This scoping review aimed to establish the approaches employed to improving patient safety in integrated care for community-dwelling adults with long-term conditions.Scoping review.All care settings.Systematic searches of seven academic and grey literature databases for studies published between 2000 and 2021. At the full-text review stage both the first and second reviewer (SW) independently assessed full texts against the eligibility criteria and any discrepancies were discussed.Overall, 24 studies were included in the review. Two key priorities for safety across care boundaries for adults with long-term conditions were falls and medication safety. Approaches for these priorities were implemented at different levels of an integrated care system. At the micro-level, approaches involved care primarily in the home setting provided by multi-disciplinary teams. At the meso-level, the focus was on planning and designing approaches at the managerial/organisational level to deliver multi-disciplinary care. At the macro-level, system-wide approaches included integrated care records, training and education and the development of care pathways involving multiple organisations. Across the included studies, evaluation of these approaches was undertaken using a wide range of process and outcome measures to capture patient harm and contributory factors associated with falls and medication safety.For integrated care initiatives to fulfil their promise of improving care for adults with long-term conditions, approaches to improve patient safety need to be instituted across the system, at all levels to support the structural and relational aspects of integrated care as well as specific risk-related safety improvements. Highlighting how key components of integrated care can also improve patient safety across care boundaries particularly in reducing falls and medication safety management.Another strength of the study was the rigorous approach to scoping and selecting the literature including the comprehensive searching of several academic and grey literature databases and sources.Nonetheless, the identification of relevant studies was possibly hindered by the lack of consistency and interchangeability of the terms ‘integrated care and patient safety’ and their use in the literature.While the review was able to identify the different types of patient safety approaches (scope) it was more challenging to describe their scale across care boundaries.Health and social care systems globally are facing the challenges of an ageing population with complex comorbidities that require multi-faceted care provision to better manage their health and care needs.7The WHO defines patient safety as ‘the absence of preventable harm to a patient during the process of healthcare and reduction of risk of unnecessary harm associated with healthcare to an acceptable minimum’.Integrated care may contribute to improving the safety of care for people with long-term conditions at different levels of the system, particularly by addressing the risks posed by multiple referrals, handovers and discharges that arise as the responsibility for care crosses care boundaries and involves different practitioners, teams, organisations and systems.Integrated care initiatives encourage care provision closer to home that is, in the community setting which are safer environments compared with hospitals.16 17A handful of conceptual models of integrated care have been described in the literature. One such model suggests integrated care has a supporting role at all levels of the system, micro (services), meso (organisations) and macro (systems).19Initial scoping of the literature on how safety is improved for adults with long-term conditions in integrated care revealed a limited evidence based on the scale and scope of safety approaches implemented in integrated care systems. As the relevant literature to address this issue was likely to be extensive, complex and potentially heterogeneous, a scoping review was selected over a systematic review.This scoping review was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses Extension for Scoping Reviews guidance.The scoping review explored the breadth of literature to answer the research question, ‘What type of integrated care approaches exist at different system levels to improve patient safety for community-dwelling adults with long-term conditions and how have they been assessed?’.Free text search terms were developed based on our research question. The search term strategy  was broa10.1136/bmjopen-2022-067441.supp2Supplementary dataA comprehensive search strategy was employed to include both the peer-reviewed and grey literature. Seven electronic databases were searched including MEDLINE, Social Policy and Practice, Web of Science, CINAHL, Google Scholar, Proquest and OpenGrey. These were supplemented by forward and ancestry citation searches using reference lists of several relevant studies.Study selection was based on the inclusion and exclusion criteria listed in The first reviewer (ML) undertook initial searches and based on information in the title and abstract selected those meeting criteria for full-text review. At this stage, any studies that the first reviewer was uncertain about in terms of meeting eligibility criteria were checked by the second reviewer. At the full-text review stage both the first and second reviewer (SW) independently assessed full texts against the eligibility criteria and any discrepancies were discussed.The first reviewer extracted and tabulated the data from the included studies in Microsoft Excel. Details of the studies extracted included the overall aim, population, study design, level of system, integrated care approach, setting and approach to measuring safety. The second reviewer reviewed and verified the data extraction table. Descriptions of the levels of the system, that is, micro, meso and macro and the approach to measuring safety Box 1Levels of care systemMicro-level: typically comprises an approach at the patient level where multiple professionals from different types of organisations provide care commonly in the home setting but sometimes in primary care alone or in primary and secondary care if linked by a common pathway.Meso level: approaches at organisation level that involve multi-professionals in planning or designing local structures, care pathways and services that span two or more different types of organisations.Macro level: system wide approaches that may involve several providers with a typical focus on strategy, infrastructure development such as shared care records and other wide-ranging cultural and educational initiatives. Approaches implemented over a wider a geography within a country, for example, region, county, state, etc.Approaches to measuring safetyOutcome measures: indicate the impact of a healthcare service or approach on the patient’s health status.Process measures: practices delivered in order to achieve the desired outcome of an approach.Qualitative outcomes: perspectives of study participants on the implementation and/or impact of an approach .Due to the heterogeneity of the studies in terms of their methodological design, settings in which an approach was implemented as well the design and scope of the approach itself, and in line with similar scoping reviews, formal quality assessment was not undertaken.25 26No patients or members of the public were directly involved in this work. However, this study is part of a wider programme of research for which there is a research advisory group whose membership includes patients/public representatives. In the conceptualisation phase of the study, the research advisory group provided advice and guidance on the study’s aims and purpose.The original searches yielded 2957 records. After removing duplicate records and screening of titles and abstracts, 86 were allocated for full-text review. After application of eligibility criteria, 24 studies were included in the review. The flow of studies from initial identification to final inclusion are presented in All included studies were published between 2007 and 2019. We identified 1 review10.1136/bmjopen-2022-067441.supp1Supplementary dataOf the 24 included studies, 11 involved approaches designed to reduce falls risk,15The studies included a range of settings. A total of 13 studies described approaches implemented in a single setting involving a group or team of professionals from different sectors; the home setting27 33 40 43Various approaches were implemented at different levels of the care system; micro, meso and macro. Ten studies were at the micro-level,At the micro-level, approaches were characterised by the delivery of person-centred coordinated care for adults with long-term conditions involving the home (community) setting or primary care setting alone or as part of a care pathway with secondary care settings. Care was provided by a range of health and care professionals working together. Three studies outlined multi-disciplinary approaches to prevent and reduce falls, primarily in the home setting such as exercise therapy, home-based assessments for hazards with accompanying modifications, vision assessment, home medication review and a 24-hour call service staffed by a home intervention team.34 38 49et al focused on the development of a multi-disciplinary care pathway following a hip fracture.37A further five studies described approaches implemented across different parts of a care pathway to reduce falls, although Wallace Three studies involved medicines reviews to reduce the risk of adverse drug events (ADE) including the reduction of falls.31 42 45At the meso-level approaches were mainly focused on multi-professional management to plan and design services across at least two different types of organisation, primarily hospitals and community care. Approaches tackled areas with overarching safety risks such as poor communication or dispersed leadership. All five studies used different approaches.et al described an MDT approach involving medication reviews, home fall risk assessments and blood pressure monitoring.31Three studies aimed to improve medication safety for older people. One study employed an Integrated Medicines Management model  which comprised medicines reconciliation and review, patient counselling on medicines usage during hospital stay and greater provision of information and communication with primary care at discharge and postdischarge.A further study, outlined a multi-disciplinary falls committee (within a newly created integrated care system) whose role was to provide leadership, direction and coordination to frontline staff promoting new evidence based practices and QI support to prevent falls.15At the macro-level, system-wide approaches centred on managing medication safety and reducing