Families experiencing high levels of psychological distress are considered a particularly vulnerable population for adverse effects on mental and physical health. Moreover, highly stressed individuals engage less in mental health promoting activities and show low stress management competencies. App-based stress interventions seem promising for the treatment and prevention of stress outcomes and might be a low-threshold solution.The aim of this study was to identify the requirements for a tailored app to reduce stress in a cohort of highly stressed families that have low stress management skills.Parents  completed an extensive web-based survey and were subdivided into a target  and nontarget group according to their reported stress level and stress management competencies. Group differences were analyzed using analysis of variance. In principal component analysis with Kaiser varimax rotation, personally defined stress management goals were grouped into components. Linear regression models were also calculated.F1,978=27.67, P<.001), health index , personally defined general-competency goal , as well as “information acquisition”  and “need for stimulation”  personality traits. A regression model showed that for the active strategies goals of interest, only app feature information or instructional videos had a significant effect (P=.02). The general competency factor showed none, and the passive strategies factor showed significant effects for 2 app features—suggestions for planning possible activities with the family (P=.01) and diaries for documentation and development of strategies (P=.03).A 3-factor solution cumulatively explained 56% of the variance in personally defined goals of interest for stress management with (1) active strategies (25.61% explained variance), (2) general competency (17.95% explained variance) and (3) passive strategies (12.45% explained variance). The groups differed in age (The results of this survey study highlight the need to develop an app to increase stress management competencies that takes into consideration perceived stress level, stress management skills, personality, and personally defined goals of the user. The content of the app should be tailored to previously detected personality traits, especially selective information acquisition and low need for stimulation. Furthermore, personally defined stress management goals seem to affect interest in some features. Stress is associated with heightened risks of adverse physical and mental health consequences, such as impaired sleep , gastroiAn increasing amount of literature suggests that interventions using different stress management techniques, such as mindfulness, lead to significant psychological health benefits in a wide range of populations -22. Varistress management competencies. It should, however, be noted that highly stressed individuals are less likely to engage in mental health promoting activities [In this study, we define the subjective ability to apply and perform such stress management techniques according to personal demands and stress level as tivities -40. ConsIn an increasingly computer-educated European population, information and communication technology might provide unique and low-threshold opportunities to engage parents and families in mobile health –related services and encourage behavior change, to improve health and reduce stress -43.New concepts, such as the PSYCHE system , have emTailoring  was idenany combination of information or change strategies intended to reach one specific person, based on characteristics that are unique to that person, related to the outcome of interest, and have been derived from an individual assessment. A meta-analysis on tailored print health behavior change interventions has demonstrated that tailored messages were superior compared to generic messages and were associated with larger effect sizes . MoreoveResearch on tailored web-based stress management interventions is scarce, yet tailoring could be an effective tool to empower users in their stress management skills and to reinforce self-determined health-related behaviors.On the other hand, studies show that certain personality traits are associated with specific coping behaviors ,59 and afunctional relationships among affective and cognitive macrosystems, i.e., the dynamic processes that underlie human mental functioning and might be more suitable to detect and predict self-regulation and volitional aspects of health behavior. PSI theory distinguishes between 2 emotional—(1) the need for stimulation and (2) the need for security—and 2 cognitive systems—(1) the need for information and (2) information processing . MeixnerTo develop and implement a tailored mobile app that appropriately reaches vulnerable und highly stressed families in order to improve their stress management competencies, the following aspects should be addressed: (1) existing stress management techniques and perceived stress management competencies in families, (2) the influence of personality traits, and (3) potentially suitable features for a mobile stress management intervention such as gamification and (4) defined goals of interest in order to individually manage stress.Previous studies have focused on evaluation of the usage and tailoring effectiveness; however, evidence on the assessment of users' needs and preferences is limited. Given the adverse impact of low adherence on treatment outcomes, understanding technological and content-related factors is crucial for the design and large-scale implementation of app-based stress reduction interventions into routine health care, and ultimately, to help users to interact in a health-promoting way. With respect to the health impairing consequences of high stress levels for each family member, it seems highly relevant to evaluate the families' needs and preferences for mHealth approaches.Therefore, the aim of this exploratory study was to identify the requirements of an individualized app to reduce stress in a cohort of highly stressed families that have low stress management skills.The main research questions were (1) Which characteristics can be identified that describe stressed individuals with low stress competency? (2) Which app features and gamification elements are of the most interest for highly stressed participants with low stress-management competency? (3) Which app features and gamification elements are relevant for different types of stress management goals?This cross-sectional study was part of a project that aims to develop a tailored mHealth intervention for family members and to design health promotion in a sustainable manner. This study was approved by the University of Hamburg ethics committee (file reference: AZ: 2019_270).Every family insured by a small German health insurance cooperative  was invited by post to participate in a web-based survey. Participation in the study was voluntary, in accordance with the principles for medical research involving humans, and participation was not rewarded in any way. The questionnaire development process included several team-internal evaluation procedures and was implemented using Questback software , which aThe questionnaire is available as health behavior was based on self-assessment in the dimensions of physical activity (2 items), dietary behavior (2 items), and stress (2 items).Age in years (1 item) and gender (1 item) were assessed. In order to provide a holistic framework, the concept For dietary behavior and physical activity, in each case, 2 questions from the CALO-RE taxonomy of behavior change  and the A health behavior index was developed based on the physical activity, dietary behavior, and stress questions. For this purpose, each question was first evaluated on a scale of not achieved (0), partially achieved (1) and achieved (2) based on the reference values mentioned above. These values were added, resulting in a score between 0 and 12—if all questions were consistent with the proposed reference values in all 3 dimensions, a person reached an overall health index of 12. This means that the higher the health index, the more health-promoting a person's behavior.The following items were extracted from qualitative interviews: performance of meditation exercises, performance of breathing exercises, performance of yoga exercises, performance of mindfulness exercises, performance of relaxation exercises, improvement of stress management competencies, improvement of the ability to perform stress management techniques from anywhere, improvement of personal resilience to stress, spending time in nature, benefit from wellness and sauna offers. We first conducted interviews and then developed a quantitative survey with items extracted from the interviews. A query of the interest for these items was conducted using multiple checkboxes.The personality questions were derived from previous qualitative interviews and checked for construct validity using the Visual Questionnaire . The perThese variables were integrated into the web-based survey to identify tailoring requirements in accordance with our exploratory approach. The questions focused on preferences, ideas, and needs of the respondents in order to design an app in a user-friendly way that was adapted to their needs. The items were individualization of app content, fulfilling common weekly goals and tasks, connecting the app with wearables, increasing knowledge about a healthy lifestyle, suggestions for activities with the family, diaries for documentation and development of strategies, reminders of goals, informational or instructional videos, and analog format for children. Each item was rated by participants on a 6-point scale that ranged from 1  to 6 .Questions asking which gamification elements respondents found appealing—comparison with others, in a ranking or on a high score list; controlling and checking progress; collecting points for performance; collecting shared points with other family members; receiving awards, recognition, or encouragement; monetary incentives for achieving goals; linking to the bonus program of the health insurance company; designing an avatar; completing tasks under time pressure, for example, a countdown; advancing to another level or increasing the level of difficulty; sharing and comparing my achieved goals with others; an accompanying storyline; receiving auditory, haptic, or visual feedback; and rating other family members—were rated on a 6-point scale from 1  to 6 . Similarly, these were integrated into the web-based survey in an exploratory manner.The web-based questionnaire  was preWe used SPSS software  for statistical analyses.All variables of the questionnaire that asked for personally defined goals of interest for stress management were factor-analytically reduced to 3 factors  in principal component analysis with Kaiser varimax rotation. Bartlett and Kaiser-Meyer-Olkin measure of sampling adequacy tests were performed to test the suitability of variables for factor analysis.Perceived stress level and stress-management competency variables were dichotomized in order to identify stressed individuals with low stress competency as a target group. The characteristics of the target group and the rest of the participants were descriptively characterized. We