According to an article published in 2013 in the International Journal of Information Management, by Michel Laroche et al., entitled “To be or not to be in social media: How brand loyalty is affected by social media?”, there seems to be an emergent debate regarding the activities of brands and companies on Social Media. Some researchers consider that Social Media offer an exclusive opportunity for brands to cultivate their relationships with customers, while others think the opposite. As consequence, a new concept appeared, that of brand community based on Social Media. Considering this concept and the one of brand trust and loyalty, there seems to be an influence on the customer centric model, meaning the relationships between the targeted customer and brand, services, ophthalmological organization, and other customers, and brand loyalty. Thus, it was concluded that brand communities established on Social Media have positive effects on the customer and the services, the brand, and the ophthalmological organization, which have positive effects on brand trust and brand loyalty. Brand loyalty can be defined as a behavior of the customer that implies the repeatedly purchase of a product or service offered by the same ophthalmological organization, instead of selecting a similar product or service offered by the competition. Brand loyalty is measured by marketers in terms of brand recognition, brand preference and brand insistence. Loyal customers continuously buy products or services from their preferred ophthalmological organizations or brand, regardless of the price. For example, an eccentric person who likes and has been accustomed with Gucci eyeglasses will always choose this brand because it satisfies his/ her needs at all levels. Regarding loyalty, there are two types: transactional and emotional. According to The Clarus Blog (www.claruscommerce.com), there is a focus on experiential benefits in the media, but transactional benefits still have an important role. Therefore, transactional loyalty refers to traditional benefits, such as discounts and free shipping/ giveaways, which affect consumer’s behavioral loyalty. Moreover, transactional loyalty seems to be an attractive and necessary element in building brand advocates. At the same time, experiential loyalty increases the member experience and creates sustainable emotional connections between brands and customers. It is a fact that customers seek material benefits along with special treatment, which, most of the time, is expressed in the form of experiences. Experiences lead to emotional loyalty, which is the liaison between transactional and true loyalty. Emotional loyalty is defined by a psychological preference and affective attachment to the brand. In the same vein, it has been uncovered that there are two types of loyal customers, who are influenced by four factors: dependability, emotional connection, superiority, and Social Media presence. In order to have loyal customers, brands must prove their superiority compared to the competition. Once the customers become loyal, they will improve the brand’s image by commenting, sharing, liking, or posting brand-related content on social platforms. These actions will lead to lots of followers. In conclusion, there are some methods to build and maintain customer loyalty, such as offering discounts, rewarding customers, promoting the rewards program, encouraging referrals, creating a point system, creating a partnership with another company, setting up a subscription service, asking for feedback, asking for reviews, responding to feedback & reviews, paying attention to social sentiment, showing gratitude, using a CRM for loyalty management, personalizing sales & marketing, creating loyalty tiers, engaging customers, maintaining a human connection, making the ophthalmological organization available, prioritizing emotional relationships, speaking the language of the customers, being honest, being flexible, remembering the customers’ special days, offering the customers wish lists, etc. With the latest analytics technology, ophthalmological organizations can offer discounts on products or ophthalmological services that customers purchase regularly, as well as products that complement prior purchases. Even if it is for elderly, students, or children, offering a discount is the perfect way to recognize (and retain) key segments of the ophthalmological organization base.Rewards usually represent a pleasant surprise for the customer. When offering rewards, it is important to include an expiration date, so that ophthalmological customers are encouraged to buy the products or services before the deadline. A rewards program should be created, but it should also be made known to the customers, so that they would sign up. A friend referral program should be created in order to reward both existent customers and gain new ones. Considering the loyalty systems that exist nowadays, ophthalmological organizations can offer various types of rewards on purchases, status level, and other customer features. Some ophthalmological organizations offer their customers the possibility to receive rewards or points with partner companies, thus, partnering with other relevant brands represents another way to boost and improve the image of the ophthalmological organization. A subscription-based program is also very important to retain customers on long-term and offers incentives for the customers that they may not receive anywhere else.Informing customers that their feedback is much appreciated by the ophthalmological organization only proves that the organization is committed to improving products or services in order to better satisfy their needs. Reviews represent authentic testimonials from real people. A customer who is unsure will always check reviews to find out other people’s experiences with the ophthalmological organization, and decide if they wish to benefit from the products or services of a certain ophthalmological organization. Moreover, collecting reviews also represents an opportunity to transform happy customers into brand advocates. Asking the customers for their opinions is of utmost importance, as it is to answer to the customers’ reviews received by the ophthalmological organization. Analyzing social sentiment (public perception) is another way to find out how customers think and feel about the ophthalmological organization, expressed via social media platforms. Expressing gratitude to the customers is a key element. In addition, ophthalmological organizations should find a way to thank every customer who has bought a product or a service. Gratitude can be expressed via “Thank you” notes, packaging inserts, holiday cards, birthday cards, etc.A CRM system helps collecting and storing customer data, such as purchase habits, transaction histories, customer service records, etc. This Customer Relationship Management system helps to better understand customers, in order to personalize their experiences and increase the chances of turning them into loyal customers for the brand.In addition, personalization of the products and services represents one of the most effective ways to draw attention to the brand. More purchases and rewards can be offered by setting up a tiered customer loyalty program. Thus, customers earn points with every visit to the ophthalmological organization, which materialize into discounts. It is a fact that engaged customers are loyal customers. As far as one-on-one interactions are concerned, they are very much valued, even if everything is digitized nowadays. As already known, the customers can take different and many roads to get to the organization, so it is important that there is “speaker” to represent the brand. In the competitive market nowadays, customer satisfaction is not considered the element that makes the difference anymore. The modern customer wishes to have an experiential experience, besides the meeting of his/ her basic needs.Speaking the customer’s language is an expression that may be taken literally, meaning that it is important that the products or services are translated into the native language of the customers so that they are purchased and, at the same time, offering multilingual services is a good way to demonstrate that the ophthalmological organization values all its customers, no matter their ethnicity. Honesty is always the best policy, because a small mistake that is not solved immediately, may lead to data breach, which leads to loosing trust and loyalty of the customers. Flexibility is also a key element, which will ensure a positive review of the ophthalmological organization. The ophthalmological organization should make sure that the marketing department sends emails or postcards to acknowledge the customers’ special days, such as birthdays, for example. They can even offer special birthday discounts or free products or services to help the cause. Last, but not least, there are loyalty programs, whose aim is to remind about customers who need to be given the ability to keep track of their favorite products, such as eyeglasses, sunglasses, contact lens, etc. Giving customers the ability to keep track of their favorite items or create wish lists is another feature that most successful loyalty programs offer. Assist. Prof. Consuela-Mădălina Gheorghe, PhD,Philologist, Authorized translator


