation, the molecular mechanism of XBCQD in the treatment of monkeypox virus was systematically investigated. According to our results, the top 5 compounds  and the top 10 targets  were identified. We also found that XBCQD in the treatment of monkeypox virus could be mainly related to Hepatitis B, AGE-RAGE signal pathway of diabetes complications, Breast cancer, Proteoglycans in cancer, Human cytomegalovirus infection, MAPK signaling pathway, Estrogen signaling pathway, Epstein–Barr virus infection, Human immunodeficiency virus 1 infection and Chemical carcinogenesis-receptor activation. Moelcular docking showed that estrone-AR and estrone-ESR1 exhibited stronger binding affinities than the other moieties. And the estrone-AR possessed higher structural and interaction stabilities than the estrone-ESR1 with the extension of molecular simulation time. Our study provides a comprehensive explanation of the multi-component, multi-target and multi-pathway intervention mechanism of XBCQD in the treatment of monkeypox, which is expected to provide a basis and new insights for further pharmacological research.The original contributions presented in the study are included in the article/YS designed the simulations. YJ and CS performed the simulations and analyzed the data. YS, YJ, and CS wrote the manuscript. All authors contributed to the article and approved the submitted version.This work is supported by the National Natural Science Foundation of China (Ref: 12102113) and the Major program of the National Natural Science Foundation of China (T2293720/T2293722).The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


Cardiovascular diseases (CVDs) cause most deaths globally and can reduce quality of life (QoL) of rehabilitees with cardiac disease. The risk factors of CVDs are physical inactivity and increased BMI. With physical activity, it is possible to prevent CVDs, improve QoL, and help maintain a healthy body mass. Current literature shows the possibilities of digitalization and advanced technology in supporting independent self-rehabilitation. However, the interpretation of the results is complicated owing to the studies’ high heterogeneity. In addition, the added value of this technology has not been studied well, especially in cardiac rehabilitation.We aimed to examine the effectiveness of added remote technology in cardiac rehabilitation on physical function, anthropometrics, and QoL in rehabilitees with CVD compared with conventional rehabilitation.t tests and Mann-Whitney U test. Within-group differences were analyzed using a paired samples t test or Wilcoxon signed-rank test.Rehabilitees were cluster randomized into 3 remote technology intervention groups (n=29) and 3 reference groups (n=30). The reference group received conventional cardiac rehabilitation, and the remote technology intervention group received conventional cardiac rehabilitation with added remote technology, namely, the Movendos mCoach app and Fitbit charge accelerometer. The 12 months of rehabilitation consisted of three 5-day in-rehabilitation periods in the rehabilitation center. Between these periods were two 6-month self-rehabilitation periods. Outcome measurements included the 6-minute walk test, body mass, BMI, waist circumference, and World Health Organization QoL-BREF questionnaire at baseline and at 6 and 12 months. Between-group differences were assessed using 2-tailed P=.04; 12 months: 3 cm; P<.001) and increment in self-assessed QoL were greater  in the remote technology intervention group than the reference group. Both groups achieved statistically significant improvements in the 6-minute walk test in both time frames (P=.01-.03). Additionally, the remote technology intervention group achieved statistically significant changes in the environmental domain at 0-6 months (P=.03) and waist circumference at both time frames (P=.01), and reference group achieve statistically significant changes in waist circumference at 0-6 months (P=.02).Overall, 59 rehabilitees aged 41 to 66 years  were included in the study. Decrement in waist circumference (6 months: 1.6 cm; Remote cardiac rehabilitation added value to conventional cardiac rehabilitation in terms of waist circumference and QoL. The results were clinically small, but the findings suggest that adding remote technology to cardiac rehabilitation may increase beneficial health outcomes. There was some level of systematic error during rehabilitation intervention, and the sample size was relatively small. Therefore, care must be taken when generalizing the study results beyond the target population. To confirm assumptions of the added value of remote technology in rehabilitation interventions, more studies involving different rehabilitees with cardiac disease are required.ISRCTN Registry ISRCTN61225589; https://www.isrctn.com/ISRCTN61225589 Technology-based rehabilitation with physical activity has been widely studied in rehabilitees with several diseases ,2. CardiTelehealth-   and smarThe current goal of rehabilitation is to support and maintain individuals’ physical, mental, and social resources  and to mThere is a lack of specific knowledge regarding the effectiveness or added value of remote technology-based rehabilitation in rehabilitees with CVD. To the best of our knowledge, 2 studies have examined the added value of digital health interventions and yielded contradictory results ,30 on boIn this study, a biopsychosocial perspective on technology-based self-rehabilitation was considered. This study aimed to investigate at the individual level the added value of remote technology in cardiac rehabilitation on physical function, anthropometrics, and QoL in participants with CVD compared with conventional rehabilitation. Rehabilitees attended standard group-based cardiac rehabilitation courses at a rehabilitation center in Finland. Because of the possibility of cross-contamination between the experimental and control groups, cluster randomization was performed.This study (registration number ISRCTN61225589) was a cluster randomized trial. Recruitment and data collection were conducted between September 2015 and May 2017 at the Finnish Rehabilitation Center. This study was a real-life research project with a 1-year data recruitment period.Rehabilitees were distributed into 6 groups by officers of the Social Insurance Institution of Finland. Randomization occurred at the group level in pairs of 2 consecutive groups with following two experimental arms: (1) conventional cardiac rehabilitation with remote technology (remote technology intervention) group and (2) conventional cardiac rehabilitation (reference) group. The rehabilitees were randomized into 3 remote technology intervention clusters and 3 reference clusters. Rehabilitees were cluster randomized into cluster pairs, which bypassed any systematic bias that occurred because of the season. The clusters began in autumn (September to November), winter (December to February), and spring (March to May). The other cluster randomization–specific confounding factors, such as department and caregiver factors, were controlled in the study design using the same rehabilitation center and caregivers in all remote technology interventions (n=3) and reference groups (n=3).Randomization was accomplished with sealed envelopes within rehabilitation groups, and a person outside the research group  processed the randomization under the supervision of 2 researchers (TS and Heikki Kivistö). Randomization was performed 3 times for 2 consecutive groups, considering the season and months. In total, 59 rehabilitees were randomly assigned in pairs into (1) the remote technology intervention group (n=29) or (2) the reference group (n=30) in consecutive order. At the beginning of the rehabilitation, the researchers (TS and HK) informed the rehabilitees about the group (n=6) their rehabilitation group had been randomized. After randomization, rehabilitees provided written consent for their participation in the intervention. Because of the nature of the intervention, it was not possible to blind the rehabilitees and caregivers in terms of the intervention. The outcome assessor was not blinded to the intervention, but one educated person who was not involved in the study group performed the anthropometric measurements, and another person performed the 6-minute walk tests (6MWTs). The statistician was blinded to the interventions.Cardiac rehabilitation was implemented in groups of rehabilitees. The rehabilitees attended 3 sessions during the 5-day in-rehabilitation period in the rehabilitation center. Between these rehabilitation periods, there were two 6-month self-rehabilitation phases. All outcome measurements were performed at baseline and at the 6- and 12-month follow-ups .The study was approved on October 15, 2015, by the Ethics Committee of the Central Finland Health Care District (Dnro: 12 U/2015).A total of 59 rehabilitees within the 6 rehabilitation clusters were recruited among the rehabilitees attending coronary heart disease rehabilitation courses between September 2015 and May 2017. The rehabilitees applied for the course with a physician’s referral. The primary eligibility criterion for the study was an adult (aged <18 years) with coronary heart disease and having independent basic level of management of IT and remote technology applications. The exclusion criteria included having serious musculoskeletal disorders, cognitive diseases, and memory diseases that affect essential functional abilities to ensure the capability of rehabilitees to use technology. The inclusion and exclusion criteria were based on functional ability because this study is interested in the added value of technology in cardiac rehabilitation, regardless of the background of the rehabilitees, for example, medication or comorbidities. All rehabilitees who underwent cardiac rehabilitation fulfilled the inclusion criteria. There were