compared groups using analysis of variance.In order to analyze which app and gamification characteristics are relevant for stressed individuals with low stress competency, the data set was then reduced to only those participants, and to reduce data to relevant variables, all feature and gamification variables with a mean value <3.5 in the target group, indicating irrelevant features, or that did not differ significantly between groups were excluded.We performed 2-way correlation analysis between app and gamification feature variables not excluded in step 3 and the 3 stress reduction target factors  from step 1.Three linear regression models were calculated, each with 1 of the 3 target factors for stress management strategies  as a dependent variable. As independent variables, the remaining variables from step 3  were included.In order to be able to demonstrate the anticipated small effect sizes (<0.05) in a multiple linear regression model with 95% power and 8 predictors, a minimum sample size of 463 was calculated .Only fully completed questionnaires were included. For bi- and multivariate analysis procedures, list-wise case exclusion was used.Of 18,000 families invited by post to participate in the web-based survey, 1008 families completed the questionnaire (a response rate of 17.86%). The total sample consisted of 599 female, 398 male, and 7 diverse participants; 4 participants did not give any gender information. The average age of respondents was 47.79 years (SD 6.13).245=2105.563, P<.001) and measure of sampling adequacy (Kaiser-Meyer-Olkin .854) revealed that 10 stress-related target variables , health index , active strategies , general competency , information acquisition , and need for stimulation . App feature and gamification variables that met Step 3 criteria were individualization of app content , fulfilling common weekly goals and tasks , increasing knowledge about a healthy lifestyle , suggestions for activities with the family , diaries for documentation and development of strategies , reminders for objectives , informational or instructional videos” , and controlling and checking progress .A comparison of participants with low perceived stress, high stress management skills, or both versus participants with high perceived stress and low stress management  demonstractive strategies factor was correlated with 5 of the 8 features   . The genactive strategies factor, only information or instructional videos had a significant effect (P=.02). The general competency factor showed none, and the passive strategies factor showed a significant effect for suggestions for planning possible activities with the family (P=.01) and diaries for documentation and development of strategies (P=.03).We found that the correlations were partially eliminated in multivariate models . For theThe main goal of this cross-sectional study was to identify the requirements for an app that addresses stress management competencies in a cohort of highly stressed family members. We analyzed the characteristics of the target group, their individualized interests in app features and gamification aspects, their personality traits, and different types of personally defined goals.Almost half of the study sample was identified as the high-risk population—stressed individuals with low stress competency. This underlines the importance of this study's aim. Furthermore, this group's size reflects the ever-increasing proportion of people who feel unable to effectively cope with stressors in their everyday and work–life situations, which is why the World Health Organization classified stress as the health epidemic of the 21st century and called for prevention strategies . As expeNotably, the target group also differed in their personally defined goals of interest for stress management. The parents who stated that they experience high stress and have low stress management competency aimed to achieve general competencies such as improvement of stress management competencies, acquisition of the ability to perform stress management techniques from anywhere, and improvement of personal resilience to stress. The nontarget group, however, aimed to achieve active strategies including performance of yoga exercises. This highlights the need to differentiate between the groups when developing and implementing mobile solutions to improve stress management competency. According to our results, the target group did not formulate specific goals but tended to have unspecific, general goals. Therefore, one might speculate that participants with subjectively higher stress levels and lower stress management competencies need more help with goal setting and more information about which strategies might reduce stress. These results further emphasize the need for tailored app features for highly stressed families. In line with Control Theory, behavior change techniques, such as goal setting, have been associated with increased intervention effects ,74. A stThe analysis of specific app features revealed further differences between the 2 groups regarding their app-related interests. The target participants, with low stress management competencies, indeed showed higher ratings for app features that can be used as goal-setting techniques: weekly goal and task achievements, diaries for documentation, and development of strategies and reminders for objectives. Furthermore, they had higher ratings for content individualization, connecting wearables to the app, increasing knowledge about a healthy lifestyle, suggestions for activities with the family, and informational or instructional videos. Overall, these results indicate that users identified as the high-risk population, with low stress-management competencies and high perceived stress levels, wish for features that facilitate the usage of the stress management apps. These requested features can be primarily interpreted as a need for coaching and instruction. In fact, such guided interventions have been shown to be more effective compared with unguided interventions . MoreoveA comprehensive systematic review  has estaP<.001) and need for stimulation (P<.001). According to PSI theory, stressed individuals with low stress competency thus have more selective information acquisition and lower needs for stimulation than the nontarget group members [Interestingly, persons reporting high stress levels and low stress management skills were younger than participants with lower self-reported stress and differed significantly in 2 personality traits variables. Specifically, their personality structure indicated lower scores in information acquisition ( members . Kuhl [7 members  describe members  by point members . This is members ,81, with members ,83. For  members  were abl members .. While multiple correlations were found between personally defined goals and app features, correlations were partially eliminated in multivariate models. Nevertheless, our results indicate that the probability of interest in informational or instructional videos was higher when active goals had been set. Similarly, interest in suggestions for family activities and diaries was higher when personally defined goals yielded passive strategies.Furthermore, it appears that interest in some features was higher, depending on specific personally defined goals of interestOur results support the theory that creating a stress management app requires tailored content to address the differences in perceived stress levels, stress competencies, and personality traits. These findings build on those of Lustria et al , who poiOne limitation of the study is that only individual parents were surveyed. Assessing more than one family member could not be realized at this stage of the project but will be aimed for in future studies. With respect to spill-over effects of perceived stress across family members -10, a hoA further limitation is that the identification of our target group was only based on 2 items. This was due to practical reasons and the length of the existing survey in a larger research project. The results presented and discussed in this paper can, thus, only be regarded as exploratory and should be replicated using validated scales such as the Perceived Stress Scale . NeverthFuture research should bring these preliminary data into practice and develop and evaluate an app that adequately addresses the stress level and stress competency as well as personality traits and personal goals of the user. Furthermore, there is still no evidence to support whether already existing apps are well accepted by our target group and whether these apps provide motivating factors for long-term use to build and maintain stress management skills. For this reason, further studies on the sustainable development of apps and the support of behavior change processes, in the course of stress management, should identify the situations and conditions that can have an impact on work–life stress, coping, and goals of individual family members.There is also a need for further research in this area to provide sustainable evidence for features and gamification elements with the aim of developing age- and gender-specific stress coping skills and, if necessary, to enable transfer to other digital media.Nevertheless, there are some important practical implications. Health authorities and mHealth or app developers should take our findings into account when planning and implementing tailored app-based mental health promotion interventions for families. In a first step, target group identification is necessary. The target sample—highly stressed families with low stress competencies, in this case—can be characterized by age, gender, health behavior, and personality. The design of the app, as well as its promotion, should address the unique characteristics of the target group, for example, in this case, a minimalistic user interface that decreases stimulation. In a second step, the app should be designed in such a way that individual setting of a stress management goal is possible. These self-defined goals, defined beforehand, represent specific demands and wishes for relevant app and gamification elements .The results of this cross-sectional study show that, in order to develop an app to increase stress management competencies within families, the content should be based on preassessed of competencies, goals, and personality traits of the potential user, and thus, tailored to the user’s needs. Highly stressed parents with low stress management skills want features in an app that make it easier to use and include goal setting techniques. In fact, a need for coaching and instruction was identified, which underpinned prior research showing that guided stress management interventions have more promising results.This study delivers first results and directions to inform further research in the growing field of mobile and web-based solutions in mental health care. The relationship between integrated elements of behavior change techniques, the usage of gamification elements, and most notably, tailoring of the content of a web-based intervention and the resulting health behavior change show promise that is urgently needed with respect to increasing stress levels and its associated adverse health effects.