Access to exercise for cancer survivors is poor despite global recognition of its benefits. Telerehabilitation may overcome barriers to exercise for cancer survivors but is not routinely offered.Following the rapid implementation of an exercise-based telerehabilitation program in response to COVID-19, a process evaluation was conducted to understand the impact on patients, staff, and the health service with the aim of informing future program development.A mixed methods evaluation was completed for a telerehabilitation program for cancer survivors admitted between March and December 2020. Interviews were conducted with patients and staff involved in implementation. Routinely collected hospital data  were also assessed. Patients received an 8-week telerehabilitation intervention including one-on-one health coaching via telehealth, online group exercise and education, information portal, and home exercise prescription. Quantitative data were reported descriptively, and qualitative interview data were coded and mapped to the Proctor model for implementation research.The telerehabilitation program received 175 new referrals over 8 months. Of those eligible, 123 of 150 (82%) commenced the study. There were no major adverse events. Adherence to health coaching was high , but participation in online group exercise classes was low . Patients improved their self-reported physical activity levels by a median of 110 minutes per week (IQR 90-401) by program completion. Patients were satisfied with telerehabilitation, but clinicians reported a mixed experience of pride in rapid care delivery contrasting with loss of personal connections. The average health service cost per patient was Aus $1104 (US $790).Telerehabilitation is safe, feasible, and improved outcomes for cancer survivors. Learnings from this study may inform the ongoing implementation of cancer telerehabilitation. International guidelines promote exercise and rehabilitation as part of high-quality cancer care . ExercisFew specialized exercise-based rehabilitation programs exist for cancer survivors . Cancer A rapid uptake of telehealth to provide exercise for cancer survivors occurred during the COVID-19 pandemic due to social distancing restrictions . There iA process evaluation using a mixed methods approach was completed to understand the implementation of cancer telerehabilitation within a subacute hospital setting. The Proctor model for implementation research provided an evaluation framework comprising a taxonomy of three categories  of which this study focused on eight key outcomes: safety, acceptability, adoption, feasibility, fidelity, cost, satisfaction, and quality of life . This stThe study was set in a large publicly funded health network in metropolitan Melbourne, Australia. The health network services approximately 3000 cancer survivors annually. A multidisciplinary, in-person group, exercise-based cancer rehabilitation program delivered in an ambulatory setting was replaced by a comprehensive telerehabilitation program in March 2020 due to COVID-19 restrictions. Prior to COVID-19, telehealth was not offered to patients. Pre–COVID-19, the cancer rehabilitation program included twice-weekly, 1-hour supervised group exercise and once-weekly multidisciplinary group education over 7 weeks. The average cost of the in-person program to the health service was Aus $1402 (US $1004) per patient (Aus $108 [US $77] per session), to which patients contributed Aus $140 (US $100).The telerehabilitation program was an 8-week supervised program with multiple components delivered by a nurse coordinator, 3 physiotherapists, and an allied health assistant . PatientPatients were referred and admitted to the telerehabilitation program between March 23 and December 1, 2020. Patients who were referred to the oncology rehabilitation program prior to March 23 and transitioned from an in-person program, and who received more than one telerehabilitation session were also included in the analysis. To be eligible, patients had to be adult cancer survivors currently receiving or within 12 months of cancer treatment . Patients with a cognitive impairment or receiving end of life care were excluded from the program. Patients may have been referred to an alternative rehabilitation service offering more supervision if they had recently been discharged from the hospital or had higher functional needs  in line with existing service criteria. For routinely collected data, individual patient consent was not sought, as the clinical members of the research team would normally have access to these data. Consent for postprogram data was implied through completion of an online survey, which included a participant information sheet.Clinicians, administration staff, and managers directly involved in the implementation of the cancer telerehabilitation program were invited to participate in an interview. Staff participating in interviews provided written informed consent.Data were collected from a variety of sources .Staff were invited to participate in either a 1-hour focus group or 1:1 interview at the conclusion of program implementation to discuss their perceptions and experience of delivering the telerehabilitation model. These discussions focused on areas of safety, acceptability, adoption, feasibility, fidelity, and costs .Patient perceptions and experiences of telerehabilitation were collected via an online survey  or telephone following the conclusion of the program to determine acceptability, feasibility, and satisfaction. The survey included the System Usability Scale, a 10-item questionnaire measuring usability with five response options (strongly agree to strongly disagree) . Four opSafety was assessed by recording adverse events from the medical record. Other routinely collected service data, including participant demographics , were cRoutine patient-reported outcome measures described the feasibility and client outcomes. These included health-related quality of life (EQ-5D ), total An analysis of session content documented in the medical record further assessed safety, feasibility, and fidelity. Routinely collected online metadata from the iLearn platform also informed feasibility and fidelity.Program costs of the traditional and telerehabilitation model were derived from the calculation of staff salaries in line with industrial agreements and estimates of software costs for delivery of telehealth obtained from the organization’s information technology department. An average cost per patient, per session was calculated using the total admitted patients and total program costs.Patient characteristics, adherence, safety, costs, and satisfaction were reported descriptively. Completers were defined as patients who completed at least 50% of the health coaching sessions (4 sessions). Only completers with completed postprogram measures were included in the analysis of client outcomes. Pre- and postpatient outcome data are reported using means and SDs calculated from normally distributed data and medians and IQRs for nonnormally distributed data. Within-group changes were calculated using Wilcoxon signed rank tests, as data were not normally distributed.The content of the open-ended survey comments were coded and grouped into themes by two researchers independently using an inductive approach. Interviews were audio recorded and transcribed verbatim. Transcripts were deidentified and assigned an identification number to ensure anonymity. Transcripts were read and independently coded line by line by three authors  and using open coding . Codes were categorized and discussed until consensus was reached on themes that were then mapped deductively onto the Proctor model.A content analysis of telerehabilitation sessions was completed from a random sample of medical records from 50 patients. The documentation recorded in the medical record was assessed against predetermined criteria  to deterDuring the 8-month data collection period, 175 new referrals were received, most from oncology/hematology outpatient specialist clinics. Of the eligible referrals, 123 patients (including participants referred prior to COVID-19) commenced the program, representing 82% (123/150) uptake . The medPatients admitted to the program on average were aged 65 (IQR 56-72) years and 57% (n=66) were female. The most common diagnosis was breast cancer , followed by multiple myeloma . A total of 74 (60%) patients had advanced cancer, and 85% (n=104) were receiving treatment on admission to the program with the primary treatment being chemotherapy . One patient had a noninjurious fall