no statistically significant differences in the demographic and clinical characteristics at baseline between the remote technology intervention and reference groups .P=.65) at baseline and only minor lifestyle changes were observed before the intervention. Of the 59 rehabilitees, 8 (14%) reported changing their lifestyle to a healthier direction during the last 12 months. Rehabilitees reported minor changes, such as eating more vegetables (n=4), changing the quality or amount of fat (n=2), decreasing salt use (n=1), or losing weight  years, and 81% (48/59) of them were men. Rehabilitees underwent coronary angioplasty or coronary artery bypass 3-12 months before the intervention.Cardiac rehabilitation courses were held at the Finnish Rehabilitation Center and arranged by the Social Insurance Institution of Finland. The aim of conventional Finnish cardiac rehabilitation courses was to promote the biopsychosocial functional ability of rehabilitees and their ability to work . The totBoth the remote technology intervention and reference groups received conventional cardiac rehabilitation. The initiation of the intervention included a 5-day in-rehabilitation period. Furthermore, 2 follow-up periods of 5 days at the 6- and 12-month time points in the rehabilitation center were included in the study . BetweenThe researchers at the University of Jyväskylä, Finland, were in equal contact with the rehabilitees in the remote technology intervention and reference groups during the different phases of the study. Furthermore, intervention, initiation, and follow-up periods in the remote technology intervention and reference groups were equal in the time sequence of the rehabilitation stages.The rehabilitees in the reference group only received printed materials for conventional cardiac rehabilitation. They did not have any mobile phone apps or other remote technology, but the reference group had standard phone communication with rehabilitation staff if needed. In the reference group, self-monitoring was performed using pen and paper.At baseline, during the initiation of the 5-day in-rehabilitation period in the rehabilitation center, the remote technology intervention group received instructions on how to use the Movendos mCoach internet software (Movendos Ltd) via a mobile phone, computer, or tablet computer. Movendos mCoach is a browser-based tool that enables communication between the rehabilitee and instructor and monitors the progress of rehabilitee. Wrist-worn Fitbit Charge HR (Fitbit) accelerometers were used for self-monitoring and motivating physical activation during the 12-month intervention period. The accelerometers were guided to be worn daily and to follow the number of steps and other parameters describing physical activity. If required, the rehabilitees had an opportunity to use the Fitbit app, which described graphically and cumulatively reported daily, weekly, and monthly activity levels.During the in-rehabilitation periods, the rehabilitees used the Movendos mCoach app, for example, in goal setting and exercise instructions, and Fitbit accelerometers for self-monitoring of physical exercises. In addition, the accelerometer serves as a motivational tool. In the remote technology intervention group, the remote technology application was used in home exercise instructions, advice, and monitoring of the rehabilitees during the 5-day in-rehabilitation and 6-month self-rehabilitation periods. Researchers and health care professionals did not receive real-time feedback from the accelerometers.During the self-rehabilitation period, the remote technology intervention group performed monthly tasks that aimed to increase participants’ ability to cope with cardiac illness in everyday life. Web-based software (Movendos) sent monthly automatic motivational messages. In addition, peer support was possible in group discussions. The coaching software also allowed for changing experiences with the peer group. If required, the rehabilitees formed WhatsApp (Meta) groups, but this was not part of official rehabilitation. There was also the possibility of sending messages to the physiotherapist through coaching software. In addition, rehabilitees had an opportunity to contact the researcher responsible for measurement and technical support in problems related to the use of technology, if needed.The primary outcome of this research project was a physical activity assessment published by Hakala et al . This sePhysical function was evaluated using the 6MWT. In the 6MWT, a rehabilitee walked at a self-selected pace for a 6-minute period. The rehabilitees were allowed to stop if needed and continue walking when they felt comfortable doing so ,33. The 2 and >30 kg/m2 [Body mass was measured using a calibrated floor scale. The rehabilitees wore light clothes, such as T-shirts and shorts or tights, and shoes were off. BMI was calculated by dividing the weight by the square of the height in meters . Waist c30 