falls risk such as key infrastructure developments—integrated care records, training and education initiatives spanning several organisations within a system and creating care pathways involving multiple organisations. Approaches were generally implemented across a wider geography, for example, county, state or region.Three studies described digital approaches to medication safety monitoring such as a digital database for patients transitioning from secondary to primary care with indicators to alert practitioners to potential ADE39Two studies described educational approaches comprising training of inter-professional teams  from a range of settings on developing strategies for preventing falls in accordance with national evidence-based guidelines.27 28The remaining studies described multi-component models such as QI collaborative approaches, or other models comprising multi-disciplinary working, care coordination and strategies to strengthen leadership to promote patient safety and reduce hospital admission or readmission. The QI collaborative aimed to reduce the risk of ADE and involved MDTs with professionals from primary and acute care who adopted a change package involving clinical pharmacy services47Of the 23 empirical studies, the majority included a multi-disciplinary approach to care provision involving different health professional groups. Four of the approaches also included social workers as part of the team.There was heterogeneity in the approaches to measuring safety. We categorised measures as process, outcome or qualitative.Two studies included process measures alone. The first involved the monitoring and surveillance of medication safety including the proportion of older patients prescribed falls risk medication, and the proportion of medicines prescribed that have a high potential for major drug interaction.28In 11 studies, outcome measures alone were mentioned. Four of these studies stated falls incidence during follow-up over a period of 6–12 months43Six studies included both process and outcome measures. Process measures associated with falls included adherence to falls prevention strategies, proportion of falls risk assessments undertaken, documenting of falls and medical history risk of falling, and level of independence in activities of daily living.Process measures associated with medication safety comprised medication appropriateness and use of harmful medications.15The remaining studies described qualitative outcomes for the integrated approaches i.e. based on the perceptions of study participants. These included assessing approaches designed to prevent falls such as the perceived usefulness of an MDT home-based fall prevention programme.39This scoping review brings together the published literature on approaches to improve patient safety in integrated care for community-dwelling adults with long-term conditions and demonstrates the range of approaches employed in safety improvement strategies for care across boundaries within several countries. The approach identified in the included studies focus primarily on two common patient safety targets for harm, falls and ADE through falls prevention and medication safety programmes spanning micro, meso and macro levels of a health and care system. Just over a third of the included studies involved the implementation of system-wide approaches (macro-level) such as digital shared care records, training/educational initiatives and the strengthening of care pathways between providers. A higher proportion (40%) of studies described micro-level approaches, primarily MDT delivering care to older people in the home setting alone or as part of a care pathway involving hospitals and primary care. The review also highlighted that the evaluation of approaches indicated a perspective of safety focused primarily on measurement—changes in rates of adverse events or contributory factors at individual patient level.A key strength of this study was the highlighting of how key components of integrated care can also improve safety across care boundaries particularly in reducing falls and medication safety management. Instituting integrated care practices at the different levels of a care system, for example, digital shared care records (macro), strengthening of care pathways  and promoting MDT working (meso and micro) will strengthen safety approaches and reduce the risk of harm across an integrated care system. The study findings also highlight how in some cases MDT working, particularly in community care does not directly involve doctors. This reflects an increasing trend in some Western European countries where integrated community care teams (without doctors) are primarily responsible for care provision in the home setting for older and/or frail patients with complex care needs, partly promulgated by the extension of roles of community care professionals and a shortage of primary care doctors.The study was not without limitations. Articulating a precise definition for patient safety was challenging, as, in several studies, the term was associated with preventing hospitalisation. Hence, we selected the WHO definition which is broad ranging and encompasses the notion of errors of commission and omission. Nonetheless, the identification of relevant studies was hindered by the lack of consistency and interchangeability of the terms ‘integrated care and patient safety’ and their use in the literature. We may have screened for word choice rather than presence or absence of a similar term or its description. Despite including a range of search terms associated with patient safety some studies may have been missed. Our search strategy did not include social care as a specific search term, although integrated care including care coordination and multi-disciplinary working increasingly involves social care professionals. We also did not search for ‘person-centred care’ or ‘self-care’ both of which are potentially effective risk management strategies. This may explain why we were unable to identify any studies reporting the experience of patients/carers. The nature of our search did not lead to papers that talked about implementation of structures or their measurement and hence we only included process and outcome measures. While the review was able to identify the different types of patient safety approaches (scope) it was more challenging to describe their scale across care boundaries.Integrated care initiatives identified in this study involved the design of a range of new structures and processes to support the delivery of safer care, although further work is required to establish their effectiveness in improving patient safety. Integrated digital care records have been cited as a key enabler for structural integration in integrated care systems as they promote sharing of information thus minimising the risk of care-related information being overlooked as people (particularly older and more frail) move along a care pathway.19 54The levels of the system  approach to identifying integrated care and patient safety approaches presented in this study provides a useful means of understanding how organisations can implement change, improvement and innovation across an integrated care system. At the macro-level, the implementation of integrated care records to collate information and support communication alongside the promotion of a learning culture supported by inter-professional training and education is required. At the meso-level, the focus would be on organisations jointly planning and designing multi-disciplinary approaches to develop seamless care pathways, minimising the risk of harm as people transition between providers. At the micro-level, a range of multi-disciplinary working practices to improve safety could be deployed from near real time safety monitoring within ‘community huddles’ to protected time sessions to compare and reflect on performance across teams promoting longer-term changes.19The studies included in this review evaluated falls reduction and medicines safety approaches using clinical process and outcome measures with several authors looking at associations between these outcomes and wider health system outcomes, for example, hospital (re)admissions and length of stay. System outcome measures have been widely used as performance indicators to assess the impact of integrated care.60 61A wide range of process and outcome measures were used across the studies predominantly to capture patient harm and contributory factors. Expanding measurement to incorporate the capture of the variation in performance of key processes that lead to desired outcomes, would not only identify the most effective approaches for improving patient safety but also open up a wider range of options to support building resilience across and integrated care system.Safety approaches in this review were mainly focused on medication safety management and falls prevention which is unsurprising as both account for a notable proportion of unplanned hospital admissions. In England, in 2018 falls accounted for a total of 220 160 hospital admissions in those aged over 65 years. A study of medication errors in the UK estimated that ADE accounted for 27 362 hospital admissions annually, relating to 136 811 bed days at a cost of £83.7 million to the National Health Service.64 65Future research should focus on the role of other patient safety targets  such as healthcare associated infections, community acquired infections and pressure ulcers/sores which also increase the risk of harm for people with long-term conditions especially in the community setting. Furthermore, research must establish the effectiveness of the structural and relational aspects of integrated care such as care coordination as well as the approaches identified in this review, for example, integrated care records and education and training, in terms of their impact on reducing the risk of harm across care pathways. This would provide the evidence for policymakers and system leaders to implement the necessary changes to support integration, safety governance and service improvement.In order to maximise the potential for to fulfil their promise of improving care for people with long-term conditions, approaches such as integrated care records, allocating resources for training and education, greater efforts to form robust and risk-limited care pathways as well as support for MDT working, especially in the community setting will have to be key priorities for improving safety across systems. They also align to the goals of by reducing fragmentation and enhance personalisation of care. Such a focus would ensure that integrated care reaches its full potential as an enabler of safety supporting risk management and personalisation of care for people with long-term conditions.