while completing their home exercise program unsupervised, another fell while walking (outside of the program) resulting in a hand fracture, but these events did not limit ongoing program participation. Five patients fell unrelated to exercise. One patient developed new lymphedema during the program.A total of 12 patients experienced disease progression after program admission. Overall, 16 patients were admitted to the hospital during the program , with 4 unable to continue beyond initial assessment and 3 unable to continue their rehabilitation program on discharge from hospital. Two patients died from an acute medical deterioration unrelated to program participation.Overall, telerehabilitation was perceived as safe but staff acknowledged difficulty balancing safety needs with providing an adequate exercise prescription. Perception of safety was increased when patients used video. Staff also expressed reservations related to their competency to provide telehealth safely due to the rapid transition .I think in terms of fitting with the model, the key difference [with telerehabilitation was] of safety and clinicians being able to monitor or assess their technique or how they're responding to the exercise.Participant 3Surveys were returned by 82 cancer survivors (67% response rate). A total of 7 staff  participated in a focus group, and 1 manager was interviewed.The program was acceptable to both patients and clinicians. The median score on the System Usability Scale was 77.5 (IQR 67.5-90), indicating above average usability of telerehabilitation.rollercoaster. The program was largely viewed by staff as a positive and acceptable form of delivering care. The team described pride in being able to deliver an innovative model of care in a short time frame:Staff described implementation of the program as a They [the team] all see it as a positive...all of them are quite proud of what they've achieved...Participant 8The manager highlighted the value of the program’s flexibility, and all staff perceived it to be convenient for patients. However, the positives of telerehabilitation were counterbalanced by challenges of this new service delivery mode.Staff felt isolated from each other and patients, and reflected on the importance of personal connections. Nonphysiotherapy staff felt a loss of connection with patients, while physiotherapists described a strengthening of patient connections. The whole team felt disconnected from each other, emotionally drained, and missed the dynamic group environment of the traditional rehabilitation model.Program staff described being impressed with the rapid transition to telehealth. Clinical and administrative staff attributed the success of the implementation to the combined efforts of the team, including their organizational, technical skills, and can-do attitude:It was quite a rapid COVID force transitioning to this model...amazing how hurdles were jumped...There was very much a can-do mindset, from the team I think, across the board.Participant 2There was desire from all staff to continue with telerehabilitation into the future. The manager described the need for this model to be translated to other rehabilitation settings although questioned whether implementation of telerehabilitation in other chronic disease programs within the health service would be as successful as cancer rehabilitation who they perceived to comprise a cohort of younger patients in better health. This view contrasted with clinical staff who described a challenging cohort deconditioned with advanced cancer.The main concern with ongoing adoption of the telerehabilitation model was from clinicians, who perceived that existing resources may be insufficient to provide the time and staff required to implement the model long term.Staff acknowledged telehealth could be implemented in a cancer rehabilitation setting and described being seen by others within and beyond the organization as exemplars for telerehabilitation. They described the advantage of accessing existing supports that facilitated the transition. This included the organization’s existing telehealth platform and remote information technology support. However, clinicians at times felt underprepared to deliver telerehabilitation and wanted more guidance:What we were giving our patients was safe and effective but then that was the tip of the iceberg...all the way below was all these other systems and processes that we had to get our heads around...Participant 3One of the main challenges of the program described by participants was poor internet infrastructure and lack of private space to complete online consults. Participants had difficulty accessing rooms for teleconferencing as they were shared with other programs within the hospital. There was also poor Wi-Fi coverage within certain hospital areas. Staff described the benefits of having hardware but that it was not helpful when the internet did not work.All patients received health coaching from a physiotherapist. A total of 61 (50%) patients received at least one nursing session. A total of 17 patients were referred to other disciplines from supporting programs . Most sessions were conducted via videoconference , followed by telephone , with the remaining sessions conducted in person. The average individual telehealth session duration was 25 (SD 9) minutes. Patients attended 80% (674/843) of scheduled 1:1 telehealth sessions. The primary reasons for nonattendance were unable to contact/forgot , followed by conflicting appointments . Of the 50 patients included in the retrospective file audit, 44 (88%) received a home exercise program. Behavior change interventions were used by physiotherapists in all 1:1 consults. Goal setting was the most used intervention , followed by demonstration  and evoking change talk .A total of 36 (29%) patients attended all telerehabilitation components at least once . A total of 61 (50%) participants accessed the online portal at least once. The exercise webinar received the most views (n=40), followed by advanced care planning (n=34). A total of 18 (15%) patients attended >50% of online group exercise sessions. In the file audit, 19 of 50 (38%) patients attended online group exercise, and 17 of 50 (34%) attended live online group education. The most frequently attended live online education session was from the dietitian .Physiotherapists perceived the program was effective for some patients, particularly those who engaged well with technology. However, they described a preference for delivering in-person care, as they felt more able to assess, monitor, and correct exercise prescription. Patients also described exercise monitoring as a key advantage of in-person care. Staff described adequate resourcing as essential to effective telerehabilitation delivery :It’s hard knowing that they might not get, as much benefit...because ideally they would push a bit harder but just from a safety perspective. I didn’t want them to.Participant 4There was no cost to patients receiving telerehabilitation. Three patients required a home visit due to safety concerns, and 8 participants attended sessions at the center, as the program transitioned in and out of COVID-19 restrictions at a cost of Aus $10 (US $7) per in-person visit.The primary resource cost was funding of staff . ExistinThere were differing perceptions about the costs of telerehabilitation among staff. The manager described minimal costs associated with program setup and perceived efficiency in the new model. In contrast, clinicians described telerehabilitation as resource intensive compared to the previous group program due to perceived higher human resource costs from additional administrative burden of program setup and delivery, and the 1:1 nature of consults:If they understood the funding requirement to get the throughput they want they couldn’t possibly support it.Participant 4Overall, 71 of 80 patients surveyed were satisfied with the telerehabilitation program, and 65 of 79 patients surveyed thought their health and well-being improved. Patients rated their confidence to continue exercising after the program positively (average 8/10). A positive experience was reported by most users in the open-ended responses :I am so impressed by the wonderful support the team gave me. It was unexpected but truly made a huge difference in my wellness journey.Most benefits of the telerehabilitation program related to general support provided by the program. Patients commented frequently on their positive interactions with staff, who were described as helpful, friendly, and knowledgeable. Patients enjoyed learning new information to aid their recovery, especially related to exercise. The main challenge of the program was technology difficulties such as poor internet connection or audio-visual feedback. Other challenges were personal barriers related to their medical status including low motivation and fatigue.Benefits of telerehabilitationConvenience and efficiency“Telehealth