Evidence suggests that the patient‐reported outcome (PRO) content of cancer trial protocols is frequently inadequate and non‐reporting of PRO findings is widespread. This qualitative study examined the factors influencing suboptimal PRO protocol content, implementation, and reporting, and use of PRO data during clinical interactions.Semi‐structured interviews were conducted with four stakeholder groups: (1) trialists and chief investigators; (2) people with lived experience of cancer; (3) international experts in PRO cancer trial design; (4) journal editors, funding panelists, and regulatory agencies. Data were analyzed using directed thematic analysis with an iterative coding frame.Forty‐four interviews were undertaken. Several factors were identified that could influenced effective integration of PROs into trials and subsequent findings. Participants described (1) late inclusion of PROs in trial design; (2) PROs being considered a lower priority outcome compared to survival; (3) trialists’ reluctance to collect or report PROs due to participant burden, missing data, and perceived reticence of journals to publish; (4) lack of staff training. Strategies to address these included training research personnel and improved communication with site staff and patients regarding the value of PROs. Examples of good practice were identified.Misconceptions relating to PRO methodology and its use may undermine their planning, collection, and reporting. There is a role for funding, regulatory, methodological, and journalistic institutions to address perceptions around the value of PROs, their position within the trial outcomes hierarchy, that PRO training and guidance is available, signposted, and readily accessible, with accompanying measures to ensure compliance with international best practice guidelines. Patient‐reported outcomes (PROs) capture patients’ experience of the physical, functional, and psychological effects of disease and treatment. However, research to date indicates the design and reporting of PRO data in cancer clinical trials are suboptimal. Our findings highlight a number of potential factors contributing to observed suboptimal PRO protocol quality and reporting in cancer clinical trials. We provide potential solutions to uphold best practice to improve the quality of PRO data for the benefit of cancer patients. PROs provide valuable information, including data on physical symptoms, treatment toxicities, psychosocial problems, global health‐related quality of life, to assess treatment effectiveness, and tolerability.Patient‐reported outcome data support informed decision‐making by patients from diagnosis and throughout treatment.The Evaluation of Patient‐Reported Outcome Protocol Content and Reporting in UK Cancer Clinical Trials (EPiC) study used mixed methods to investigate PRO protocol content and reporting in a cohort of international cancer clinical trials. Phase I highlighted inadequate PRO protocol components, widespread non‐reporting of PRO trial results, and considerable delay and poor standards of reporting where PRO data were published.The current paper reports Phase II of the project: a qualitative study involving key stakeholders. Our aim was to examine and describe perceptions of the factors influencing suboptimal PRO protocol content, implementation, and reporting, including barriers, solutions, and examples of good practice.2The study was completed according to the published protocol,2.1Purposive sampling was used to recruit participants from four stakeholder groups: (1) trialists and chief investigators with experience of cancer trials collecting a PRO as a primary or secondary outcome; (2) individuals with lived experience of cancer; (3) international experts in PRO cancer trial design, including members of international cancer and quality of life research organizations, national advisory bodies and industry; and (4) journal editors, funding panelists, and regulatory agency representatives (Appendix S1). Approaches were via email, either directly, where contact details were available in the public sphere, or via the center from which they were identified where appropriate. Recruitment continued on a rolling basis until data saturation was reached. Eligible individuals were provided with a brief outline of the study and those interested in participating were invited to take part in an interview. Participants completed and returned a consent form prior to the interview or gave verbal recorded consent.2.2All interviews were conducted by a qualitative researcher (AR). The interviews were digitally audio‐recorded and professionally transcribed verbatim. A preliminary topic guide was formulated in advance of the interviews informed by the research aims, which were iteratively refined to explore emerging themes. Additional prompts were developed for each participant group as required (Appendix S2).2.3Transcripts were analyzed by AR using directed analysis.3The interviews lasted for 30–60 minutes. For recruitment, participants were assigned to one of the four pre‐defined stakeholder groups . However, several participants identified with or had features and experiences that resonated with more than one stakeholder group Table .Interviewees highlighted several barriers and facilitators to optimal PRO practice relating to study inception, PRO collection, analyses, data publication, and training and guidance Table .3.1During study inception, interviewees reported that PROs were often included in discussions at a late stage; or added as an “afterthought” to meet funding requirements for example, and were considered to be of lower importance in the hierarchy of trial outcomes. The relevance and priority of PRO endpoints in trial design were considered dependent upon the clinical characteristics of the cancer type and the nature of the intervention. Participants described how, where interventions were intended to prolong life, survival would be a key outcome, and PRO data may be of lesser importance to the research question. In cases where a range of curative interventions was available or in a palliative setting, PRO data had greater prominence. Other respondents commented on difficulties associated with selecting appropriate PROs in trials and perceived reluctance by some trial investigators to include PROs owing to concerns regarding their subjectivity or cost. Recommendations to address these issues included: the need to formulate a clear PRO rationale early in the trial design process which incorporated the patient perspective; identifying specific PRO aims and objectives; and ensuring involvement of PRO expertise during protocol development. Participants described how advances in cancer treatment supported more curative options, development of less toxic treatments, and greater awareness of the effects of living with consequences of radical interventions, leading to a growing awareness of PRO data and its place in cancer trials and clinical practice.3.2Identified barriers centered around: perceived lack of standardized PRO administration compared to more “objective” clinical trial outcomes; concern around participant and staff burden associated with PRO completion; and a lack of communication with data collection staff regarding the importance of PRO data to the trial. Missing data were considered to be a significant challenge for analyses and concluding data. Subsequently, there was a view that the volume of missing data and its perceived poor quality could contribute to underreporting due to possible damage to reputation and limiting future funding prospects. Interviewees also highlighted a perceived lack of clarity surrounding PRO analysis methods as a key barrier. Others felt that a lack of trial resources often resulted in the prioritization of the primary outcome at the expense of PRO data.Facilitators to optimal implementation of PRO within trials included: ensuring adequate PRO coverage in the protocol to help foster “buy‐in” from trial staff; engaging research participants by communicating the importance of their PRO data; development of a priori plans to minimize avoidable missing PRO data by identifying poor PRO compliance in real‐time, establishing statistical management of missing PRO data in advance, and pre‐specifying PRO analyses; and the use of innovative data‐capture technology to reduce burden and increase data quality.3.3Discussion focused upon academic publication rather than inclusion in regulatory submissions or Health Technology Assessment applications. Interviewees highlighted issues around selective reporting of PROs, either linked to the significance of the primary outcome or of the PRO itself, or due to the “lower ranking” of PRO results by trialists. There was also a perception that PRO findings were of little interest to journals unless particularly “novel” or “dramatic,” and that the inclusion of PRO data alongside the primary outcome could be impeded by restrictive word count limits. Interviewees discussed solutions including the generation of a dissemination plan that includes PROs; encouraging Patient and Public Involvement (PPI) throughout the trial to foster accountability and promote complete reporting; and the availability of the option to include PRO data as supplementary files or appendices. When asked about perceived demand for PRO data from journals, participants who had successfully led and published research using PROs in high‐impact journals described how well‐written papers aimed at appropriate journals would get published. Participants, including those employed as journal editors, noted that journals are keen to publish high‐quality PRO data, particularly those from large‐scale RCTs, depending on the clinical area.3.4A recurring theme was the perceived difficulty of acquiring and providing PRO training in practice. Respondents felt this was due to the lack of awareness of training resources; possible expense; limited time; and particularly for generalists, the notion that PROs were one of a multitude of competing for potential training needs, or that PROs were not within their remit. However, the majority of interviewees felt there was a role for all institutions involved in regulatory, funding, educational, methodological, and journalistic activities throughout the research process to ensure that PRO training and guidance was available, signposted, and readily accessible to stakeholders, with accompanying measures to ensure adherence and compliance to best practice guidelines.3.5There were two unanticipated themes resulting from the interviews (Appendices S3 and S4), drawn from all stakeholder groups. The first relates to the usefulness of PRO data in meeting the information needs of people during diagnosis, treatment, and when living with and beyond cancer (LWBC). When asked about their experience of accessing PRO information, several participants with lived experience described how the availability of PRO data during clinical decision making would have enabled more informed treatment choices. The second related to the generation of data valued by patients through PROs in cancer clinical trials, via effective PPI in study question formulation; development and use of PRO measures that are relevant and reflect patients’ interests; and the simplification of PRO delivery to minimize patient burden and improve engagement (Appendices S3 and S4).4Existing research has drawn valuable insights into the challenges faced when administering PROs in trialsMissing data were a recurring theme and was posited as a reason for skepticism around the value of PROs. This is reiterated in the literature, where high rates of missing PRO data continue to be reported.A number of interviewees also supported the a priori development of statistical analysis plans including methods to address missing PRO data. The imminent publication of guidelines arising from the Setting International Standards in Analyzing Patient‐Reported Outcomes and Quality of Life Endpoints (SISAQOL) Data Consortium should help support trialists to implement this recommendation.There were diverging views around the non‐publication of PRO data.In summary, our interviewees suggested future cancer trials should include more comprehensive PRO trial design and protocol development involving PRO expertise and patient input, with a focus on standardized administration. They also emphasized the need to minimize the burden for patients and staff; prevent missing data; address missing data with appropriate analysis methods; develop a priori PRO analyses and dissemination plans; and train staff. The use of PPI throughout a trial life‐cycle was identified as integral to ensuring PRO data generated through cancer clinical trials are relevant and accessible to people with cancer. Unfortunately, the study findings suggest that stakeholders perceive and observe barriers to the interpretation and dissemination of PRO results, and that key factors that arise during the design and data collection of cancer clinical trials compromise