Mental health problems are common among men who have sex with men (MSM) living with HIV and may negatively affect medication adherence. Psychosocial interventions designed to address these urgent needs are scarce in China. Incorporating behavioral health theories into intervention development strengthens the effectiveness of these interventions. The absence of a robust theoretical basis for interventions may also present challenges to identify active intervention ingredients.This study aims to systematically describe the development of a mobile health–based intervention for MSM recently diagnosed with HIV in China, including the theoretical basis for the content and the considerations for its technological delivery.We used intervention mapping (IM) to guide overall intervention development, a behavioral intervention technology model for technological delivery design, and a human-centered design and cultural adaptation model for intervention tailoring throughout all steps of IM.Turning to Sunshine, comprised 3 components: app-based individual skills learning, group-based skills training, and on-demand phone coaching. The theoretical basis for the intervention content is based on the DBT model of emotions, which fits our conceptualization of the intervention user’s mental health needs. The intervention aims to help MSM recently diagnosed with HIV (1) survive moments of high emotional intensity and strong action urges, (2) change emotional expression to regulate emotions, and (3) reduce emotional vulnerability, as well as (4) augment community resources for mental health services. Technological delivery considerations included rationale of the medium, complexity, and esthetics of information delivery; data logs; data visualization; notifications; and passive data collection.The dialectical behavior therapy (DBT)–informed intervention, Turning to Sunshine, aims to improve mental health outcomes for MSM newly diagnosed with HIV in China. The IM framework informed by human-centered design principles and cultural adaptation considerations offered a systematic approach to develop the current intervention and tailor it to the target intervention users. The behavioral intervention technology model facilitated the translation of behavioral intervention strategies into technological delivery components. The systematic development and reporting of the current intervention can serve as a guide for similar intervention studies. The content of the current intervention could be adapted for a broader population with similar emotional struggles to improve their mental health outcomes.This study laid out the steps for the development of a DBT-informed mobile health intervention that integrated app-based individual learning, group-based skills training, and phone coaching. This intervention,  Approximately 38.4 million people worldwide live with HIV . Men whoHealth behavior theories and models play an important role in guiding the development of behavioral health interventions . Theory-Behavioral health interventions delivered on mobile platforms  such as mobile apps have the advantage of higher accessibility and potential for scalability, with the flexibility to be used independently or adjunct to other health services . In addiThe tailoring and adaptation of behavior change techniques and delivery to the target population is a critical step in the development of mHealth interventions. A community-engaged research approach harnesses the expertise of community stakeholders and emphasizes mutual learning and shared decision-making between the community and academic researchers. In health disparities research, this approach enables researchers to gain a deeper understanding of the determinants of health at individual and contextual levels . In digiContextual factors need to be considered early in the formative stage of intervention development to inform adaptation and tailoring to the target population . The fieIn this paper, we illustrate (1) the steps of IM that guided the development of the current intervention; (2) the design of technological features for delivery components using the BIT model; and (3) how content and delivery were tailored using HCD principles, cultural adaptation of evidence-based psychotherapy, and a community-based participatory approach.This section focuses on reporting the theory-based rationale underlying the intervention development process. The details of co-design and usability testing are mentioned when relevant to the intervention rationale. A full report of the procedure and results of the co-design and usability testing sessions is underway and will be published elsewhere.The intervention development followed the steps outlined in the IM protocol, including step 1—conducting a needs assessment, step 2—determining the intervention goals and objectives, step 3—selecting intervention and behavior change methods, and step 4—designing and developing program materials .Needs assessment was the first step of IM. We conducted one-on-one stakeholder interviews with MSM living with HIV (n=15), staff at Shanghai Municipal Center for Disease Control and Prevention , and Shanghai China Sex Worker and MSM Center  to identify unmet mental health needs guided by stress and coping theory as well as a socioecological framework. The inclusion criteria for MSM living with HIV were as follows: (1) being aged ≥18 years, (2) being HIV positive, (3) having engaged in sex with a man in their lifetime, (4) having already started antiretroviral therapy, and (5) having access to the internet. Moreover, participants filled out the Patient Health Questionnaire–9 and were included if their score was <15 . The inclusion criteria for staff members at SCDC and SCMC were as follows: (1) being aged ≥18 years and (2) working with individuals living with HIV.The interview questions are presented in Tell me about the process of getting the diagnosis. How did you feel the moment you received the positive diagnosis? How did you contract HIV? Who informed you? How did they inform you? How did you react? How did that make you feel?How has HIV impacted your life, especially in the first few months of receiving the diagnosis? How was your mood and emotional status overall? What did you do to feel better? How did it work out (helpful or not helpful)?Describe problems or difficult situations related to HIV. Tell me how you approached it, what happened next, and what was the outcome? How did you feel about the outcome?What support have you received from Shanghai China Sex Worker and Men Who Have Sex With Men Center? What support did you not get but would like to have?Looking back, is there anything that you wish you had done differently to deal with the situation better?An intervention matrix was developed as a result of step 2 to represent the overall program goals , performance objectives , and change objectives . In the intervention matrix, the performance objectives in each row intersected with the behavioral determinants in each column to generate change objectives in each cell. The performance objectives were selected based on needs assessment results and relevant theories . The selection of behavioral determinants was guided by the model of behavior  and behavior change models (Behavior Change Wheel [BCW]), as well as the relevance of the constructs to this study . The intThe BIT model aims to facilitate the design of technological features that maximize the impact of the behavioral intervention. This framework integrates the theoretical why  and how  with the technological what , how , and when . This study used the BIT framework to promote the synergistic relationship between intervention content, delivery methods, and technological design. The integration of IM and BIT in this study aimed to translate the intervention objectives and strategies into app features by guiding design considerations of the digital delivery platform.HCD places users’ needs and preferences at the center of attention when designing a service or product, drawing from human-computer interaction, service design, and cognitive psychology. Other important HCD principles include (1) involving users in the design process and critical design decision-making, (2) aligning the product with users’ needs, and (3) incorporating user feedback into the design-prototyping iterative process to improve user experience gradually . The genFor the purpose of this project, we used the following HCD strategies to tailor our intervention strategies to users. Cultural adaptation of evidence-based treatment or intervention refers to modifications of the protocol to improve the compatibility of the treatment or intervention with individuals’ cultural background, which includes but is not limited to cultural values, practices, beliefs, and preferences . The EVFThe adaptation of evidence-based psychotherapy techniques considers therapist characteristics , therapeutic elements , and delivery setting (location and method of access) . Most psThis work was guided by community stakeholders and expert consultation. The first author, a predoctoral trainee in clinical psychology, led the intervention development with extensive engagement with community partners and consultation with content experts. We established partnerships with SCDC and SCMC to gain a deeper understanding of the community’s needs and priorities. SCDC and SCMC collaboratively provide services such as postdiagnosis consultation, in-person gatherings, and phone call follow-ups to assist individuals in transitioning to living with HIV. The researchers drew upon input from community partners in project planning, conceptualization, data collection, and manuscript preparation. One SCDC and 1 SCMC staff member were consulted through biweekly meetings throughout the study period to seek feedback and make timely adjustments to the study protocol. The intervention content outline was first presented to our SCDC and SCMC partners, after which SCMC staff (n=6) were gathered for a feedback session after the intervention content was created. The details are reported elsewhere.All study participants in the needs assessment, co-design sessions, and usability testing provided informed consent before enrollment in the study. Data were deidentified to protect participants’ privacy. All participants received compensation (20 USD) for their time and contribution to the study. This study was reviewed and approved by the institutional review board of the University of Washington (STUDY00011948).We describe the development of the current mHealth intervention following the four steps outlined in the IM framework: (1) conducting a needs assessment, (2) determining intervention goals and objectives, (3) selecting intervention and behavior change methods, and (4) designing and developing program materials. The results of each IM step also incorporated insights obtained from HCD principles and cultural adaptation dimensions to demonstrate the rationale behind intervention tailoring. In IM step 4, the BIT model was presented to describe the technological delivery of the intervention.Overall, we found that stress from multiple