kg/m2 , respect30 kg/m2 . It has 30 kg/m2 . They ar30 kg/m2 ,39, and 30 kg/m2 .QoL was measured using the WHOQOL-BREF questionnaire. The researchers were responsible for completing the questionnaires at the rehabilitation center in paper format. The questionnaire has 26 questions, one of which is related to general health and the other to overall QoL. The other 24 questions are related to 4 different domains: physical (7 items), psychological (6 items), social (3 items), and environmental (8 items). Higher scores reflected higher QoL. The WHOQOL-BREF has been translated into several languages, such as Finnish, German, and Japanese , and theChanges between the remote technology intervention and reference groups were compared between baseline and month 6 and between baseline and month 12. The changes in the measurement results were obtained by subtracting the results of the previous measurements from those of the previous measurements. Because of missing observations, testing was always performed by testing one time frame at a time, not all time frames at once. This approach provided an opportunity to test periods other than consecutive periods, for example, from baseline to 12 months.t tests and Mann-Whitney U tests. The normality of the groups had to be tested because the sample size in both groups was ˂50. Normality was tested using the Shapiro-Wilk test. If the P value was >.05, an independent samples t test was performed; otherwise, the Mann-Whitney U test was used. Variance in group equality was tested using Levene test. This was used in the case of the independent samples t test. If the P value was ˂.05 Levene test, 1-way ANOVA was performed. Otherwise, the variances were assumed to be equal and 2-way ANOVA was performed. Changes within groups were analyzed using a paired samples t test or Wilcoxon signed-rank test. In addition, between-clusters (1-6) differences were tested using 1-way ANOVA and Tukey test (0-6 and 0-12 months).Between-group differences were assessed using 2-tailed P=.02). At baseline, the remote technology intervention group used unhealthier fat than did the reference group. However, for other diet-related questions, there were no statistically significant between-group differences.Among the 59 rehabilitees, the dropout rate was 10% over the 12-month period . At the P=.04) and 12-month  follow-up points in the remote technology intervention group than at those in the reference group (P=.02). There were no statistically significant differences in the other outcomes. In the between-cluster difference analysis, there were no statistically significant differences in any outcome.The waist circumference decreased significantly more at the 6-month  and in the remote technology intervention group at 0-12 months , as did the environmental domain in the remote technology intervention group at 0-6 months  and reference  groups during the intervention (0-6 and 0-12 months). In this study, there were no statistically significant changes in any outcome between clusters. The sample size of the clusters was small, which could have affected the results. Therefore, the results of the cluster analyses were indicative. In the future, it is important to study the individual and group factors that affect the function of the group. A possible cluster effect should be considered in the future when planning and implementing rehabilitation interventions. For example, peer support has been found to be important in the process of weight loss, as rehabilitees learn together, share experiences, and feel a sense of belonging. They value the support of their peers in the same situation . Social The strength of this study is that the conventional cardiac rehabilitation, rehabilitation staff, and background were the same in both the groups. Another strength is that this study evaluated the added value of technology in the everyday lives of rehabilitees in their home environments during self-rehabilitation periods. Most previous studies have evaluated the effectiveness of technology in clinical settings; however, in this study, we also investigated the effectiveness of rehabilitation during the self-rehabilitation period. A strength of this study is the comprehensive view it provides, in which the measurements were based on the biopsychosocial aspect of a rehabilitee. To the best of our knowledge, only one study  has inveA strength of this study is that cardiac rehabilitation was implemented by a multidisciplinary team. Previous studies have revealed that multidisciplinary rehabilitation is effective in body weight reduction -59. The The strength of this study was controlling for significant background factors of rehabilitation  before intervention and the factors of the rehabilitees (comorbidities and cointervention) at baseline. There were only minor differences in the number of comorbidities and no statistically significant differences in the background factors of the rehabilitees at baseline. In