means no driving or paying for parking which is good”“Better use of time, because I could do it when it suits me”“Telerehabilitation is my preferred option for its convenience. The easier it is, the more likely I am to participate”“I loved the whole experience. You could exercise at your own pace and I was able to conserve the energy usually taken up by getting in and out of the car for the appointment to be able to exercise more efficiently”Safe“It was better because I did not get exposed to COVID, but I could still connect to people, which was very important during these times, especially in lockdown and I was isolated”“Obviously being immunocompromised after transplant not having to travel for physio and risk exposure was beneficial”“It is a very good alternative to in-person rehabilitation, when in-person is not feasible”Communication“liked reading the followup notes - did a few days ahead of appointment prepare”“Pictures and clear instructions were easy to follow. The online tutorials were helpful as well”“I found [Physio] very easy to talk to and she was able to explain the various exercises clearly and concisely”General clinician support and understanding“the support of the clinicians and the professionalism, everyone answered my questions”“being able to have someone to talk to as to how I was feeling and understood where I was at particularly during COVID lockdown”“probably the tailored exercises and having an excellent physiotherapist who listened and understood my issues”Access to friendly, knowledgeable staff“being able to see the rehab specialist smiling face”“The weekly chats/inspiration with [physio] and her practical solutions”“Focussed presenters and knew their subject”Gained motivation“It has been just excellent for me, the physiotherapist talked me through the program, it was had the biggest impact on me because I was lazy and not exercising due to my diagnosis and COVID. The program gave me the motivation to exercise and made me feel good and confident to exercise with cancer”“The weekly checkins and being able to talk to someone made me accountable. I felt inspired, [Physio] was super and had good tips”“Weekly contact made me supported and motivated”Learning new things“Every week was outstanding, I learnt new things and all my questions were answered”“Having one person to discuss the benefits and advice given when needed, also having someone there for clarification. The education program also was very beneficial especially the Pharmacist session”“Learning how to exercise and I could feel myself getting stronger”Access to exercise“It was good to make me exercise while I was incapacitated”“The demonstration of the exercises is useful and the introduction to other forms of exercise such as Tai Chi and Feldenkrais were great. It encouraged me to look these forms of exercise on Youtube”“Suggestions of exercises that I would not have thought of myself”Personalized care“Targeted exercises for my special needs”“personal involvement in my rehab prior to my return to regular gym”“Individualised care and exercise program adjustments”Challenges of telerehabilitationLack of social interaction“I enjoy the social interaction and seeing the person so I think I would have gotten a lot more out of attending a group at the centre”“The physical presence provides other support, like motivation, conversation, interaction , and spontaneous reaction with the physiotherapist and fellow participants, leading to a more relaxed environment”“I feel more motivated if I have to go to the centre, it gets lonely having to do exercise by yourself”Issues with fidelity“It is different because your movements are not checked by a qualified person rather, it’s just shown to you via a video. So if a movement is incorrectly performed it’s not corrected”“1:1 and in person is better because someone can monitor you in real time”“Not attending on site and having access to the additional exercise equipment”Technology difficulties“I am not proficient at using the computer so found it tricky to get into the program at times”“Phone reception terrible but otherwise ok”“Variable connectivity in telehealth sessions”Lack of audio/visual feedback“some exercises were hard over the phone”“Not getting feedback about how I was performing and making adjustments, corrections, changes when appropriate. Sometimes it was difficult to see and hear the exercise performed- distance from the camera of the person performing the exercise/quality of the microphone...”“I am wary about services where the clinician cannot see the patient, you lose some input”Managing symptoms“Became challenging to do rehab as pain increased”“I have been attending other health appointments through the phone as well and I get tired talking over the phone. I did not get to exercise in a group with other people”“Sometimes I had low energy to participate in the classes”Low motivation“It had a big impact on my mental health, I was not motivated and I felt isolated”“Being inconsistent with the exercises during lock down. It's funny how excuses seem to infer with the exercise program and at times medical conditions interfere as well”“Daily exercising in house is hard. My day is busy with household activities”P<.001). There was no change in EQ-5D index scores .Health-related quality of life improved on the EQ-5D VAS . Reported sedentary behavior decreased from 7.5 (IQR 5-10) hours per day to 6 (IQR 4-8) hours per day .From available data, 39% (n=43) of patients were meeting recommended physical activity levels at baseline, completing a median 100 (IQR 20-240) minutes of moderate-to-vigorous physical activity per week. By the end of the program, 65% (n=57) of patients met recommended physical activity levels, completing a median of 210 (IQR 90-401) minutes of moderate-to-vigorous physical activity per week (Z=–4.896; This process evaluation demonstrated that a comprehensive telerehabilitation program is safe and feasible to improve health outcomes for cancer survivors. There was good program uptake and adherence to individual telehealth sessions, which was facilitated by convenience. Patients reported high satisfaction and ease interacting with telerehabilitation. Staff also described a positive experience with telerehabilitation, but this was counterbalanced by emotional fatigue and loss of personal connections. This process evaluation provides a practical outline of how telerehabilitation can be implemented and guidance for future development of cancer rehabilitation programs.Telerehabilitation is an acceptable and feasible alternative to in-person care. Patients described the program as easy to use despite technical difficulties, and many would opt for a similar model in the future. Program satisfaction came from emotional and practical support rather than factors related to the modality of training. Key benefits related to interactions provided by staff, consistent with traditional models of cancer rehabilitation . HoweverTelerehabilitation may help facilitate access to exercise for cancer survivors. Uptake was higher, and adherence to 1:1 telehealth sessions was comparable to in-person cancer rehabilitation delivered in nonresearch settings -35. PatiCost-effectiveness data for cancer telerehabilitation is lacking . In thisPatients made clinically significant improvements in self-reported physical activity levels. At baseline, patients completed a median of 100 minutes of moderate-to-vigorous physical activity per week, while at program completion, patients completed a median of 210 minutes per week, exceeding physical activity recommendations. This is noteworthy given that low physical activity is a problem in people receiving cancer rehabilitation  and thatTo our knowledge, this is the first study to conduct a process evaluation with an exercise-based cancer telerehabilitation program. This study was reported in accordance with STROBE and TIDieR guidelines, which will assist replication of findings in other cancer settings. A strength of this research increasing generalizability is that it evaluates a pragmatic program in a public hospital setting, including older people and those with advanced cancer who are frequently omitted from exercise oncology research.A limitation of this study is that it includes a relatively small nonrandomized sample of patients with a risk of selection bias. However, a broad demographic of cancer survivors was represented, and the inclusion of telephone interventions ensured access to the program would not be limited to patients with internet. A limited cost analysis was completed that did not consider patient, travel, or infrastructure costs, which may underestimate the value of telerehabilitation. Physical activity levels in this study were measured by self-report and therefore are subject to recall bias. In addition, no outcomes from the in-person program were available for comparison, as routinely collected outcome measures were changed in response to the change in program delivery. However, the primary aim of this study was not to demonstrate efficacy but rather to understand implementation to guide future models of cancer rehabilitation.rollercoaster. Our findings demonstrate telerehabilitation is affordable and can be translated pragmatically and quickly into hospital settings, which may improve access to exercise for cancer survivors. However, staff implementing telerehabilitation programs need adequate support. Further research is required to confirm the efficacy and cost-effectiveness of exercise-based telerehabilitation programs, so they can be integrated into standard care.This study demonstrated that exercise-based cancer rehabilitation delivered by telehealth is safe, feasible, and accepted by patients. Clinicians reported a mixed experience with telerehabilitation implementation, describing it as a