sociological levels interacted with each other and produced compounded effects on the psychological struggles among MSM living with HIV. MSM living with HIV reported being overwhelmed by emotional turbulence upon receiving a positive diagnosis. They reported prolonged distressing HIV-related thoughts and emotions as they adjusted to living with HIV. However, these mental health needs were largely unmet and sometimes led to destructive and maladaptive behaviors  and prolonged distress . Individuals lacked the skills to regulate distressing emotions and thoughts and relied heavily on close relationships for support. Those who did not have support from friends or family mainly used self-help books and mental health apps  to cope with their emotional pain. Individuals reported a lack of mental health support from the community organization. Services at SCMC and SCDC focused on linkage and engagement with HIV-related care. The staff provided occasional check-ins and organized peer support groups but felt ill-equipped to provide appropriate mental health services. Both MSM living with HIV and staff at SCDC and SCMC recognized the mental health needs and the service gap.On the basis of the needs assessment results, implications for multiple-level intervention development were reported by L Wang , including (1) individual coping skill training on emotional difficulties  to improve mental health outcomes, (2) peer or lay provider training to increase community mental health resources and support, (3) leveraging role models to reduce internalized HIV-related stigma, and (4) disclosure interventions to increase friend and family support.The intervention goals were determined based on the results of the needs assessment. The intervention objectives were then specified using relevant theories and results from the co-design sessions.The program goals are listed in the first column of Performance objective refers to the behaviors that each intervention user needs to perform to reach the overall program goal. We modified this definition to incorporate the community organization given the existing service structure and the importance of community support to MSM recently diagnosed with HIV. The results from the needs assessment, the DBT model of emotions, and co-design sessions informed the identification of performance objectives .The needs assessment revealed the emotional struggles among MSM living with HIV, with intense emotions immediately after diagnosis and chronic emotional distress. Recognizing the difficulties regarding coping with emotions and their implications for long-term mental health, we decided to use the DBT model of emotions to guide our understanding of emotions and identify behaviors that individuals can perform to address emotion regulation difficulties . The DBT model of emotions offers a framework to understand emotional responses and outlines concrete skills to regulate emotions to reduce the risk of developing mental health problems, decrease their negative consequences, and improve global functioning ,38.According to the DBT model of emotions, emotional responses are systemic responses that include the following subsystems: (1) emotional vulnerability, (2) prompting events , (3) interpretation of the prompting events, (4) biological changes and experience of emotions , (5) verbal and nonverbal expression of emotions, and (6) aftereffects of emotional response . The subsystems are interactive so that the overall emotional response can be modified by changing 1 or more of the components of the system.The co-design sessions further revealed that the number of coping strategies for high–emotional intensity situations (n=19) was smaller compared with that of strategies for lower–emotional intensity situations (n=26). In addition, substance use, such as smoking and drinking alcohol, emerged as a coping strategy, especially for situations with high emotional intensity. For example, in one of the co-design sessions, both participants mentioned that they drank when they felt overwhelmed by high-intensity emotions. Regardless of the emotional intensity levels, the most commonly used strategies by participants were distraction , talking with trusted friends or family, problem-solving, and exercise. Spending time alone was the most frequently mentioned coping strategy when they felt overwhelmed by emotions. In summary, the co-design sessions suggested limited skills regarding emotion regulation, especially skill deficits in coping with high emotional arousal.On the basis of these results, we selected three components from the DBT model of emotion to derive performance objectives: (1) biological changes and experience of emotions , (2) verbal and nonverbal expression of emotions, and (3) emotional vulnerability given its broad implications for other subsystems. Survive moments of high emotional intensity and strong action urgesEmotions are accompanied by biological changes and action urges. For example, fear is often associated with the activation of the sympathetic nervous system, which increases our heart rate, leads to sweating, enlarges the size of our pupils, and leads to the active urge to fight or flight. In a crisis situation, such as the moment of receiving the positive diagnosis, the emotional intensity is high, and the emotional pain can be overwhelming. The related performance objective is to survive the crisis and tolerate the pain and distress without acting on destructive urges .Change emotional expression to regulate emotionsEmotional expression includes facial expressions, body language, and behaviors. For example, sadness is often expressed through eyes dropping, not smiling, sobbing, and a quiet and monotonous voice.Changing emotional expression can lead to changes in emotions as well. When the emotional intensity is not as extreme, such as when taking medication every day reminds individuals of their diagnosis, the effective use of emotion regulation skills can help reduce emotional pain. The related performance objective is to change emotional expression to regulate emotions .Reduce emotional vulnerabilityVulnerability factors increase individuals’ sensitivity to a prompting event, may lead to biased interpretations of the event, and may increase the intensity of biological reaction and expression. Vulnerability factors may include lack of sleep, hunger, influence of substances , or a series of negative life events. When these vulnerability factors are modified, the emotional response or the intensity of that response can change. Thus, the related performance objective is to reduce overall emotional vulnerability.Regarding the program goal of promoting community and structural mental health support, the performance objective was to create a structured environment to support individuals’ learning. Learning behavioral skills is especially challenging when the person does not receive reinforcement from a supportive environment for such learning . In mHeaIn summary, to reach the overall program goal, the individual- and community-level performance objectives need to be attained, as listed in the second column of We determined the change objectives of the intervention program based on the aforementioned performance objectives and the behavioral determinants delineated by the COM-B model of behavior, including capability, motivation, and opportunity . Table 3The COM-B model connects the model of behavior directly with intervention functions that can target one or more behavioral determinants through the BCW . Thus, tSelecting appropriate intervention functions to fit the characteristics of the target population and contextual features could optimize the effectiveness of the intervention ,41. ThusEducation: knowledge and understanding of emotion can increase psychological capability, and the rationale behind and benefits of emotion regulation can enhance the reflective motivation for the participants to learn skills.Training: learning and practicing cognitive and behavioral skills both individually and in a group setting can help participants gain psychological capability.Enablement: a skills group and SCMC phone coaching can guide the participants to select and practice appropriate skills, especially in a situation with high emotional arousal; in addition, staff and app-assisted goal setting, monitoring, and timely feedback are reinforcers of behavior change.Modeling: the skills group training environment provides ample opportunities for imitative learning and role modeling.In summary, the intervention will use education, skills training, enablement, and modeling to target the capability, motivation, and opportunity of behaviors to reach the performance goals described in the previous step .The intervention program includes 3 components: individual skill learning using the mobile app, accompanied by a skills group, and on-demand phone coaching. This overall program design is informed by the results from co-design sessions and the elements of DBT treatment programs.The rationale for each intervention component is as follows:App-based individual skills learning: emotion regulation and coping skills were highlighted by the participants regarding the content of the program that they would like to receive. They preferred the content to be tailored to the needs of the HIV-positive community. They emphasized that the content needs to have credibility while using language that could be easily understood by a general public without much mental health background. Each individual skills-learning module is followed by a quiz to reinforce learning and increase engagement.Group-based online skills training facilitated by SCMC staff: the skills training group was perceived by participants as efficient in providing low-intensity mental health support in which the shared experience was perceived to increase their ability to empathize with one another. SCMC staff has established trusting relationships with HIV-positive MSM and was perceived as a trusted resource for HIV-related information. Compared with in-person groups, web-based groups have the unique advantage of protecting participants’ privacy.On-demand phone coaching: phone coaching was incorporated to meet higher needs for mental health support, especially in the early stages after HIV diagnosis.quan ran) accordingly rather than being translated verbatim as “全然” (ji jin), which means extreme. We also used culturally relevant metaphors, stories, and skill practice examples that resonated with HIV-positive individuals to design the intervention content. Examples of adaptations in other dimensions are shown in The cultural adaptation of the DBT skills was based on the EVF, including the following dimensions: language, persons, metaphors, content, concept, goals, method, and context . For exaOn the basis of the previous steps of IM and co-design sessions (see steps 2-3), the content of individual skill learning includes the following modules and is delivered in the form of podcasts over the course of 5 weeks: (1) psychoeducation of emotions: the process of emotion response, types of emotions, emotional intensity, and functions of