this process.4.1Our qualitative results suggest that the specific features of cancer and treatment affect whether PROs are placed lower in the trial outcome hierarchy as compared to survival outcomes. This appears to shape the expectations of those in the field, conceptualizing trials and determining research questions, perpetuating the relatively low position of PROs in the trial outcome hierarchy. However, the interview findings also suggest that the relative position of PROs in the cancer trial outcome hierarchy could be changing over time. Participants described the growing demand for PRO data due to increasing awareness around the impact of cancer on individual quality of life and the considerable burden associated with the acute, medium‐term, and late effects of treatment. Participants described witnessing relatives and friends undergoing treatment and the lasting long‐term consequences and how this informed the type of information they would seek while considering treatments for themselves. This is echoed in studies outlining the research priorities of those with lived experience of cancer,4.2The strength of this work lies in the use of rigorous methodology; the broad expertise of the interviewees; and the inclusion of numerous stakeholder groups. However, a limitation is that international recruitment efforts were focused on the PRO and cancer methodology experts rather than across all stakeholder groups. A further limitation is that the study was at risk of self‐selection and social desirability bias, whereby participants participated due to a pre‐existing interest in PROs, portray their behaviors positively due to the nature of this study, with increased awareness of methodological issues and need for training. Despite this, the divergence of opinions identified indicates that individuals were sampled with a wide range of views related to PROs. Another possible limitation is that through the inclusion of people with lived experienced of cancer, there may be a bias toward the views of those who have survived and are LWBC. Their perspectives are more likely to reflect issues that pertain to the long‐term impacts of cancer treatments. Similar studies in the future may benefit from the inclusion of people affected by cancer more broadly, including carers, and those who are bereaved.5Our aim was to explore with stakeholders the factors influencing suboptimal PRO protocol content, implementation, and reporting. These qualitative findings suggest that a lack of training, understanding about the value of PRO data (that results in low prioritization of PROs in outcome hierarchy), difficulties associated with the numerous ways to analyze PRO data, and the expertise required to this end can undermine their planning, collection, and reporting can undermine their planning, collection, and reporting.DK, AR, KA, TK, and MC were supported by project funding from Macmillan Cancer Support. JA, LC, AGa, AGl, DK, AL, RT, and DG are all members of the National Cancer Research Institute Psychosocial Oncology and Survivorship CSG subgroup: Understanding and measuring the consequences of cancer and its treatment. AR is partially funded by NIHR Applied Research Collaborative West Midlands. MC is a National Institute for Health Research (NIHR) Senior Investigator and receives funding from the NIHR Birmingham Biomedical Research Centre, the NIHR Surgical Reconstruction and Microbiology Research Centre at the University Hospitals Birmingham NHS Foundation Trust, NIHR Applied Research Collaborative West Midlands, Health Data Research UK, Innovate UK (part of UK Research and Innovation), Macmillan Cancer Support, UCB Pharma, GSK, and the Patient‐Centered Outcomes Research Institute (PCORI). The views expressed are those of the authors and not necessarily those of the NHS, the NIHR, or the Department of Health. MC has received personal fees from Astellas, Takeda, Merck, Daiichi Sankyo, GSK, and Glaukos outside the submitted work. MC has led the development of SPIRIT‐PRO and CONSORT‐PRO international guidance and is a member of the SISAQOL and PROTEUS Consortia. LC has received personal fees from Boehringer Ingelheim outside the submitted work. JA receives funding from EU FP7, NIHR HS&DR, Chief Scientist's Office, Scotland, Macmillan Cancer Support. FE reports consultancy for Abbvie, Amgen, Janssen, Orsenix, Takeda, and grants from Amgen (to his Institution), outside the submitted work. MTK is supported by the Australian Government through Cancer Australia. MTK has received funding from the Australian National Health and Medical Research Council, ABBVIE, and BMS for research unrelated to the submitted work. MTK co‐led the development of SPIRIT‐PRO international guidance and is a member of the SISAQOL and PROTEUS Consortia. JMB receives funding from NIHR, YCR, and CRUK. DK reports grants from Innovate UK, the NIHR, NIHR Birmingham Biomedical Research Centre, and NIHR SRMRC at the University of Birmingham and University Hospitals Birmingham NHS Foundation Trust, and personal fees from Merck outside the submitted work. RMT receives funding from the NIHR Economic and Social Research Council (ESRC), Sarcoma UK, and UCLH Charity. DG and RMT are National Institute for Health Research (NIHR) Senior Nurse Research Leaders. GV is a University of Leeds Professor of Psychosocial and Medical Oncology and Consultant in Medical Oncology at St James's University Hospital, The Leeds Teaching Hospitals Trust and receives funding from Breast Cancer Now, NIHR, EORTC, Yorkshire Cancer Research, Pfizer, and IQVIA. GV reports personal fees from Roche, Eisai, Novartis, and Seattle Genetics outside the submitted work. GV is Chair of the NCRI Living with and Beyond Cancer group and is a member of the board of the EORTC. The views expressed in this article are those of the authors and not necessarily those of the University of Leeds, the NHS, the NIHR, or the Department of Health and Social Care.Appendix S1‐S4Click here for additional data file.


Late working life patterns differ across different social groups and birth cohorts. The mechanisms of these participation differences and role of working life policies can be understood better by using additional working life indicators and historical perspective. This paper investigates how late working life patterns of different age, gender, education groups and birth cohorts are structured in Sweden using participation, employment type, employment break and exit trajectories of different groups. Using Swedish National Registry Data, employment trajectories of the age groups of 60-68 of the birth cohorts 1930, 1935, 1940, 1945 and 1950 are followed. Results show that for all birth cohorts, participation is higher for younger age groups, men and higher educated; leaving the working life before 61 is more common among primary educated; changing employment type in late working life is observed more among higher educated men and usage of sickness compensation is higher among primary educated and women. However, the peak age that individuals exit, and experience employment breaks differs over the years. In addition, although higher educated individuals have lower shares in usage of unemployment and sickness compensation for all birth cohorts, the structure of benefits usage of the other education and gender groups change over the years. Overall, results give important insights how changes in working life policies affect working life patterns of different groups over the years.


Musculoskeletal multimorbidity is common and coexisting lumbar spinal stenosis (LSS) with knee or hip osteoarthritis (OA) has been reported. The aim of this review was to report the prevalence of multimorbid degenerative LSS with knee or hip OA based on clinical and/or imaging case definitions.Literature searches were performed in MEDLINE, EMBASE, CENTRAL, and CINAHL up to May 2021. Studies involving adults with cross-sectional data to estimate the prevalence of co-occurring LSS with knee or hip OA were included. Study selection, data extraction, and risk of bias assessment were performed independently by two reviewers. Results were stratified according to index and comorbid condition, and by case definitions .Ten studies from five countries out of 3891 citations met the inclusion criteria. Sample sizes ranged from 44 to 2,857,999 (median 230) and the mean age in the included studies range from 61 to 73 years (median 66 years). All studies were from secondary care or mixed settings. Nine studies used a combined definition of LSS and one used a clinical definition. Imaging, clinical, and combined case definitions of knee and hip OA were used. The prevalence of multimorbid LSS and knee or hip OA ranged from 0 to 54%, depending on the specified index condition and case definitions used. Six studies each provided prevalence data for index LSS and comorbid knee OA  and comorbid hip OA . Two studies provided prevalence data for index knee OA and comorbid LSS . No studies reporting prevalence data for index hip OA and comorbid LSS were found. Few studies used comparable case definitions and all but one study were rated as high risk of bias.There is evidence that multimorbid LSS with knee or hip OA occurs in people (0 to 54%), although results are based on studies with high risk of bias and surgical populations. Variability in LSS and OA case definitions limit the comparability of studies and prevalence estimates should therefore be interpreted with caution.CRD42020177759).PROSPERO (The online version contains supplementary material available at 10.1186/s12891-022-05104-3. Multimorbidity (the co-existence of two or more chronic conditions) is an increasing health challenge as global populations continue to age –3. ChronThe prevalence of degenerative lumbar spinal stenosis (LSS) with knee or hip osteoarthritis (OA) – three of the most common chronic musculoskeletal conditions in the aging population – continue to rise –10. SimiIn both LSS and OA, radiological and clinical case definitions are used in prevalence estimates, and results differ according to the case definition employed , 16. No Irrespective of criteria used, co-occurring disease is likely important in the clinical decision-making process. Multimorbidity in general is associated with a worse quality of life and future functional decline –20. MuscA comprehensive summary of available literature is needed to determine how frequently LSS and knee and hip OA coexist as a first step in improving clinical decision-making. The overall aim of this review was to report the prevalence of multimorbid degenerative LSS with knee or hip OA based on clinical and/or imaging case definitions.The protocol for this review has been published  and regiThis review had four objectives:To estimate the prevalence of index LSS with comorbid knee OA based on imaging, clinical, and combined case definitions.To estimate the prevalence of index knee OA with comorbid LSS based on imaging, clinical, and combined case definitions.To estimate the prevalence of index LSS with comorbid hip OA based on imaging, clinical, and combined case definitions.To estimate the prevalence of index hip OA with comorbid LSS based on imaging, clinical, and combined case definitions.All case definitions for degenerative LSS and knee and hip OA were included and were broadly classified into three categories as imaging; clinical; and combined diagnoses encompassing both imaging and clinical diagnoses. The following diagnoses and clinical manifestations were included based upon study eligibility criteria: All imaging diagnoses based on radiographic, magnetic resonance imaging, or computerized tomography for the lumbar spine, knee, and hip; clinical diagnoses based on signs and symptoms of LSS, knee OA, and hip OA; all clinical manifestations of LSS  as they represent central, lateral, and combined central and lateral canal stenosis . PatientThe literature search was performed on May 03, 2021 in the following databases with no publication date or language limitation: MEDLINE, EMBASE, CENTRAL, and CINAHL. The search strategy was developed with a health sciences librarian based upon previous Cochrane reviews on LSS  and kneeForward citation tracking of included studies was performed in Web of Science and reference lists were searched for additional relevant studies. The reference list from a recent review on LSS prevalence  was searStudies were considered for inclusion if they: (1) were cross-sectional, cohort or case-control studies, or randomized controlled trials; (2) included adults 18 years or older; (3) assessed the prevalence of co-occurring LSS with knee and/or hip OA or present sufficient cross-sectional data for estimating the prevalence ; and (4) were full-text papers published in English in peer-reviewed journals. Studies were excluded if they: (1) included individuals with low back, knee, or hip pain due to other origins ; (2) were laboratory or cadaveric studies; (3) were conference abstracts; (4) included congenital or non-degenerative forms