In gout, crystallization of uric acid in the form of monosodium urate (MSU) leads to a painful inflammatory response. MSU crystals induce inflammation by activating the complement system and various immune cell types, and by inducing necrotic cell death. We previously found that the soluble pattern recognition molecule C-reactive protein (CRP) recognizes MSU crystals, while enhancing complement activation. In the absence of CRP, MSU crystals still induced complement activation, suggesting additional CRP-independent mechanisms of complement activation. In the present study, we searched for additional MSU crystal-binding complement activators. We found that all healthy individuals, even unborn children, have MSU crystal-specific immunoglobulin M (IgM) in their blood. This indicates that innate IgM, also known as natural IgM, recognizes these crystals. In serum lacking IgM and CRP, MSU crystals showed negligible complement activation as assessed by the production of the anaphylatoxins C4a, C3a, and C5a . We show that IgM and CRP both activate the classical complement pathway on MSU crystals. CRP was more efficient at fixating active C1 on the crystals and inducing release of the most inflammatory anaphylatoxin C5a, indicating non-redundant functions of CRP. Notably, while CRP recognizes MSU crystals but not the related calcium pyrophosphate dihydrate (CPPD) crystals, natural IgM bound to both, suggesting common and distinct mechanisms of recognition of individual crystal types by complement activators. Crystals also indirectly stimulate and recruit immune cells by activating the complement system6 and by inducing cell death, which leads to release of danger-associated molecular patterns that further drive the inflammatory response8. Together these mechanisms cause a sterile inflammatory response that is hardly distinguishable from a microbe induced inflammation. Bacterial infection is thus the most important differential diagnosis of acute gout3.Deposition of crystals within joints can lead to the development of arthritis. While crystallization of uric acid in the form of monosodium urate (MSU) leads to gout, the symptomatically similar disease, pseudogout, is caused by the formation of calcium pyrophosphate dihydrate (CPPD) crystals. Both crystal types are inducing sterile inflammation by directly activating immune cells9. It is characterized by the sequential activation (proteolytic cleavage) of its protein components upon binding to a surface, e.g., of bacteria. Three main pathways for complement activation have been described, which converge at the activation of the central complement component C3: (1) the classical pathway relies mainly on binding of complement activators like IgM, IgG, or CRP, which recruit and activate complement factor C1. (2) The lectin pathway is C1-independently initiating the cascade through MBL, ficolins, or IgA, activating MASP-1/2. Both classical and lectin pathway activate C2 and C4 to generate a C3 convertase. (3) The alternative pathway relies on auto-activation of complement protein C3 which is enhanced by other factors 10. Activated C3 then leads to cleavage of C5 to induce formation of the membrane attack complex consisting of factors C5b-9 , which forms pores in the membrane of attacked cells. Activation (by proteolytic cleavage) of C4, C3, and C5 leads to release of inflammatory peptides C4a, C3a, and C5a, which are collectively called anaphylatoxins. They activate distinct receptors and lead to distinct responses. While C4a mainly enhances endothelial permeability11, C3a and C5a act chemotactic for immune cells, activate mast cells, or induce inflammatory gene expression. The membrane attack complex can also be released in its soluble form (sC5b-9) and induce immune cell activation12.The complement system is part of the humoral immune system14. In normal human serum, a functional C5 convertase assembles on the surface of MSU crystals and cleaves C5 to generate anaphylatoxin C5a and sC5b-95. C5a generated by MSU crystals was found to enhance IL-1β production in vitro15. Recently, mice deficient for the central complement component C3 or the receptor for anaphylatoxin C5a were shown to exhibit strongly reduced neutrophil influx and IL-1β production upon intraperitoneal injection of MSU crystals17. C6-deficient rabbits showed reduced MSU crystal-induced inflammation suggesting C5b-9 may also be involved18. MSU crystals activate the classical complement pathway independently of IgG, which was believed to depend on binding of C1 directly to the crystals19, while one report showed that complement activation (C3 cleavage) could be enhanced by addition of CRP and IgG20. Others found that the alternative pathway contributes to MSU-dependent complement activation22. CPPD crystals also activate the alternative complement pathway. Complement activators recognizing CPPD crystals are unknown.As early as 1973, Naff and Byers found that MSU crystals activate the complement system23. It is unclear if the complement system uses similar mechanisms to recognize crystals.To recognize microbes, the complement system uses innate complement activators that recognize conserved microbial patterns, called pattern recognition molecules, or antibodies that have been raised by the adaptive immune system against a specific microbe or microbial structure24. As an acute phase protein, CRP concentration in the blood strongly increases during inflammation, e.g., during gout flares. We showed that CRP is required for fixation of active C1 of the classical and active MASP-1 of the lectin complement pathway on the surface of MSU crystals. We also showed enhanced fixation of C3 and C5b-9 in the presence of CRP suggesting CRP principally activates the complete complement pathway on the surface of MSU crystals. Similarly, CRP had been found before to bind to cholesterol crystals to activate the complement system25, which suggests that CRP may be a more general crystal-recognition molecule. In the absence of CRP, complement activation by both MSU and cholesterol crystals was partly preserved, so CRP-independent mechanisms of complement activation exist. CPPD crystals are special in that they are not recognized by CRP24, while still activating the complement system.We recently purified MSU crystal-binding proteins and found that C-reactive protein (CRP) is one of the strongest MSU crystal-binding proteins in human body fluidsIn this study, we set out to find the additional complement activators for MSU crystals. We found a second innate immune sensor  that binds to both MSU and CPPD crystals to drive CRP-independent complement activation, and we compared the ability of IgM and CRP to induce production of the anaphylatoxins C4a, C3a, and C5a.S. cerevisiae containing mainly β-glucans. We had incubated both MSU crystals and zymosan in human serum, washed away the unbound proteins, eluted the bound proteins, and subjected them to LC-MS26. Among the bound proteins, we had found CRP and the related pentraxin serum amyloid P (SAP)24. So far, we were unable to show a role for SAP in complement activation by MSU crystals (data not shown). Thus, we searched for other complement activating proteins within the identified crystal-binding proteins. As antibodies are common activators of complement, we analyzed the fraction of each immunoglobulin isotype bound to MSU crystals and zymosan . IgA was also low in these IgM-deficient sera, while IgG levels were in the normal range. In these IgM/IgA-deficient serum samples very low signals were obtained, showing the specificity of the assay. Staining with anti-IgG showed again more IgG binding to zymosan than to MSU crystals. However, in this analysis using a flow cytometer, one of the normal human serum samples also showed binding of IgG to both MSU crystal preparations, suggesting that weaker interactions are retained in this assay. Next, we tested if IgM binds directly to the crystals or indirectly via other serum proteins. IgM purified from healthy individuals  showed slightly stronger binding in serum-free albumin (BSA) solution than in IgM-deficient serum, indicating that in principle IgM can bind directly