emotions; (2) how to increase tolerance of distress and get through a crisis situation; (3) how to accept reality and relieve emotional suffering; (4) how to regulate emotions through change behaviors and how to reduce overall emotional vulnerability; and (5) summary of all skills and highlights of takeaways.The 5 weekly group-based skills training sessions are parallel to the individual skills learning on the app. Program users will first learn the content on the app each week before attending the weekly skills groups (3-5 group members) facilitated by trained SCMC staff. In the skills group, the topic of each skills training session is the same as the content covered by the app in a given week. The skills group will have an onboarding meeting (1) to orient the group members to the purpose of skills training, introducing the skill deficit model of emotional and behavioral dysregulation and outlining the content covered in this intervention; (2) to introduce the group format and guidelines, including the roles of the skills trainer  and the group members; (3) for group members and SCMC staff to get to know each other; and (4) for individual group members to share their personal goals through this intervention, including behaviors to reduce and skills to increase.The skills training group structure was adapted from the standard DBT skills training. The weekly session lasts approximately 1.5 hours and comprises the following components: (1) mindfulness practice (5-7 min), (2) summary of the skills covered by the app in the week before this session (5-10 min), (3) homework review (45 min), (4) preview of the following week’s content (5-10 min), and (5) assignment of a worksheet (to practice the learned skill on a given week) for the following week and goal setting for the following week (5 min).The homework aims to help program users identify opportunities in their day-to-day lives. The content of each homework assignment was designed to match the skills learned on a given week. For example, in the week in which individuals learn distress tolerance skills, their homework will guide them to describe a situation in which their distress was high, note down their distress level before and after skill practice, and reflect on how well it went and areas for improvement.The purpose of the skill group is to provide a supportive environment at the community level for peers to learn and practice skills together through peer and SCMC staff modeling. The group members will take turns to share how they practiced the skills during the week, and the rest of the group members and the SCMC staff will provide validation and constructive feedback. If the individual encounters any problems with applying the skills on their own, the group will help the individual problem-solve and provide constructive feedback as needed. The norm of attending groups regularly and practicing skills between sessions established through the skills group can motivate people who conform to this norm and increase their probability of practicing skills between sessions. This allows group members to interact with people with similar struggles, and the development of a validating and supporting environment is therapeutic for all members. Stickers will be given out to those who attend the skills group and practice skills that week .Adapted from the DBT skills training group guidelines, the skills group guidelines serve as a structure that outlines a set of behaviors and principles that group members are expected to follow while in the skills group:Participants in the skills training group support each other by preserving confidentiality, attending groups regularly, validating others, practicing skills in between sessions, providing noncritical feedback, and opening up to receive help from other group members or SCMC staff.Participants need to call ahead of time to let the SCMC staff know if they are going to be late or miss a session.Participants need to be aware of how dysfunctional behaviors such as self-injury and substance use are discussed in the group given that others may be influenced to engage in these behaviors. The mention of these behaviors should be brief and the focus should be on skills practice or problem-solving around the behavior.To prevent interpersonal conflicts from complicating the group dynamic, participants can obtain the contact information of other group members and form supportive peer relationships outside the group after completing the study period.In addition, the same SCMC staff trained to facilitate skills groups will be available for on-demand between-session skills coaching via phone call or SMS text message to help participants identify and practice skills in difficult situations and get through crisis situations when emotional pain is intense and dysregulated behaviors may occur as a result. It is common for individuals to have difficulty asking for help. Some contributing factors may be not being aware of the situations in which they might need help, failing to ask for the type of help they need, or asking for help indirectly . Phone coaching enables the SCMC staff to cultivate individuals’ ability to effectively ask for help, provide feedback, and help problem-solve with ineffective help-seeking skills.The general goals of phone coaching are (1) skills generalization, (2) validation of participants’ need for contact, (3) intervention on suicidal behavior (skill use and problem-solving), (4) crisis coaching (shaping them to context and using skills before the problem behavior occurs), and (5) contingency management.The general guidelines for phone coaching include the following:Validate and reinforce skillful help-seeking behaviors, such as clearly stating the situation, what they have tried, and what they need more help with.Generally focus on how to use skills to prevent rather than manage a crisis when it occurs so that the frequency of phone coaching will reduce over time.Keep the phone coaching session to between 5 and 15 minutes and use a directive communication style given the limited time.Decrease crisis behaviors, increase skill generalization, and reinforce effective skill use.We used the BIT model to guide the design and report of the technological delivery of the intervention, including elements, characteristics, and workflow . The eleWorkflow refers to the user’s interactions with the app to receive the intervention . The mobThe hierarchical design of the home page presents all features and content of the app to the user in a top-down organization. Users will be taken through intervention modules following the tunneling design, where a step-by-step flow helps users navigate through the modules. The user has access to all the completed modules in a matrix design. The combination of these information architecture designs can achieve the following goals: (1) the hierarchical presentation of the home page is familiar to most users and provides a dashboard for all tasks and content; (2) tunneling optimizes the ordering of information delivery and, thus, intervention effectiveness and titrates the information presented to the user to reduce information anxiety; and (3) the matrix design allows for flexibility in accessing content ,43.This study illustrated the development of a DBT-informed intervention that integrated app-based individual skills learning, group-based skills training, and phone coaching to improve mental health outcomes for MSM recently diagnosed with HIV in China.We used interdisciplinary theoretical frameworks and approaches, including behavioral science, clinical psychology, human-centered principles, and behavioral intervention technological delivery. Specifically, we used the IM protocol to guide the conceptualization of program goals and intervention development. The DBT model of emotion and emotional regulation skills informed the specification of performance objectives. The COM-B system of behavior and BCW further connected the performance objectives to intervention functions and strategies. Although the aforementioned theories informed the conceptual specification  of the behavioral intervention, the BIT model guided the technological delivery  of this intervention. The user-centered principles and strategies, as well as cultural adaptation considerations, were applied throughout all steps of intervention development to tailor behavioral components and technological delivery to the community.Complex decision-making is involved in all steps of the development of interventions that aim to solve a specific health problem. This study presented a detailed intervention rationale that outlines the theoretical reasoning and behavior change mechanisms behind each intervention component. This is critical to the analysis of the active intervention ingredients in the subsequent feasibility and efficacy trial. A thorough understanding of the effects of each intervention component will aid future efforts to adapt and improve the intervention. In this study, we used the DBT model of emotion to understand the emotional difficulties and social and behavioral consequences revealed in the needs assessment stage. By mapping emotional difficulties from low to high emotion intensity, we determined the subsystems of emotion to intervene as our performance objectives, including reducing high emotional arousal, changing emotional expression to regulate emotions, and reducing emotional vulnerability. To achieve these performance objectives, we selected education, skills training, enablement, and modeling as the key intervention functions to affect capability, motivation, and opportunity of behaviors guided by the COM-B system and the BCW. The DBT treatment model of individual therapy, skills groups, and phone coaching then informed the operationalization of behavior change methods. There is growing evidence supporting the effectiveness of theory-based behavioral interventions . IM offeIn addition to theoretical considerations, this study also engaged community members and targeted users throughout development using user-centered design principles and strategies. The needs assessment with community members played an important role in determining the multilevel program objectives of this intervention, including individual skills learning and community-level capacity building. Staff training is an inherent component of this intervention to prepare the SCMC staff to facilitate skills training groups. Intervention testing and long-term sustainability hinge on a set of contextual limitations. Therefore, it is especially important to involve both intervention users and community partners in decision-making regarding intervention design to optimize feasibility, such as the length of the intervention, the intensity of staff training, and organizational support for staff to participate in the intervention study. The co-design sessions prompted community members to generate solutions to emotional difficulties  and brainstorm services and intervention design . This co-design process naturally incorporated the cultural adaptation considerations of DBT skills, including persons delivering skills