of LSS, without separate data on degenerative LSS; or (5) provided aggregate prevalence data for knee and hip OA separately.Records identified in the search strategy were screened using a two-stage process by two reviewers (JJY and RKJ) using a sensitive screening approach where any title or abstract mentioning any of the following were moved to full-text review: (1) LSS in isolation; (2) knee or hip OA and comorbidities; (3) knee or hip OA and LBP; or (4) prevalence of multiple musculoskeletal conditions. This approach was taken to mitigate the exclusion of relevant studies due to lack of reporting of information relevant to this review in the abstract. First, reviewers independently screened titles and abstracts against the eligibility criteria. Discrepancies were resolved through discussion.Next, full-text versions of the remaining potentially relevant studies were independently screened. Discrepancies were resolved through discussion or independent review by a third reviewer (CBJ) when necessary. Reasons for exclusion of full-text articles were recorded. All references returned in the database search were managed using Endnote X9  and Covidence systematic review software . Absolute agreement and the Kappa coefficient  was calcThe following information was extracted from all included papers by two independent reviewers (JJY and RKJ) using a standardized extraction form: first author, publication year, country, study design, population , inclusion criteria, study setting, age, sex, case definitions of LSS and knee and/or hip OA, numerator and denominator for prevalence calculation, and items used in the risk of bias assessment.Two reviewers (JJY and RKJ) independently assessed the risk of bias in all included studies using a modified version of the Risk of Bias Tool for Prevalence Studies . ModificIndividual items were rated as “Yes” for low risk of bias or “No” for high risk of bias or if there was insufficient information presented for adequate judgement. No specific quantitative thresholds were used to judge the overall risk of bias. Rather, a judgement on the internal and external validity taking into consideration the responses to each item on the modified tool was used to determine the overall risk of bias  by the two reviewers.Pooled prevalence estimates with 95% CI for each combination of LSS with knee or hip OA (based on case definitions) was performed using a random effects model. Due to the limited number of studies using comparable case definitions for LSS and knee and/or hip OA, only pooled estimates for combined LSS and co-occurring (i) clinical knee OA (ii) imaging knee OA, (iii) clinical hip OA, and (iv) imaging hip OA were calculated and are summarized. One study reporting a prevalence of 0% was artificially given a numerator of 0.001. The low number of studies used in each of the pooled estimates prevented the calculation of heterogeneity statistics and no pre-planned meta-regression analyses  were perThe database search identified a total of 3891 citations with 307 additional citations identified through other sources  with a median age of 66 years (range 61 - 73).n=3) 16], and Future studies should attempt to clarify the role chronic musculoskeletal conditions like LSS and OA play within the larger multimorbid burden faced by individuals and health systems. Musculoskeletal conditions increase one’s risk of developing other non-communicable diseases , evidencThe main limitation of this review is the lack of original studies with a primary objective matching our review question. As a result, included studies were at a high risk of bias, but it is unclear what effect this may have on prevalence estimates. It was also difficult to assess the eligibility of articles based on titles and abstracts alone. We employed an overly sensitive approach to study screening, where any article mentioning “lumbar spinal stenosis” alone, “knee or hip OA and comorbidities”, or multiple musculoskeletal conditions was screened in full text. Despite this approach, two included studies , 45 wereHeterogeneity in case definitions for LSS and lack of studies establishing a valid and reliable method of LSS assessment also limits our findings. Two studies included case definitions such as self-report of conditions and diagnostic codes, which were not easily classified into our pre-specified case definition framework. More available relevant studies would allow for sensitivity analyses to evaluate the assumptions made when classifying these case definitions. Finally, debate exists on the most suitable method of measuring multimorbidity. The method of simply counting the presence of conditions is supported in previous literature , but mayThis review has summarized the evidence for the co-occurrence of LSS with knee or hip OA. There is evidence that LSS with knee or hip OA appears to be common, but that estimates are uncertain as the prevalence ranged from 0 to 54% depending on the joint assessed and case definition. The variability in case definitions used for both LSS and OA, lack of studies on populations outside of secondary care settings, and high risk of bias prevents us from reporting firm estimates. Future high-quality studies on the prevalence of LSS with knee or hip OA are needed.Additional file 1.Additional file 2.Additional file 3.


Although relatively rare in the United States, penile squamous cell carcinoma is encountered worldwide at a higher rate. Initial diagnosis is often made on clinical exam, as almost all of these lesions are externally visible and amenable to biopsy. In distinction to other types of malignancies, penile cancer relies heavily on clinical nodal staging of the inguinal lymph node chains. As with all cancers, imaging plays a role in the initial staging, restaging, and surveillance of these patients. The aim of this manuscript is to highlight the applications, advantages, and limitations of different imaging modalities in the evaluation of penile cancer, including ultrasound, computed tomography, magnetic resonance imaging, and positron emission tomography. Squamous cell carcinoma (SCC) represents the vast majority ≥95%) of penile cancers . While p% of peniPenile SCC can occur at any age but is most commonly seen in men between 50–70 years of age . PatientUpwards of 30% of men will present with palpable inguinal lymph nodes, of which about 60–80% represent regional metastatic spread of penile SCC, with the remainder of patients with inguinal lymphadenopathy representing an inflammatory reaction etiology . Most ofIn this review, we present an update and overview on imaging modalities used for the primary staging, restaging, and post treatment surveillance of penile SCC. We investigate the utilization of different imaging modalities such as ultrasound (US), computed tomography (CT), magnetic resonance (MRI), and positron emission tomography (PET) imaging.Ultrasound may be the initial imaging modality used if a penile mass is identified, largely due to widespread availability, low-cost, and ability to perform in nearly every healthcare setting. Owing to the superficial nature of the penis, ultrasound can readily be used to evaluate abnormalities of the penis, most commonly in cases of suspected fracture and Peyronie’s disease ,15. PeniHowever, a more widespread utilization of ultrasound is in evaluation of inguinal lymphadenopathy. In patients with palpable or suspected inguinal adenopathy, ultrasound is a first-line imaging tool utilized to both diagnose and guide potential percutaneous biopsy. In cancers that commonly metastasize to inguinal lymph nodes, including vulvar cancer, there has been considerable work on standardizing descriptors to more accurately report level of suspicion . In patiFollowing surgical resection and inguinal lymph node dissection, the National Comprehensive Cancer Network (NCCN) and European Association of Urology (EAU) guidelines recommend serial clinical exams to evaluate for recurrence . Unlike Computed tomography (CT) of the chest, abdomen, and pelvis is the most commonly available and most frequently utilized imaging modality for patients with cancer. Although not able to be done portably like ultrasound, CT provides high-contrast images of the soft tissues of the body with high spatial resolution and makes an excellent imaging modality for the detection of metastatic disease. CT is a widely available imaging modality and relatively low-cost in comparison to advanced imaging modalities such as magnetic resonance imaging (MRI) and positron emission tomography (PET). CT utilizes ionizing radiation to obtain images, but the amount of radiation received from medical imaging in patients with cancer is unlikely to cause harm in the vast majority of patients ,22.Initial management strategies and imaging workup in patients with penile cancer is largely driven by the tumor stage and clinical nodal status . Per NCCFollowing definitive treatment, surveillance CT of the chest, abdomen, and pelvis is recommended for patients with N2 or N3 disease . In thesThe superior soft-tissue contrast, multiplanar capabilities, and excellent spatial resolution of MRI make it the imaging modality of choice for local staging of penile cancer. Although US employing high-frequency transducers has better soft-tissue resolution when compared to CT, MRI is superior for local staging. MRI may be used to evaluate the tumor depth of invasion, local extent of tumor (particularly when it involves the base of the penis), and involvement of the tunica albuginea and other adjacent structures. While staging has been traditionally through clinical examination, MRI is superior to physical examination for local staging, particularly for assessing involvement of the corpora cavernosa . If deptOn MR imaging, penile SCC are typically infiltrating masses that are hypointense relative to the corpora on both T1-weighted (T1WI) and T2-weighted images (T2WI) and hyperintense relative to fascia and the tunica albuginea on T2WI. Small field of view (FOV) T2WI are most important for local T-staging and assessment of adjacent structure involvement, including the corpus spongiosum (Category T2 by American Joint Committee on Cancer (AJCC) 8th edition TNM staging, 2017), corpus cavernosum T3), and scrotal skin, pubic bone, or prostate (T4)  fluorodeoxyglucose (FDG), which functions as a glucose analog and demonstrates increased uptake in cancerous lesions secondary to upregulation of glucose metabolism. Following initial injection of radiotracer, there is an uptake phase of approximately one hour to allow for appropriate biodistribution of radiotracer. This tracer is excreted in the genitourinary tract, an important aspect to note given that high concentrations of excreted radiotracer in the bladder and external contamination of radioactive urine on the penis and skin surface can mimic or even obscure malignancy. Additionally, reactive inguinal lymph nodes are commonly seen due to inflammation and can mimic malignancy on FDG-PET/CT. Currently, the NCCN guidelines state that PET/CT can be used interchangeably with CT and MRI and may be the imaging modality of choice in patients with impaired renal function or allergies that prohibit the administration of intravenous contrast.An initial study evaluating the use of FDG-PET/CT for staging patients with both recurrent and newly diagnosed penile cancer enrolled 13 patients and found a sensitivity and specificity of 75% for detection of the primary lesion with better performance for the detection of lymph node metastases . AdditioThere has also been some work in evaluating the use of FDG-PET/CT as a prognostication tool in patients with penile cancer. A study evaluating the use of FDG-PET/CT for prognostication found that patients with higher maximum standardized uptake values in the primary lesion and lymph node metastases were correlated with cancer aggressiveness and cancer-free survival . A separSimilar to CT, PET/CT is recommended by the NCCN guidelines as an option in patients with recurrent or metastatic penile cancer requiring systemic staging  20]. As. As20]. Penile cancer is somewhat of a unique cancer in that the treatment and imaging algorithm heavily relies on clinical examination, particularly of inguinal lymph nodes. Although a relatively rare cancer, it is important for radiologists to understand what drives imaging of these patients and options that exist for staging and restaging these patients. Importantly, while inguinal lymphadenectomy remains standard-of-care for surgical staging, it carries with it an operative risk of morbidity and patients may elect to not undergo the procedure. In these patients, particular attention should be made on follow-up examinations to the inguinal nodal chains to evaluate for metastatic disease. Finally, novel combinations of molecular imaging and sentinel node biopsy offer the potential for disease prognostication and improve the ability to stratify which patient populations benefit from certain treatment approaches more than others.