to the crystals , silica particles (SiO2), and cholesterol crystals. IgM only weakly bound to these particles as compared to MSU crystals . As a control particle we had used zymosan, a fungal cell wall preparation from san Fig. ”. All issan Fig. . We testsan Fig. c. As a cals Fig. d. A monoTo test the impact of IgM on crystal-induced complement activation, we used the same serum samples obtained from CVID patients with serum IgM concentrations below 0.05 mg/ml.We reconstituted IgM/IgA-deficient serum with polyclonal and monoclonal IgM that we already used in Fig. We started this study to find the complement activator that can compensate for CRP in its absence. To test if CRP has non-redundant roles in complement activation in the presence or absence of the identified second complement activator IgM, we reconstituted normal human pool sera or IgM/IgA-deficient sera with CRP. We analyzed the production of anaphylatoxins  and the final product of the pathway (sC5b-9) after incubation with MSU or t-CPPD crystals, which are not recognized by CRP, as a control.In pool sera from healthy individuals, CRP did not significantly enhance C4a and C3a production  but enhanced the production of C5a and sC5b-9   Fig. b. Both i24) Fig. b, confir25, CRP induced C4a generation by cholesterol crystals, while some C3a and C5a production was seen in the absence of CRP, likely activated by redundant complement activators30.To verify that CRP-mediated complement activation is dependent on the presence of MSU crystals, we repeated the experiment with three IgM/IgA-deficient sera and incubated them without crystals, MSU crystals, and cholesterol crystals, which are also recognized by CRP Fig. . CRP did24. Since IgM is known to activate the classical pathway via C1, we analyzed C1s, C3, and C5 fixation on MSU crystals in the absence of IgM . C1s is activated by cleavage and one of the cleavage products is observed at 55 kDa (denoted as C1s*). Upon activation, we always observed another band of C1s, which has an apparent molecular weight higher than full length C1s (denoted C1s + X). As it is stable in reducing SDS-PAGE, it is likely a fusion with another protein via a peptide bond. In the absence of IgM/IgA, we did not see reduced binding of the activated C1s. When we quantified the intensity of the band of activated C1s* observed on blots of four normal and six IgM/IgA-deficient serum samples, the difference was not statistically significant  on the surface of MSU crystals even in IgM-sufficient serumant Fig. . TogetheIn summary, we have identified natural IgM as a CRP-independent complement activator for MSU crystals, while we show that CRP is more efficient at fixating complement factors on the crystals and inducing later complement activation products C5a and sC5b-9.32. Uptake of crystals not necessarily requires specific receptors either, as the crystals directly interact with the plasma membrane34. However, several transmembrane receptors have been shown to recognize MSU crystals rather specifically and/or to be involved in MSU crystal-induced inflammation39. Additionally, we found a remarkably specific binding of CRP to MSU crystals but not the related CPPD crystals, suggesting soluble pattern recognition molecules recognize crystal surfaces. In this study, we identify natural IgM as a second soluble molecule for MSU crystal recognition by the complement system. Most proteins that show strong binding to MSU crystals have in common that they have multiple binding sites: CRP and IgM are homopentamers, MARCO is a homotrimer, and Clec12A oligomerizes40. Multiple interactions of low affinity may lead to a high avidity interaction of the whole molecule with the crystal surface, which is probably necessary since a classical key-lock recognition mechanism seems unlikely for the various crystal surfaces. In line with this notion, the CRP related pentraxin SAP and ficolin 2, both pentamers bind to cholesterol30, and we found both also on the surface of MSU crystals24.Inflammation during a gout flare is hardly distinguishable from inflammation induced by microbes. Thus, it is likely driven by the same pattern recognition molecules/receptors as microbe-induced inflammation. What remains unclear so far is if these receptors specifically recognize the crystals. The NLRP3 inflammasome is a main driver of crystal-induced inflammation, but it does not seem to interact with crystals but rather senses damage induced by the crystals to plasma membrane or lysosome41. It has been shown not only to bind various microbes but also to play a role in complement activation by necrotic cells and the heparin:PF4 complex, which is targeted in heparin-induced thrombocytopenia44. Other “naturally occurring” antibodies arise from the poly-reactivity or cross-reactivity of IgM produced in infancy in response to ubiquitous microbes, as has been established for antibodies against ABO blood type antigens45. We found similar binding of IgM to MSU crystals incubated in cord blood or adult serum, suggesting that the MSU-specific IgM in adult serum is natural. As we cannot differentiate between the origins of the MSU crystal-binding IgM in adult serum, we also cannot exclude the possibility that IgM raised against foreign antigens contributes to the pool of crystal-binding IgM in adult serum. Still, natural IgM recognizes MSU crystals and unlike CRP also binds to CPPD crystals.Natural IgM is believed to be produced by B1 B-cells independent of any foreign antigens, presumably in response to self-antigens30. It will be interesting to see, if absence of C1q also enhances binding of IgM to MSU and CPPD crystals.As expected, we found that both IgM and CRP activate the classical complement pathway on the surface of MSU crystals. Notably, IgM was less efficient at fixating complement factors on the surface of the crystals. This could be due to a weaker or unstable binding of IgM to the crystals or partly indirect binding. While we showed that IgM is in principle capable of binding the crystals directly Fig. d, it may17, and C5b-9 may activate the NLRP3 inflammasome in bystander cells48. Thus, it is likely that high CRP levels during an acute phase reaction increase the likelihood of the initiation of a gout attack.CRP binds directly to the crystals and is especially efficient at inducing the late complement activation products C5a and sC5b-9. Both C5a and C5b-9 have been shown to be involved in MSU-induced inflammation in animal models. C5a acts as a chemoattractant and can induce expression of inflammatory genes like proIL-1β25. Thus, also on those crystals, CRP drives the complement system to the very end. This is in contrast to other ligands of CRP, where CRP additionally recruits the inhibitory complement factor H (CFH) to stop complement activation beyond C349. This does not appear to happen on MSU and cholesterol crystals for yet unknown reasons.Before our findings, CRP had already been shown to recognize cholesterol crystals to activate the complement system, and to co-localize with C5b-9 complexes in human atherosclerotic plaques29, the lectin pathway via ficolin-2, and recruit C1q via IgM30, showing some overlap with MSU crystals. Two early reports also demonstrated alternative pathway activation by MSU crystals22. Whether this requires CRP or IgM remains to be seen. Recently, it was shown that several nanoparticles activate the alternative pathway via IgG50. This may also happen on MSU crystals, depending on the presence of MSU crystal-binding IgG. We have found very low levels of MSU crystal-binding IgG in most individuals, at least when tested in serum. In line with earlier results51, we found that purified IgG binds to MSU crystals in the absence of competing serum proteins (data not shown), similar to the unspecific monoclonal IgM we used in this study , or under certain experimental conditions. One report showed that addition of IgG could enhance complement activation by MSU crystals20. Thus, it remains to be seen under which conditions IgG activates complement on MSU crystals. It is possible that gout patients develop MSU crystal-specific IgG as MSU crystals may act as antigens for an immune response, or that there are individuals with autoantibodies reacting with serum proteins that coat the crystals. At least one serum we used in our study showed IgG binding to MSU crystals. So, it may be worthwhile to screen patients for these antibodies to find out if these antibodies are associated with a medical condition and what they bind to: crystals or coated proteins.Cholesterol crystals additionally activate the alternative pathwayIn two out of eleven IgM/IgA-deficient sera in which CRP was depleted, early complement activation was preserved Fig. a. These 54, while the pentraxin PTX3 has been shown to inhibit crystallization of calcium oxalate55. It remains to be seen if CRP or human IgM also alter crystallization of urates, the prerequisite for the development of gout.Besides activation of the complement