training groups, metaphors and examples used in skills training materials, the use of existing cultural idioms to communicate DBT concepts, the method of using groups to complement app-based individual skills learning to reduce HIV- and mental health–related stigma, and the use of staff-delivered phone coaching to enhance effective skill generalization. The behavioral elements of this intervention went through iterative rounds of design and development through community engagement and consultation with experts to ensure appropriate translation of clinical and behavioral science into user-centered and practical intervention strategies. Many interventions developed by academic researchers have been mainly based on evidence from the literature and could benefit from end-user input early in the formative stage. The cycle from development to a randomized controlled trial for efficacy takes years, and more time is needed to transition to the effectiveness and implementation stage. A community-engaged and user-centered approach enables the research team to align their research goals with users’ needs and conduct iterative and rapid revisions to increase the contextual appropriateness, acceptability, and feasibility of the intervention and, thus, may significantly shorten the cycle from development to implementation and bring about a meaningful social impact faster. For example, the application of multiple frameworks such as multiphase optimization strategy and discover, design, build, and test synthesized the iterative nature of HCD principles and implementation of a forward approach to developing effective and scalable health interventions with rigor and efficiency .This study used the BIT model to strive toward the synergistic effect between behavioral intervention content and technological delivery. In addition to the evidence-based behavior change strategies and coping skills, the effectiveness of behavioral health interventions hinges on operational factors such as the characteristics of the persons delivering them. We addressed this by providing training for SCMC staff who will facilitate the skills training groups as part of the intervention. The technological delivery of intervention functions  was guided by the BIT model. The characteristics of each technological element  were carefully determined based on design theories and standard practices to optimize the usability of the digital platform and create an engaging and pleasant user experience . The comThis study holds significant potential for improving mental health outcomes among MSM recently diagnosed with HIV in China, with the content and delivery of the intervention tailored to meet target users’ unique needs. Integrating app-based individual skills learning, group-based skills training, and phone coaching, the program aims to promote coping skills, foster community connection, counter feelings of stigma and isolation, and increase adherence to HIV treatment regimens among MSM recently diagnosed with HIV. The cultural adaptation considerations applied throughout the development process ensure a culturally sensitive care model that can effectively bridge the mental health service gap often encountered by this demographic. In addition, the findings of the future feasibility trial of this intervention could inform public health policy and serve as a template for similar initiatives in the future both in China and worldwide. Using mHealth technologies to deliver individual skills learning also allows for scalability, potentially affecting a broader population.There are several limitations to this work. First, the needs assessment stage collected qualitative data and would benefit from quantitative survey data to evaluate the community service gap in mental health services and staff attitudes toward mental health training to provide such services. Second, personalization is still lacking in the current version of the mHealth app that delivers the individual skills training component. The user is able to mark their favorite coping skills for future reference, but the functionality of recommending similar skills to the user based on the user-reported problem situation is yet to be developed. Given the highly contextual nature of coping skill use, the next version of this app aims to use computational models to account for the dynamic interaction between individual behavior change progress and situational factors. Third, this study used co-design sessions as a user-centered design strategy to engage end users in designing the intervention. At the same time, the extent of user engagement in our study fell on the lower end of the participatory design spectrum for intervention delivery design because of limited exposure to mental health services among the study participants. Approaches such as using a user journey map can engage end users in actively conceptualizing the overall intervention program. Fourth, our ability to engage the community in a co-design session may be hindered by the limited interactions that can occur within a brief time frame. Future iterations of intervention design and improvement could adopt a longer participatory design process by following up with the participants over several months to build rapport with them and understand their needs. For example, users can participate in the cultural adaptation of DBT-based skills by cocreating intervention materials such as culturally informed metaphors. In addition, we made modifications to the structure of the last 3 co-design sessions after realizing that the participants had difficulty distinguishing between coping strategies for low- and high-intensity emotions. We started the co-design session by asking participants to rank emotion intensity first before asking them to generate coping strategies. Finally, our usability testing collected feedback from users, which generated valuable design insights. Although we were not able to implement every design solution in the current version of the app owing to timeline constraints, we implemented changes that were important to the user experience and effective delivery of our intervention content in the current version of the app.We designed a DBT-informed intervention that aims to improve mental health outcomes for MSM recently diagnosed with HIV in China using a systematic approach that may serve as a blueprint for future interventions. The detailed description of the theoretical basis for intervention development will aid the identification of active intervention ingredients in future trials. The content of the individual skills learning can also be easily adapted to help a broader group cope with similar acute and chronic emotional struggles. The IM framework informed by user-centered design principles and cultural adaptation considerations offered a systematic approach to develop and tailor the current intervention. Specifically, the DBT model of emotion, COM-B system of behavior, and BCW informed the conceptual mechanism of the behavioral intervention. The BIT model facilitated the translation of behavioral intervention strategies into technological delivery components . Future research, currently underway, will pilot-test the intervention to gauge acceptability; feasibility; and, ultimately, efficacy and effectiveness.


Immunogenicity continues to pose a challenge in the development of biotherapeutics like conventional therapeutic-proteins and monoclonal antibodies as well as emerging modalities such as gene-therapy components, gene editing, and CAR T cells. The approval of any therapeutic is based on a benefit-risk evaluation. Most biotherapeutics address serious medical conditions where the standard of care has a poor outcome. Consequently, even if immunogenicity limits the utility of the therapeutic in a sub-set of patients, the benefit-risk assessment skews in favor of approval. Some cases resulted in the discontinuation of biotherapeutics due to immunogenicity during drug development processes, This special issue presents a platform for review articles offering a critical assessment of accumulated knowledge as well as novel findings related to nonclinical risks that extend our understanding of the immunogenicity of biotherapeutics. Some of the studies in this collection leveraged assays and methodologies refined over decades to support more clinically relevant biological samples. Others have applied rapidly advancing methodologies in pathway-specific analyses to immunogenicity. Similarly, the reviews address urgent issues such as the rapidly emerging cell and gene therapies which hold immense promise but could have limited reach as a significant number of the patient population could potentially not benefit due to immunogenicity. In addition to summarizing the work presented in this special issue we have endeavored to identify areas where additional studies are required to understand the risks of immunogenicity and develop appropriate mitigation strategies. Immunogenicity has been a central challenge in the development of biotherapeutics, which includes conventional therapeutic-proteins and monoclonal antibodies as well as emerging modalities such as components of gene therapy, gene editing, and CAR T cells. The approval of any therapeutic is based on a benefit-risk evaluation. Most biotherapeutics address serious medical conditions where the standard of care has a poor outcome. Consequently, even if immunogenicity limits the utility of the therapeutic in a sub-set of patients, the benefit-risk assessment skews in favor of approval for licensure. A few cases have resulted in the discontinuation of biotherapeutics development due to immunogenicity in the clinical trials. There continues to be an inconsistency in immunogenicity assessment strategy despite known risks of immune responses to biologics that can render them ineffective. Hence, immunogenicity continues to be a challenge in the clinic and characterization of immunogenicity and safety continues to be an issue during advance clinical development.Understanding the mechanism of immunogenicity is critical to 1) the development of precise and accurate methods to measure antibody and T cell responses, 2) design novel molecules to overcome the immune-modulatory effects, and 3) develop immune suppression/modulatory regimes to overcome the adverse effects of unwanted immune responses. Over the past three decades a critical mass of guidance documents from different regulatory agencies, white papers from industry-regulatory agency collaborations and research reports from academia and industry have delineated the causes, consequence, and clinical effects of immune responses to biotherapeutics. This special issue presents a platform for review articles offering a critical assessment of accumulated knowledge as well novel findings related to nonclinical risks that extend our understanding of the immunogenicity of biotherapeutics. Some of the studies in this collection leveraged assays and methodologies refined over decades to more clinically relevant biological samples. Others have applied rapidly advancing methodologies in pathway-specific analyses to