Traits of organisms are shaped by their living environments and also determined in part by their phylogenetic relationships. For example, phylogenetic relationships often affect the geographic distributions of animals and cause variation in their living environments, which usually play key roles in the life history and determine the functional traits of species. As an ancient family of mammals, bears widely distribute and have evolved some specific strategies for survival and reproduction during their long‐term evolutionary histories. Many studies on the ecology of bears have been conducted in recent decades, but few have focused on the relationships between their geographic distributions and ecological adaptations. Here, using bears as a model system, we collected and reanalyzed data from the available literatures to explore how geographic distributions and phylogenetic relationships shape the functional traits of animals. We found a positive relationship between phylogenetic relatedness and geographic distributions, with bears distributed in adjacent areas applying more similar strategies to survive and reproduce: (a) Bears living at high latitudes consumed a higher proportion of vertebrates, which may provide more fat for adaptation to low temperatures, and (b) their reproduction rhythms follow fluctuations in seasonal forage availability and quality, in which bears reach mating status from March to May and give birth in approximately November or later. We used bears as a model system, and collected and reanalyzed data from the available literature to explore how geographical distribution shapes the functional traits of animals. This is the first time to use the species within a family to explore the relationships between geographic distribution and functional traits of animals and demonstrate the ecological adaptations of animals with close phylogenetic relationships. Gramino2.2http://www.iucnredlist.org). Using the WorldClim database (http://worldclim.com), the monthly and annual temperatures (°C) and precipitation (mm) from 1950 to 2000 were calculated for each species, and the resolution was 340 km2. The nonrandom impact of human activities has had a major impact on the ecology of bears over the past thousand and particularly past hundred years, resulting in the selective loss of ecotypes such as brown bears from the American Southwest . RMT model, diet composition, and seasonal macronutrient composition were carried out and created with GraphPad Prism software version 5.0 (GraphPad Software Inc.). Cluster analysis by environmental variables, including mean temperature, latitude, mean precipitation, ratio of forest area, and human footprint, was used to assess the similarity of different bear environments. Variables were standardized first to remove the influence of dimension and magnitude . To characterize further the relationship between functional traits, phylogeny, and environments, we calculated the Spearman nonparametric rank correlation coefficients for all bears. The correlation in matrix analysis was carried out by using the corrplot package to perform the Pearson correlation analysis through software R (with the corrplot package downloaded from https://cran.r‐project.org/web/packages/corrplot). The correlation coefficient and significance  were extracted through programming statements cor and res. Statistical significance was established a priori as p < .05.We used right‐angled mixture triangles (RMTs) to explore the annual macronutrient composition in eight bears, which represents the 3‐component composition of mixtures in a multidimensional nutrient space , and another consisting of the American black bear, brown bear, and polar bear . Across geographic gradients, the polar bear, brown bear, and American black bear are widely scattered around higher latitudes, while the Asiatic black bear, sun bear, and sloth bear have smaller ranges with adjacent or partly overlapping distributions. The spectacled bear is the only bear species in South America, and the giant panda has the smallest distribution area, located in the mountains of central China.Bears are distributed at different latitudes from the Northern to Southern Hemispheres with increased annual mean temperature  and the highest proportion of invertebrates  and the spectacled bear consumed the highest proportion of plants . The annual macronutrients of bears varied in the RMT model , while the deposition of protein of the hibernating bears was significantly lower than that of the nonhibernating bears . Among all bears, the giant panda ingested the smallest amount of nonprotein energy , summer , and fall .The hibernating bears  and the nonhibernating bears  exhibited different strategies of energy deposition before winter. From spring to fall, the deposition of nonprotein energy (carbohydrates + fat) of hibernating bears was significantly higher than that of nonhibernating bears , bearded seals (Erignathus barbatus), harp seals (Pagophilus groenlandica), and beluga whales (Delphinapterus leucas) ; Data curation (lead); Formal analysis (lead); Methodology (lead); Writing‐original draft (lead); Writing‐review & editing (lead). Meng Wang: Formal analysis ; Methodology ; Software ; Visualization ; Writing‐review & editing . Fuwen Wei: Conceptualization ; Project administration ; Supervision ; Writing‐review & editing . Yonggang Nie: Conceptualization (lead); Project administration (lead); Supervision (lead); Writing‐review & editing .Table S1Click here for additional data file.