system, binding of CRP or IgM to crystals may alter gout pathophysiology also by other mechanisms. In mice, MSU crystal-binding IgM are required for precipitation of uric acid and its adjuvant propertiesWe used left-over diagnostic samples of serum obtained from healthy individuals  and 11 CVID patients who showed IgM and IgA levels below 0.05 g/l . All serum samples had IgG levels in the reference range, while we did not inquire in which cases this was due to immunoglobulin replacement therapy. Most sera were collected before any SARS-CoV-2 vaccines were available in Germany. Samples were frozen at − 80 °C until use. CVID patient sera were kept at 3–5 °C o/n before freezing to allow completion of diagnostic tests first. Integrity of the complement system in those sera was verified by measuring CH50 before freezing. Only serum samples that were above the mean of the normal range of the test were used.Three additional normal single donor complement-preserved serum samples (#ICERS10ML), and pooled cord blood serum samples (#IRHUCDS1ML) were obtained from Innovative Research, Inc, Novi, MI. Pooled serum was generated by mixing serum of 3 single donors. All donors gave informed written consent. This study was approved by the Ethics Committee of the Hannover Medical School (Ref. No: 3395-2016) and was performed in accordance with the ethical standards laid out in the 1964 Declaration of Helsinki and its later amendments.2+, 0.9 mM Mg2+, and 5.5 mM d-glucose  was used. It was saturated with sodium urate to prevent dissolution of the MSU crystals.Whenever crystals were in contact with buffer, HBSS containing 1.26 mM CaPolyclonal and monoclonal human immunoglobulins used in the reconstitution experiments were obtained from Athens Research & Technology, Inc., Athens, GA . Purity of the antibodies was verified by SDS-PAGE -agarose (ca. 5 µl packed beads)  under mild agitation at 4 °C over-night. PC-agarose was removed by centrifugation at 2000×MSU crystals: Lot 1 : 10 mM uric acid  was dissolved by boiling in ultrapure water containing 10 mM NaOH. After cooling to 60 °C, the pH was adjusted to 7.7, and 500 mM NaCl was added. Crystals formed under mild agitation at RT. They were harvested and either stored as dry powder at 4 °C or taken up in Hanks’ balanced salt solution (HBSS) at 50 mg/ml. Lot 2 : 20 mM uric acid was dissolved by boiling in ultrapure water containing 20 mM NaOH. After cooling to 60 °C, the pH was adjusted to 8, and the solution was sterile filtered. Solutions were maintained under mild agitation at RT for 48 h. Crystals were harvested on a sterile filter, washed with ethanol p.a., dried overnight at 60 °C, taken up in phosphate-buffered saline (PBS) at 50 mg/ml, and stored at 4 °C or − 20 °C. An additional preparation was obtained from Invivogen .t-CPPD and m-CPPD were prepared as previously described56 using sodium pyrophosphate instead of potassium pyrophosphate as the starting material. Lot 1 was prepared in the laboratory of KN, and lot 2 was prepared in the laboratory of Christèle Combes, CIRIMAT, Université de Toulouse, Toulouse INP—ENSIACET, 31030, Toulouse, France.Silica (Silicon dioxide) particles (− 325 mesh) were purchased from Alfa Aesar (#88316). Calcium carbonate crystals were prepared as described26.Zymosan was purchased from Merck KGaA (#Z4250), washed 3× in 100% ethanol, stored in 100% ethanol at − 20 °C. Before use, zymosan was washed 3–4 times with HBSS.g for 2 min and washed with HBSS. IgM and IgG were detected using PE anti-human IgM antibody  and PE anti-human IgG Fc antibody  (both diluted 1:25 in HBSS + 5% BSA), respectively. Particle fluorescence was analyzed using a FACS Canto II (BD Biosciences) and BD FACSDiva software version 6.1.3 (www.bdbiosciences.com). Flowing Software version 2.5.1  was used for analysis of data obtained.Crystals (100 µg) were incubated in 50 µl serum or HBSS + 10% BSA for 30 min at 37 °C with mild agitation. Crystals were harvested by centrifugation at 1000×26 and images were acquired using an Olympus IX81 inverted microscope and CellR software . Brightness was adjusted, pseudo-color was inserted in the grayscale image, and scale bar was added using ImageJ .Fluorescence microscopy was performed as described beforeg for 2 min .1 mg crystals were incubated in 50 µl serum for 30 min at 37 °C and harvested by centrifugation at 1000×Supernatants were directly diluted in reducing SDS-PAGE buffer , and crystals were washed 5 × in HBSS saturated with sodium urate and transferred to a fresh 1.5-ml tube before elution of the bound proteins using 40 µl of 2 × reducing SDS-PAGE buffer at 70 °C for 10 min.Proteins were separated on precast SDS-PAGE gels  and transferred to nitrocellulose membranes . The membranes were blocked in TBST + 5% BSA and incubated with primary antibody in TBST + 5% BSA o/n at 4 °C. After incubation with HRP-coupled secondary antibodies , the blots were subjected to ECL reaction. Images were acquired using a ChemoStar imager (INTAS Science Imaging Instruments GmbH), and quantification of Western blot signals was performed with ImageJ software (version 1.53e).The following primary antibodies were used at the indicated dilution: anti-C1S , anti-C3/C3b/C3c , anti-C5 , anti-IgA , anti-IgM  , anti-ApoB , and anti-IgG (H + L) .For coomassie staining, gels were incubated in PageBlue .1.5-ml polypropylene tubes were blocked with 30% heat-inactivated FBS at 4 °C o/n. Crystals (1 mg) were incubated in 50 µl of serum in these blocked tubes for 30 min at 37 °C with mild agitation. The supernatant was harvested and C3a, C4a, and C5a concentration was determined using the BD CBA human anaphylatoxin kit  and sC5b-9 concentration was determined using human TCC ELISA  according to the manufacturer’s recommendations.www.graphpad.com/scientific-software/prism/). A p value of < 0.05 was considered statistically significant. Data generated using a flow cytometer represents the median fluorescent intensity of 5–10 k particles measured.Unless otherwise stated in the figure legends, paired or unpaired Student’s two-tailed t-test was performed to compare the means of two groups. All analyses were performed using GraphPad Prism version 9 (GraphPad Software; Supplementary Information 1.Supplementary Information 2.


ABSTRACT IMPACT: This work demonstrates the integration of interactive mindfulness and dialogue sessions in curricula is both desired by students and effective in conferring resilience, a protective factor that may aid in maintaining wellbeing of trainees interested in pursuing graduate studies in biomedical research and science. OBJECTIVES/GOALS: To support student futures in the field of biomedicine, Mayo Clinic Graduate School of Biological Sciences utilized digital platforms to deliver a summer research program in the summer of 2020. One goal of this program, in addition to scholastic outcomes and research experience, was to support and improve the wellbeing of college student participants. METHODS/STUDY POPULATION: Following the cancellation of in-person summer research programs, students were invited to attend a digital Summer Foundations in Research program. The 4-week program included 4 small group dialogue sessions led by trained facilitators and 4 large group mindfulness seminars followed with 3 Q/A style small group sessions. Surveys were delivered on days 1, 27, and 3 months following the program. Wellbeing measures included Brief Resilience, Perceived Stress, and Satisfaction with Life Scales. Students were prompted to indicate how worthwhile they found course components and comment on why they rated each component the way they did. Wellbeing results were assessed using paired t-tests with Bonferroni correction for multiple comparisons. Thematic analysis was used to interpret qualitative results. RESULTS/ANTICIPATED RESULTS: Students improved across all wellbeing measures at the program conclusion, including resilience (mean difference(SE) pre- to post-program +0.22(0.06) p=0.0007), perceived stress (-1.71(0.66) p=0.0116), and life satisfaction (+1.57(0.52) p=0.0037). Gains in resilience were maintained 3 months out (pre-program to 3 month survey +0.28(0.06) p<0.0001). To our surprise, mindfulness was the highest rated component of the research program with 85% (121/142) of students rating the mindfulness component ‘extremely’ or ‘quite worthwhile.’ At 3 months, 81% (74/91) reported continued use of one or more skills learned in the mindfulness sessions. Student comments endorsed the perceived importance of interactive mindfulness and dialogue sessions to the program and to careers in biomedical science and research. DISCUSSION/SIGNIFICANCE OF FINDINGS: Our results support the use of interactive mindfulness and dialogue programming as a participant supported, evidence-based approach to strengthen the resilience of undergraduate students pursuing careers in biomedicine. In the future, booster programming may be considered to maintain improvements in perceived stress and life satisfaction.