immunogenicity. Similarly, the reviews address urgent issues such as the rapidly emerging cell and gene therapies which hold immense promise but could have limited reach as a significant number of the potential patient population could potentially not benefit due to immunogenicity. In addition to summarizing the work presented in this special issue we have endeavored to identify areas where additional studies are required to understand the risks of immunogenicity and develop appropriate mitigation strategies.This review summarizes the manuscripts in this special issue of the journal, which include critical quality attributes, genetic factors, immunogenicity to cell, gene therapy and gene editing modalities, immunogenicity to therapeutic proteins targeting autoimmune diseases and COVID-19 vaccinesThe article by Swanson et al. offers a subtle but important advance on one of the most important product related factors associated with the immunogenicity of therapeutic proteins, i.e., aggregates. Foundational work on studying aggregates, over several decades, relied on artificial stress methods to induce high levels of aggregation. While this was a necessary phase in the development of appropriate assays and methodologies, artificially generated aggregates have limited biological or clinical utility. The study reported here is one of the first of its kind that evaluates spontaneously generated aggregates during the manufacturing process and during storage. An important finding was that such aggregates elicited innate immune responses for several donors in a PBMC assay with cytokine and chemokine production as a readout for immune activation. On the other hand, no significant adaptive immune responses were detected. Additionally, the extent of antibody aggregation occurring at process relevant levels are much lower than those induced through artificial stress. It is imperative that this novel approach is more widely applied to gain a better understanding of the clinical consequences of aggregation and the most appropriate methods utilized to assess such quality attributes during drug development.in vivo, they do affect the sensitivity of the cell-based assays. Additionally, the investigators found that detection of model IIRMIs was negatively impacted when they tested three representative biotherapeutics: a monoclonal antibody, a growth factor, and a peptide. This report like the one previously discussed brings a new insight and suggests approaches for ensuring that assessments that are routinely carried out to evaluate immunogenicity are more meaningful.While aggregates generally involve the protein/active ingredient itself, a large body of literature has established that product- and process-related impurities often function as adjuvants that activate the local or systemic innate immune response which increase the likelihood of an immune response to the active protein ingredient. The rationale for identifying/assessing innate immune response modulating impurities (IIRMIs) is clear. Unfortunately, identifying trace levels of individual IIRMI can be difficult and testing individually for all potential impurities is not feasible and cell-based assays that use human blood cells or monocyte-macrophage reporter cell lines are frequently exploited to detect minute quantities of impurities capable of eliciting innate immune activation. An important technical challenge associated with these assays is addressed in the report by Thacker et. al., i.e., excipients could blunt the cell responses, masking the presence of immunogenic IIRMI. The study painstakingly explored the impact of frequently used excipients  on the sensitivity of reporter cell lines (THP-1- and RAW-Blue cells) and fresh human blood cells. An important finding was that although excipients do not modulate the innate immune response elicited by TLR agonists While the articles described above focus on extant methods and approaches to extract more clinically useful information, the report by Wang et al. exploits the advances in identifying genetic variabilities associated with clinical outcomes to better understand immunogenicity. TNF inhibitors are now the standard of care in treating many autoimmune diseases such as ankylosing spondylitis, and rheumatoid arthritis. The study investigated the role of TNF-α gene polymorphisms in concert with neutrophil-to-lymphocyte ratio and platelet-to-lymphocyte ratio in predicting the efficacy and safety of TNF inhibitor therapy. Using samples from 515 subjects the study was successful in identifying biomarkers and defining a measure (TNF-α 308G/A polymorphism with neutrophil-to-lymphocyte ratio and platelet-to-lymphocyte ratio) to predict the responsiveness and safety of anti-TNF therapy in patients.de novo Anti-drug Antibodies (ADA) against vector capsids and transgene immunogenicity poses significant challenges. The gene editing CRISPR/Cas9 machinery faces similar challenges in terms of pre-existing and de novo immune responses. These immune responses extended to Cell based therapies that utilizes gene modification techniques, thus complicating the chemistry, manufacturing, and controls requirements. These modalities activate both innate and adaptive arms of the immune system. The vector capsids activate host innate immune system through Toll-like receptors and pathogen associated molecular patterns PAMPs. The complement system of the innate arm can be activated by immune complexes formed with pre-existing anti capsid or Cas9 antibodies. The genetic material present in these modalities can also activate Toll-like receptors. Humoral responses elicited against proteins, viral capsids and transgene can neutralize and/or accelerate clearance of these modalities. In addition to humoral response, cellular responses against gene therapy vectors and transgene proteins can be developed by presentation via MHC I pathway leading to generation of CD8+ cytotoxic T-cells. Further, the role of natural killer cell activation against novel modalities is emerging. The factors influencing immunogenicity are broadly classified into three categories, patient, product, and treatment related factors. These classifications cover patient variability, disease status, presence of impurities and aggregates, duration of treatment and routes of administration.In addition to the original research described above, the special issue includes several topical reviews. The first of these addresses a key emerging issue in the field of immunogenicity. Emerging modalities such as gene-, CRISPR- and cell- based therapies have been demonstrated to offer treatment options for many currently intractable diseases and hold immense promise. The premise that unwanted immune responses to these novel modalities could severely compromise the safety and efficacy of these novel modalities is generally accepted. However, the presentation of the “active protein(s) component” is very different from that of conventional protein replacement and monoclonal therapies and it is not clear to what extent learnings, reagents, and methodologies applicable to protein therapies will be applicable to these modalities. For instance, it is estimated that about 20-70% of the population have pre-existing antibodies against viral vector capsids and their serotypes. In addition, development of Unlike the immunogenicity of therapeutic proteins, understanding the immune responses to novel modalities is a nascent field. Khan et al. have provided a comprehensive review of the current state-of-the-art with respect to immunogenicity issues related to Chimeric antigen receptor T cell (CAR-T) therapy. CAR-T cells have provided long-term remission of a few hematological malignancies but could prove to be a very powerful weapon in the oncologist’s armamentarium. Although the six approved CAR-T therapies have yielded impressive response rates, immunogenicity could be a key challenge in the broad application of this technology. This is because the scFv domain of CAR construct, is of non-human origin in majority of the CAR-T products.Khan et. al., have highlighted the plausible drivers of immune responses to CAR T cells and reviewed (the admittedly few studies currently published). Based on our understanding of immunogenicity from other therapeutic areas, the authors have suggested mitigation strategies to limit the immunogenic potential of CARs and improve therapeutic outcomes. Some of the key learnings from work related to novel modalities is the lack of guidance around development of novel cell and gene therapies, need for novel assay platforms as well as innovative strategies to leverage existing platforms to support preclinical and clinical development. The risks and associated critical quality attributes may impact innate and cellular responses apart from the conventional humoral response.In addition to original research and reviews that directly address issues related to the immune responses to therapeutic proteins, this issue also includes articles related to the treatment modalities associated with autoimmune diseases. This is because autoimmune diseases also result from unwanted immune responses to self-proteins and the progress in understanding and circumventing autoimmunity provide insights important to using small molecule drugs to modulating the immunogenicity of biopharmaceuticals. Qi et al. have provide a review of the Janus Kinase inhibitors in the treatment of the Vitiligo (a skin disorder characterized by white patches resulting from the destruction of melanocytes). Activated CXCR3+ CD8+ T cells promote melanocyte detachment and apoptosis through interferon-gamma (IFN-g secretion and chemokines secreted by keratinocytes through the Janus kinase (JAK)/signal transducer and activator of transcription (STAT)-1 signaling pathway results in further recruitment of CXCR3+ CD8+ T cells and the formation of a positive-feedback loop. JAK inhibitors target the JAK/STAT pathway and used to treat many immune-related diseases. The review discusses the success in using JAK inhibitors in targeting the interferon-γ-chemokine signaling axis in the pathogenesis and more importantly they provide a granular discussion of the molecular pathways involved in the breakdown of immune tolerance and how these may be targeted to modulate the immune responses.The final article in this collection discusses immunogenicity in the context of vaccines where the immune response is a desirable outcome. The article is included because it provides an important insight. In combating diseases developing a medication is only part of the solution. Patient engagement “buy” in, societal narratives all have a role to play when complex decisions are made. As extraordinarily expensive treatment options like gene therapy and gene editing go mainstream it will be important to counter alternate narratives and develop systematic research strategies to understand the role of human and societal factors in the adoption of complex and controversial medications. Over the past sixty years, vaccines have prevented many infectious diseases and changed the management of public health in the world. More than thirty vaccines against