The effect of diet on the composition of gut microbiota and the consequent impact on disease risk have been of expanding interest. The present review focuses on current insights of changes associated with dietary protein-induced gut microbial populations and examines their potential roles in the metabolism, health, and disease of animals. Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) protocol was used, and 29 highly relevant articles were obtained, which included 6 mouse studies, 7 pig studies, 15 rat studies, and 1 in vitro study. Analysis of these studies indicated that several factors, such as protein source, protein content, dietary composition (such as carbohydrate content), glycation of protein, processing factors, and protein oxidation, affect the digestibility and bioavailability of dietary proteins. These factors can influence protein fermentation, absorption, and functional properties in the gut and, consequently, impact the composition of gut microbiota and affect human health. While gut microbiota can release metabolites that can affect host physiology either positively or negatively, the selection of quality of protein and suitable food processing conditions are important to have a positive effect of dietary protein on gut microbiota and human health. Recent research provides strong evidence that gut microbiota plays an essential role in human health ,2. In paAmong the various food nutrients, protein has received increasing attention since it is the primary substrate for important beneficial short-chain fatty acids (SCFAs) and harmful putrefactive metabolites , which can be produced by gut microbiota through proteolytic fermentation and may influence host health and contribute to the risk of diseases ,8,9,10. The guidelines of Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) protocol , with a Electronic databases, including PubMed, Scopus, Web of Science (core collection), and Central , were chosen to collect related literature from 2011 to 2021 by using a combination of subject headings, free-text terms, synonyms, and key words relevant to this review. The search terms included “dietary protein” OR “protein intake” OR “protein consumption” OR “protein metabolism” OR “protein digestion” OR “protein fermentation” AND  AND  and de-duplicated prior to screening the abstracts for relevance. Studies that investigated the effects of protein source/dose modification on the gut microbiota were deemed as potentially relevant, and other records were deemed irrelevant. Full-text articles of the relevant studies were reviewed and assessed for eligibility according to prespecified eligibility criteria. Studies were included if they met all the following criteria: (1) performed experimental research (dietary interventions/treatments) on healthy humans, mice, rats, pigs, or in vitro; (2) dietary interventions or experimental research with protein modification was the primary aim; (3) dietary interventions that administered normal or high protein doses or increasing levels of protein; (4) presence of control; and (5) measured abundances or quantified gut microbial populations.Supplementary data or supporting information were also referred to during the extraction of relevant data from studies using a predesigned form. The extracted data can be summarized as: (1) model characteristics ; (2) the type of sample analyzed for gut microbiota ; (3) dietary protein characteristics (type and dose); (4) impact of dietary protein on gut microbiota  in gut microbial population induced by protein sources compared to the control. Gut microbiota changes that were not reported in text were derived from reported figures and tables of relative abundances or concentrations of various bacterial populations. If changes in microbial populations were not significant, the increasing and decreasing trends of various bacteria were recorded. If there were no differences in abundances of bacteria compared to the control, it was not recorded unless it was the most abundant phylum, family, or genus in the control or if the control had the highest/lowest abundance of the particular population compared to other diet groups in the study.(a)If the most abundant population in that diet group, one asterisk was placed after classification (*);(b)If the most or least abundant population in that diet group compared to all other diet groups, two asterisks were placed after classification (**);(c)If the most abundant population in that diet group, as well as compared to other diet groups, three asterisks were placed after classification (***);(d)If least abundant compared to other diet groups but most abundant in that diet group, four asterisks were placed after classification (****);(e)If there are no differences in the number of asterisks for a particular bacterial population between diet groups, then there are no differences in the abundance of the corresponding microbial population amongst those diet groups.Specific details regarding the indication of abundances are given below:n = 59), Scopus (n = 755), Web of Science (core collection) (n = 441), Central  (n = 114), and from the manual-searching of reference lists (n = 21). A total of 407 duplicate records were removed by the de-duplication process, and the remaining 983 records were evaluated for relevance, which subsequently resulted in 828 records that were deemed irrelevant according to the study selection criteria. We excluded studies that were conducted on other animals  and insects (48), studies investigated dietary interventions on unhealthy participants with an acute or chronic disease/condition (14), studies reporting on protein effects not being the primary aim (35), studies which focused on low protein or protein-deficient/restricted diets (23), and studies that implemented ineligible control (fiber) and experimental designs (6). A total of 29 studies were found to meet all the set criteria and were selected to be included in this systematic review. These studies included 6 mouse studies, 7 pig studies, 15 rat studies, and 1 in vitro study, which are discussed in detail in the subsequent sections. The bibliometric information of these 29 studies can be found in The process of the literature selection is shown in Proteins are widely found in nature, and their nutritional, structural, and functional properties vary dramatically ,44. ThesAkkermansia increased in rats fed on hen egg white, whereas higher relative abundance of Proteobacteria and Peptostreptococcaceae and lower relative abundance of Lachnospiraceae were found in rats fed on duck egg white  secreased . The decellulose , which md indole . Thus, id indole . Increass phylum . The decimmunity , and theimmunity  as well immunity . Lower aimmunity . Howeverimmunity , which cimmunity  due to pimmunity .While the impact of traditional thermal processing methods on the composition of microbiota has been studied as discussed above, the effects of novel thermal technologies, such as microwave or ohmic heating, have not been evaluated yet. Microwave processing of food proteins at high temperatures induces several modifications, such as cross-link formation, changes in secondary structures and hydrophobicity, and the glycation of proteins through the Maillard reaction . MicrowaLactococcus was markedly increased in rats fed with glycated fish protein (GFP) compared to a group of rats that were fed with fish protein (FP). Interestingly, the relative abundance of Holdemania, Streptococcus, Enterococcus, and Lactobacillus was increased upon feeding GFP heated for 48 h compared to feeding GFP heated for 24 h. This change in the microbiota population may reduce the production of ammonia and indole that have detrimental effects on the host’s health  f protein . Allobacobaculum  and Eubaacterium  are butymponents , which pParabacteroides and a lower abundance of Bifidobacterium, Sutterella, Parasutterella genera, and Clostridium Cluster XIV compared to rats fed with gelled-coarse emulsions (lipoprotein) [Akkermansia muciniphila, Clostridiaceae, Streptococcaceae, Bifidobacterium, and Clostridium Cluster XIV. Similarly, the abundance of Lactobacillaceae (in the ileum) and the β-diversity of caecum mucus-associated bacteria were enhanced in rats fed with liquid-fine emulsion [Akkermansia muciniphila is known to demonstrate favorable functions such as strengthening the integrity of the gut barrier, enhancing gut health, and providing protection from several diseases [Clostridium Cluster XIV and Bifidobacterium are involved in metabolizing undigestible nutrients and producing beneficial metabolites such as short-chain fatty acids, which maintain intestinal homeostasis [Clostridiaceae, which has been associated with protein metabolism, is known to consist of opportunistic pathogens [Clostridiaceae has been linked to the prevalence of arthritis in inflammatory bowel disease and rheumatoid arthritis patients [Streptococcaceae consists of numerous opportunistic pathogens [Additionally, digestibility and absorption of dietary protein were influenced by the structure of the lipoprotein emulsion . Rats feprotein)  (Table 1emulsion  (Table 1diseases , includidiseases . Clostrieostasis . Thus, iathogens , and an patients . Streptoathogens . Hence, PRISMA protocol was used as a key strategy to search and collect relevant studies to conduct a systematic review on the impact of protein on gut microbiota. While this approach resulted in a comprehensive summary of studies published from 2011 to 2020, there are some limitations in the present study. The animal subjects varied in breed, origin, age, and number among the summarized studies, and these are well-known factors that can affect the composition of gut microbiota ,149. SomThe gut microbiome is a complex system that is influenced by several factors, and its role in health and disease is of paramount importance. Analysis of the selected studies outlines the positive and negative effects of various dietary proteins and highlights the effects of some protein modifications on protein–microbiota interactions and their impact on gut microbiota. The reviewed studies suggest that diet induces rapid alterations in the gut microbial composition, and these alterations may be temporary due to the high resilience of the gut microbiota that can restore a balanced state. Protein content, its source, processing methods, and interactions with other nutrients are some of the factors that can regulate the digestion of dietary proteins and metabolites generated by gut microbiota. These entailing areas can be further investigated to expand our understanding of protein functionality and to minimize the adverse effects associated with proteolytic fermentation. Future studies should focus on evaluating the impact of dietary interventions of longer durations and monitor temporal microbiota changes to elucidate the impact of long-term consumption of various proteins on gut microbiota. Additionally, the complexity and variation in the gut microbial profiles of the individual subjects should be considered, which may lead to variations in physiological effects of different dietary proteins and differences in the risk of diseases among individuals. In this context, the adaptation of gut microbiota in individuals from different cultural and race backgrounds needs to be investigated to understand long-term colonization and potential sensitivities to protein and diet changes. Investigation into the influence of dietary protein on gut microbiota at a species level is also required to elucidate the impact of specific gut bacterial populations on host physiology due to high functional redundancy amongst various gut microbes.