addition, the rehabilitees did not show statistically significant lifestyle changes before the rehabilitation intervention. We used pairwise randomization in a consecutive order to control seasonal variety , which may have caused systematic effect bias. Because we were able to control several confounding factors, the statistically significant changes in waist circumference and environmental domain may be associated with the added remote technology–assisted rehabilitation intervention.A major limitation of this study is its small sample size, which affects its generalizability. However, the dropout rates were low in both groups. Because of the small sample size, we emphasized the guidance provided by the technology use. In this study, there was significant variance in the CIs. This could affect the internal validity of the study, which is typical of small studies. Another limitation of this study was blinding. It was not possible to blind the participants, caregivers, or outcome assessors because of the nature of the intervention. The protocol for cardiac rehabilitation was strictly standardized by the Social Insurance Institute of Finland, which is also responsible for rehabilitation costs. In addition, the risk of selection bias is present because the rehabilitees who participated in cardiac rehabilitation applied to the rehabilitation of their own will. In Finland, everyone who has undergone cardiac surgery has the opportunity to undergo rehabilitation. However, it is known that everyone who has undergone cardiac surgery does not apply for rehabilitation. One limitation is that we did not control for the use of health care services. The rehabilitees had normal health care services if needed.According to the nature of the study protocol, the inclusion criteria were determined such that only severe functional ability problems were determined as exclusion criteria. The main purpose of the inclusion criteria was to ensure that the rehabilitees were capable of using technology regardless of the rehabilitation background. We kept the inclusion criteria broad and created an opportunity for a larger number of rehabilitees to participate in the study. All rehabilitees met the inclusion criteria. Real-life interdisciplinary rehabilitation study designs are valuable for producing new information on rehabilitation that can be implemented directly in real-life situations and environments, compared with laboratory research. Unfortunately, in a real environment, we must make concessions in some aspects of study design, such as determining the sample size of the study population and using cluster randomization instead of randomization at individual level. In the future, with a larger study group, it would be important to study more specifically the effects of individual factors, such as medication or comorbidities, in added value of technology-based rehabilitation.Because there was some level of systematic (blinding and selection bias) error during the intervention and samples were relatively small, care must be taken in generalizing the study results beyond the target population. In order to confirm the perceptions of the added value of remote technology in rehabilitation interventions, more studies involving rehabilitees with cardiac rehabilitation are required.Several measurements were used in this cluster randomized trial, which are widely used, but have some limitations. In the 6MWT, small changes in the test methodology can affect the results. Therefore, the measurer should carefully follow the test protocol . The 6MWAlthough weight loss has been widely studied, we still do not understand all the aspects of weight loss. Therefore, in the future, it would be important to study the factors considered essential for cardiac or obese rehabilitation to help maintain motivation for weight loss. Social support and the amount of technology used are relevant to the effectiveness of an intervention ,66. TherThis study demonstrated that remote cardiac rehabilitation added value to conventional cardiac rehabilitation in terms of waist circumference and environmental QoL; however, the results were clinically relatively small. There were no statistically significant differences between the remote technology intervention and reference groups in the 6MWT; body mass; BMI; and physical, psychological, and social domains in the WHOQOL-BREF. These findings support the idea that adding remote technology to cardiac rehabilitation may improve beneficial health outcomes. There was some level of systematic (blinding and selection bias) error during the rehabilitation intervention and samples were relatively small; care must be taken in generalizing the study results beyond the target population. To confirm the assumptions of the added value of remote technology in rehabilitation interventions, more randomized and controlled follow-up studies involving rehabilitees with different cardiac rehabilitation are required.