various infectious diseases have been approved and ~240 vaccines are in various stages of development. National health policies in most countries provide vaccines to newborn children, adolescents, adults, and the elderly have saved millions of lives. More than 2 million lives are saved each year by vaccinations, which have resulted in the reduction of Infant Mortality from 93 deaths per 1,000 live births in 1990 to 39 in 2018.Development of a safe, reliable, and effective vaccine was critical to curb the global COVID-19 pandemic. The end point of the COVID-19 pandemic is protection against severe disease and mortality and eventually Herd Immunity. This outcome can be achieved only after widespread availability of an effective vaccine. Many of these vaccines have been developed and approved in unprecedented timelines. Keeping track and communicating the advancements in COVID-19 vaccine development across all the platforms, monitoring the efficacy and safety relative to the circulating strains of the virus has been an astronomical task. Shi et al. have provided one of the first systematic studies of “vaccine fatigue” described as people’s inertia or inaction towards vaccine information instruction due to perceived burden and burnout. The authors identified 37 articles from PubMed, Scopus and PsycINFO, on vaccine fatigue based on pre-defined criteria. Their study found that vaccine fatigue was reported most frequently at the pre-vaccination stage. Several reasons for the vaccine fatigue included limitations of reporting of detailed vaccine sciences, effective and empathetic vaccine communications, people’s inaction towards the frequent diverse instructions from authorities. This study underscores the importance of effective communication of science to the public and is as relevant to so-called vaccine fatigue as it is to the many emerging therapies that are the subject of this collection.It has been several decades since immunogenicity was identified as an important hurdle in the development and licensure of biotherapies. Since then, a critical mass of data has accumulated in the literature. Several disease-specific repositories also collate clinical data on immunogenicity and genomic data for individual patients. Drug Manufactures too have large unpublished data sets from different stages of the drug development. These large and complex data sets are ideal for the application of Artificial Intelligence(AI) and Machine Learning(ML) approaches to identify genetic and non-genetic risk factors associated with immunogenicity. Using training data, AI and ML can be leveraged to uncover patterns in an unbiased manner and allow the identification of biomarkers that could be used in predictive algorithms. Most importantly unlike classical statistical methods which deduce relations from data, AI and ML “learn” from the data-itself even in the absence of hypotheses to test.As we have alluded to above, most biotherapeutics are approved and used in the clinic even though immunogenicity issues were identified during phase 3 clinical trials. This is because the biotherapeutics address serious (often life-threatening conditions) and there are no alternatives. However, post-approval, the immunogenicity of individual biotherapeutics is not consistently monitored. There is an unmet need for real world studies on immunogenicity to better manage immunogenicity in the clinic. Real-world evidence can be generated by diverse study designs and the importance of such studies is increasingly being recognized. For instance, the 21st Century Cures Act required the FDA to expand the role of real-world evidence. Real world evidence is important because clinical trials carried out to obtain licensure do not account for the entire patient population as some geographic and/or ethnic and racial groups may have been excluded. Similarly, the genetic variability of the genes involved in the response or adverse events  is not fully captured in the study population. The quality of data is a critical issue in real world evidence and this needs to be addressed prior to carrying out these studies.The repertoire of technologies that can be exploited to study immunogenicity is expanding rapidly. Some of these technologies are developed in closely related fields  and can be leveraged to obtain much more granular information about the immune response to therapeutic proteins. Technologies such as MHC Associated Peptide Proteomics and single cell RNA sequencing are more accessible in terms of both cost and the level of expertise required. The large data sets obtained from the application of these technologies are amenable to Machine Learning tools and systems immunology approaches. Such learnings will eventually be useful in modulating and managing immunogenicity during drug development (by generating less immunogenic variants) and in the clinic (by developing strategies to modulate the immune response to the therapeutic).Taken together, the publications in this collection and emerging trends, indicate that our understanding of the immunogenicity is likely to expand exponentially soon. This will be welcome news for millions of patients who currently do not fully benefit from biotherapeutics and who would otherwise not be eligible for the promising advances from novel modalities such as gene and cell therapies.The original contributions presented in the study are included in the article/supplementary material. Further inquiries can be directed to the corresponding author.ZS, VJ, SB and NC all contributed equally to the writing. All authors contributed to the article and approved the submitted version.


Editorial on the Research TopicInsights in heart valve disease: 2022Heart valve disease (HVD) represents a significant burden for health systems around the world. The growing advances in imaging and diagnostics need to be correlated with improvements in management. In total, nine articles have been published in this Research Topic, with interesting new findings summarized in Hu et al.The widespread use of penicillin-like drugs and improved access to healthcare reduced the burden of rheumatic heart disease (RHD) in the past century. In some developed countries, the false perception of its under-control burden has diminished alerts in the diagnosis of RHD, worsened by reduced compliance with penicillin treatment. Regional disparities contribute to the vast medical and economic burdens of RHD. It remains the leading cause of severe valvular heart disease with the highest significant cost among cardiovascular diseases, particularly in low-income countries. The valvular involvement frequently leads to heart failure, shortening life expectancy, and is responsible for 320,000 deaths annually. The projections of the global burden in the next decade indicate, mainly in low- and middle-income countries, an increasing trend in incidence, affecting more female subpopulations. The regional disparities may be attributable to the restricted access to healthcare, education, and housing On the other side of the heart valvular disease spectrum, non-rheumatic, calcific aortic valve and mitral valve diseases are significant causes of public health concern, affecting mainly older adults in Western countries. These are highly treatable diseases and efforts to reduce the burden should be directed to modifiable risk factors, affecting the natural history of the disease, and improving interventional lines of management .The guidelines suggest treatment for severe valvular disease, identifying echocardiographic parameters of severity that professionals in the medical field can refer to in case of asymptomatic disease. A poor prognosis is associated with severe HVD and its surgical correction is mandatory to reverse cardiac remodeling and restore quality of life.What emerges from recent literature and most of the articles published in this Research Topic is the necessity to revise surgical timing. The diagnostic assessment needs to include the grading of valve disease, a mirror of the altered morphology, and the dynamic response of the overloaded and/or over-pressured heart chambers. The study of the extra-valve cardiac involvement may allow for defining different stages of the disease, with a notable prognostic impact and crucial role for surgical implications.Stöbe et al. focused their research on cardiac involvement in patients affected by moderate aortic stenosis. They differentiated the population study according to the number of pathophysiological changes: increased left ventricular mass index, diastolic dysfunction, and increased right ventricle (RV) load. The study population was homogenous for comorbidities, excluding patients with severe comorbidities as these were not attributable entirely to aortic stenosis. The group with more extent cardiac damage resulted in a significantly lower survival rate without aortic valve replacement (AVR) or progression of aortic stenosis. The extra-valve cardiac involvement may be crucial for clinical outcomes after AVR, with a staging classification that appears to have important prognostic implications  >0.3 m/s/year. The systemic inflammatory response and impairing endothelial function are recognized as causes of aortic valve degeneration. The adverse effect of diabetes on left ventricle hypertrophic remodeling with increased left ventricle (LV) filling pressures may accelerate the pathophysiological changes, proceeding along with the staging of cardiac damage extent.The natural history of aortic valve stenosis proceeds along pathophysiological changes and triggering factors may influence the clinical outcomes. A rapid progression of aortic stenosis associated with diabetes was demonstrated by Salim et al. Overall, this emergent staging classification provides an incremental prognostic value in patients with valve disease.The resulting mechanical forces, such as tensile and shear stress, are powerful promoters of aortic valve pathogenesis, with biological responses typical of aortic valve calcification The novel classification system was demonstrated to be significantly helpful for risk stratification and timing of surgery for primary mitral regurgitation. Grouping the population study according to the natural history of cardiac involvement in the context of primary mitral regurgitation, for each increase in the group, a 17% higher risk of all-cause mortality was observed .Shechter et al. Observations regarding the flow dynamic assessment in the native mitral valve and after surgery may be conducted in a standardized fashion, able to offer valid and crucial results Pugliese et al.The discussion regarding racial disparities in characteristics and outcomes of patients undergoing mitral transcatheter interventions may lead to full implementation of knowledge of surgical timing Identifying factors of greater severity in a patient, with the same group of valvular disease, is fundamental for recognizing the differences in early and long-term prognosis. Although our considerations are focused mainly on surgical timing and prognostic implications, the armamentarium of surgical techniques with less invasive access  needs to