This article comments on:Ben-Targem M, Ripper D, Bayer M, Ragni L. 2021. Auxin and gibberellin signaling cross-talk promotes hypocotyl xylem expansion and cambium homeostasis. Journal of Experimental Botany 72, 3647–3660. Secondary growth generates wood, which constitutes most of the plant biomass. Despite considerable efforts over the last decade to uncover the genetic and molecular regulation of the vascular cambium, there is still much to learn about how it produces wood (xylem) inward and bast (phloem) outward. Secondary growth is initiated when procambial cells between primary xylem and phloem begin to divide to form cambium that gives rise to more xylem and phloem, which increases organ girth. The secondary xylem supports the plant and provide means for water transport, whereas the phloem allows for sugar and signaling molecule translocation. In eudicots and gymnosperms, secondary growth is initiated in stems, roots, as well as in the hypocotyl, the embryonic stem joining the root with the stem (reviewed by WOX4 and the KNAT1/BREVIPEDICELLUS (BP) genes are mutated. Hence, the new finding by ARF6 and ARF8 in combination with KNAT1/BP also result in close to complete loss of cambium formation contributes potentially new and important players for the initiation and maintenance of the cambium.Recent research has drastically enhanced our understanding of how cambium is initiated and maintained in Arabidopsis , recentlIn the transition to the xylem expansion phase, the hormone GA plays the lead role . In roseet al. to address the relevance of these factors for xylem expansion phase regulation.Because DELLAs bind a large set of different proteins, they also constitute a means to integrate GA signaling with signaling by other hormones . In the ARF6 and ARF8, suggesting that they are important for the development of this tissue. Indeed, loss of function of these ARFs resulted in increased phloem divisions and formation of phloem fibers, but also in reduction of the xylem area. These phenotypes are similar to effects of expressing dominant DELLA mutants insensitive to GA degradation. Further supporting that the DELLAs act via ARF6 and ARF8, mutations in these genes prevented the enhanced xylem area that normally results from exogenous application of GA  Secondary growth is initiated as auxin defines immature xylem cells as cambial organizers. These organizers induce stem cell activity in neighboring cells (Populus wood development (Climate change has generated a strong need for efficient sequestration of carbon dioxide, and the woody biomass of trees is outstanding in its ability to store carbon (GA signaling and, in particular, DELLA function have been implicated in various abiotic stresses. Cold, salt, and drought stress lead to lowered levels of active GA and consequently enhanced DELLA activity (reviewed by


Since the development of a Bachelor of Arts in public health, a common question among prospective students, faculty, and community members has been asked: “What will students do after graduation?” While national data on graduates are abundant, community inquiries sought more detailed profiles of local graduates. To address this need, data on 224 graduates of the Bachelors of Arts in Public Health (BAPH) degree at the University of Hawai‘i at Mānoa were collected through alumni outreach efforts and professional online profile searches. Data were compiled into a summary presentation and program “resume”. Findings indicated roughly 30% of BAPH graduates pursued graduate-level education and 43% were employed within a year of graduation. Employment in local NGOs and healthcare organizations was common, while bureaucratic challenges limited hiring at public agencies. A review of job titles suggested graduates were employed in program coordination or support staffing. Local program profiles, such as this one, complement national employment data. Moreover, these efforts may foster interest among prospective students and support from faculty, administrators, and employers. Public health has never been more important than during this troubling time of both pandemic and health infodemic. Mass media exposure to public health professions has fostered community interest and created prospective students.The State of Hawai‘i has been short of healthcare workers perennially, particularly those trained in public health. An estimated 2200 non-physician healthcare positions were open between 2018 and 2019 , 4. The As only 17% of public health professionals are formally trained in public health nationwide , 6 underIn a recent review of 33 student outcome reports, Krasna et al. mainly found individual case studies of program satisfaction with little systematic reporting and difficulty comparing outcomes between schools. The heterogeneity among curriculum among a large number of program types  with public health majors do not allow for easy cross-comparison of outcomes, as induced from the review by Holsinger et al. .Detailed program-specific analyzes of graduate outcomes are rare . PreviouA global review of public health student outcomes yielded much information into the outcomes of master's and doctorate graduates but little regarding those earning bachelor's degrees. A detailed investigation by Dlungwane and Knight  focused The University of Hawai‘i at Mānoa (UHM) is a land-grant university, public educational center intended to provide high-quality education in service to the local and indigenous community. Besides traditional health sciences academic programs, UHM provides practical services and training to meet local vocational needs. The Office of Public Health Studies (OPHS) graduate program served as the primary educational pipeline for the local public health workforce since 1962, granting both masters and doctoral degrees .As the public health response evolved  and the Multiple stakeholders collaborated in the development of the BAPH and in the process raised a plethora of difficult but necessary questions . All parRegardless, BAPH graduates filled local health agencies and employers requested graduates to fit specific job titles and sites. In time, OPHS faculty collected this data and much more from BAPH graduates in order to address community and industry inquiries methodically and meet Council for Education in Public Health (CEPH) accreditation standards. Here, we share collected BAPH graduation outcomes with implications for community dissemination.Current education and job information was collected, including field of study/employment, to identify continuity within the public health sector. One year after commencement, faculty and staff inquired into every graduate's outcomes. First, a Student Support Specialist noted students on the commencement roster who transitioned into graduate programs within OPHS . The same staff member utilized the MyUH enrollment management system to capture outcome data on other continuing students in closely affiliated health sciences programs . While a notable portion of the graduating class continued studying at UHM, other graduates were harder to survey.Then, the Specialist transferred any results from the Undergraduate Alumni Update Form, which is regularly promoted by faculty whenever graduates contact the program or faculty. The form polls current positions, as well as accomplishments and achievements. Often, faculty and staff interact regularly with recent graduates working with partnered social service organizations and affiliated clinical settings; any student outcomes gleaned from these personnel were relayed to the Specialist, who then entered the information into the outcomes database.Next, the Specialist searched the LinkedIn social networking site for publicly available data regarding current employment or enrollment of the remaining graduates and combined these findings from public updates on Facebook and Instagram. A targeted email to undergraduate faculty requesting new contact information or outcomes findings for recent graduates was sent also. This procedure determined the outcomes for many remaining undetermined cases. Many instances of graduate-initiated contact with faculty occurs annually due to the close-knit community context, limited class sizes, and overlapping advising and teaching roles of many staff. When letters of recommendation or reference requests are made, faculty consistently asked about post-graduation schooling and employment outcomes. The aggregate findings in the student outcomes database were confirmed and verified by the Undergraduate Chair.While a standardized survey to determine graduate outcomes was developed, the dissemination of a mass survey was not ideal for three reasons: (a) logistical difficulties caused by the pivot to distance learning; (b) cultural considerations of sharing personal and professional updates; and (c) a need for a concise, informal questionnaire to complement regular, in-depth surveys for eventual reporting to CEPH, the University of Hawai‘i System, and the Office of Public Health Studies' Community Advisory Panel. Therefore, OPHS chose to collect data individually, when possible. The data collection procedure served to compile all outcome data into a singular database for analysis.From program inception to the conclusion of the Spring 2020 semester, 224 students had graduated with a BAPH degree from the University of Hawai‘i at Mānoa. The average graduating class size is 44 with a range of 32 to 56 graduates per academic year. Of the 224 graduates, 67 (29.9%) were pursuing continued education, 98 (43.8%) were employed, 8 (3.6%) were seeking employment, 4 (1.8%) were not seeking employment), 4 (1.8%) were Peace Corps Volunteers, and 43 (19.2%) were undetermined due to lack of response. Of the 67 graduates continuing their education, 29 (43.3%) were pursuing graduate degrees in public health, 17 (25.4%) were enrolled in nursing programs, either at the bachelor's or master's degree level, 5 (7.5%) were in medical school, and 11 (16.4%) were in allied health, including social work, nutrition, chiropractic, or pharmacy programs. It is essential to note a limitation of this survey methodology—the risk of selection bias is high, as non-respondents may have a higher rate of unemployment, underemployment, or no pursuit of further education.Of the 98 graduates reporting employment, 63 (64.3%) were employed in health-related positions. Employment sites included local public health non-profit agencies, residential living facilities, clinical care settings, or governmental public health branches, in Hawai‘i and throughout the Pacific. Only one graduate was employed at the local department of health where challenges exist with hiring procedures, including required years of work experience, and what opportunities may be considered toward this experience. Similar challenges are reported nationally . Other eTo facilitate communication of alumni data to the OPHS' Community Advisory Panel, as well as to respond to inquiries from community members and prospective students, alumni data was summarized in the format of a resume for the BAPH program. The program resume features summary information regarding the program, including key marketable skills, and includes sample position titles of current alumni, as well as a sampling of local and national agencies employing recent BAPH graduates. This communication tool  has sincMaintenance and growth of the healthcare workforce are critical and of increasing significance given both an aging workforce looking toward retirement  and the Employment data collected clearly shows the BAPH program at OPHS is filling public health employment opportunities, especially in entry-level public health positions, both locally and nationally. BAPH graduates are more likely to enter the job market immediately after graduation compared to graduates elsewhere due to the higher cost of living and larger proportion of jobs that do not require graduate or professional degrees; this finding supports the assertion by Resnick et al. . CompareFor alumni, entry-level employment has allowed those with a BAPH degree to both build meaningful careers in public health and gain valuable work experience in anticipation of graduate program application. Only through the methodical collection of detailed graduate outcome data, such as specific job titles and descriptions, could these determinations be made. For alumni looking to enter graduate degree programs immediately upon graduation, the BAPH program provides a strong educational foundation and a pipeline for graduate-level education. Consequently, OPHS master's degrees have appreciated access to an engaged and well-prepared student body from which to recruit.From a programmatic perspective, regularly reviewing alumni data serves both program evaluation purposes and helps support proposed revisions to curriculum and student support. In evaluation, alumni data help faculty identify current, and evolving, training and skills needed for highly marketable candidates. It further allows the BAPH program to remain sensitive to relevant community needs. It is especially critical in Hawai‘i and the Pacific to continuously gauge local and regional community needs, due to unique challenges of workforce recruitment and retention , 4. ThesWhile additional analyzes and continuous data collection are necessary, profiles of local public health degree program graduates may be supportive in complementing national graduation data, and further communicating the benefit of local alumni to address community workforce needs.The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.DN-H and MT contributed conception and design of the project and data collection. DN-H wrote the first draft of the manuscript. All authors contributed to data analysis, wrote sections of the manuscript, contributed to manuscript revision, read, and approved the submitted version.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.