Socioeconomic disparities in the adoption of preventive health programs represent a well-known challenge, with programs delivered via the web serving as a potential solution. The preventive health program examined in this study is a large-scale, open-access web-based platform operating in the Netherlands, which aims to improve the health behaviors and wellness of its participants.This study aims to examine the differences in the adoption of the website and mobile app of a web-based preventive health program across socioeconomic groups.The 83,466 participants in this longitudinal, nonexperimental study were individuals who had signed up for the health program between July 2012 and September 2019. The rate of program adoption per delivery means was estimated using the Prentice, Williams, and Peterson Gap–Time model, with the measure of neighborhood socioeconomic status (NSES) used to distinguish between population segments with different socioeconomic characteristics. Registration to the health program was voluntary and free, and not within a controlled study setting, allowing the observation of the true rate of adoption.The estimation results indicate that program adoption across socioeconomic groups varies depending on the program’s delivery means. For the website, higher NSES groups have a higher likelihood of program adoption compared with the lowest NSES group . For the mobile app, the opposite holds: higher NSES groups have a lower likelihood of program adoption compared with the lowest NSES group .Promoting preventive health programs using mobile apps can help to increase program adoption among the lowest socioeconomic segments. Given the increasing use of mobile phones among disadvantaged population groups, structuring future health interventions to include mobile apps as means of delivery can support the stride toward diminishing health disparities. Noncommunicable diseases currently account for more than half of the global burden of disease, causing an ever-increasing proportion of premature deaths in both low- and high-income countries . This ocSocioeconomic disparities in the adoption of preventive health programs are a well-known challenge ,8, with The health program examined in this study is the SamenGezond  platform. Originally introduced by the health insurance company Menzis, the health program is aimed at the general Dutch population, following the goals of improving the health behaviors and wellness of its participants. The SamenGezond program was originally offered in the form of a website (introduced in 2012) and subsequently expanded to also include a mobile app (in 2017). Currently, reaching approximately 1 million participants, the program offers a set of activities and coaching that support healthy nutrition, physical activity, and other health behaviors.With an increasing proportion of health programs being delivered through the web , it is oThe database analyzed in this study originated from the SamenGezond platform, a large-scale web-based health program delivered by a health insurance company to the general Dutch population. The health program was introduced in July 2012, initially through a website, and starting in October 2017, expanded to also include a mobile app. The website of the health program mainly comprises information and coaching related to wellness and healthy lifestyle. The mobile app is an extension of the website, introducing several additional features to the health program, such as the ability to record activities with GPS, interact with an internet-based coach, and set and complete health goals. All program participants initially used the website of the program, with a subsequent choice of enrolling for the mobile app or continuing the use of solely the website. Although the health program is offered by a health insurance company, its participants are not solely clients of this company but can also be insured elsewhere .fit-score based on the individual activities within the platform. The program also offers benefits in the form of accumulated points from participation in the various sections of the platform, which can be used to acquire specific products, vouchers for various services, gadgets, or charity contributions.The health program’s aim is to improve the lifestyle and wellness of its participants by focusing on physical activity, healthy eating habits, social activity, mental health, good sleep habits, and minimized stress. The activities that are provided involve entering or recording physical activities, reading articles, setting goals, including friends in challenges, answering health questions, being assisted by an internet-based coach, and forming a daily Enrollment to the health program was open and free, and all the participants involved in this study provided their voluntary and informed consent. Approval for this project was obtained from the institutional review board of the University of Groningen.Data were collected between 2012 and 2019 and analyzed in 2020 and 2021 within a longitudinal, nonexperimental study design. This study design was used as it allows for the examination of the duration until adoption of the 2 components of the health program for a large group of participants. The analyzed data had a weekly frequency, covering 376 weeks and including 83,466 participants. All program participants were aged >18 years and were residents of the Netherlands; no additional exclusion criteria were applied. When selecting the participants for this study, out of the 838,500 individuals who enrolled in the health program at the time, 404,398 (48.23%) individuals who had logged into the health program at least once in the past 2 years were examined for eligibility. Owing to limitations in data transfer and storage, approximately 24.73%  of the eligible group were invited randomly to participate in this study, with 83.46%  of them having provided their consent for participation. It is not possible to compare the analyzed sample with the approached sample, as no data were available on the individuals who did not provide their consent for data sharing.The effectiveness of health programs is defined by their ability to contribute to disease prevention, which critically hinges on individuals adopting and using the program. However, a reason causing overall ambiguity related to the benefits of web-based health programs is the significant number of programs that have been unsuccessfully adopted by individuals . In addiBuilding on the diffusion of innovations literature , this stExamining the rate of adoption by distinguishing between population groups allows for assessing whether there are differences in the reach of the health program depending on the means of delivery. Given that solely individual factors offer insufficient explanations of differences in health behaviors , the neiThe NSES measure was created in this study using data on key indicators for each neighborhood in the Netherlands, provided by the Central Bureau of Statistics . FollowiTo control for individual characteristics of the program participants, gender and age were included in the analysis as additional covariates. Moreover, as it can be expected that marketing campaigns that support the health program influence the rate of program adoption, the analysis was augmented with indicators for marketing activities taking place in each observed week or in the preceding week (to control for a lagged impact of marketing). The marketing campaigns considered were radio, television, and web-based campaigns.This study used survival modeling, which encompasses statistical procedures aimed at analyzing the time until an event occurs; the event of interest in this study was the adoption of the health program. The baseline population of individuals who could decide to adopt the health program was the general Dutch population, which was the target group of the health program . Registration for the analyzed program was voluntary and free, which made it possible to examine the true rate of adoption, as in such a setup, individuals are free to decide by themselves when to enroll in the health program .All the observed participants of the health program could experience two events: the adoption of the health program through the website and the adoption of the mobile app, with the former always preceding the latter. This pattern is schematically reflected in At the end of the observation period, of the analyzed participants, 46.91%  had not adopted the app (yet) and were using only the website to access the health program. Possible reasons for this occurrence could be unawareness about the existence of the app or unwillingness to use the app based on not needing the extended features offered by it. Alternatively, the reluctance toward the adoption of the mobile app can be linked to privacy concerns .As reflected in Several robustness checks were performed for changes in the model specifications based on models accounting for nonproportional hazard rates, with the estimated parameters of the main PWP-GT model maintaining their direction and statistical significance  and aged between 18 and 80  years, and 56%  of them were female. Among the participants’ characteristics outlined in On the basis of P values.Analyzing the rate of adoption of the health program generated the results shown in The estimation results indicate that the impact of association with an NSES quintile on the rate of adoption of the health program differs between the 2 means of delivery. For the health program adoption through the website , whereas the mobile app displays a higher likelihood of adoption among the lowest socioeconomic group . Additional findings originating from this study reveal that the individuals’ demographic characteristics are also linked to differences in adoption per means of delivery, with younger women (P<.001) more likely to adopt the mobile app of the health program. Marketing campaigns are estimated to increase the likelihood of mobile app adoption: 170% (P<.001) increased likelihood of mobile app adoption during, or right after, the weeks in which the marketing campaigns about the health program took place.The main findings of this study show that the website of the health program is associated with a higher likelihood of adoption among the higher socioeconomic population groups (between 2% and 3% increased likelihood of adoption; The findings in other existing research differ on the topic of health program adoption through mobile apps among socioeconomic groups. On the one hand, it is estimated that higher NSES segments are more likely to use health programs delivered through mobile apps ,15 becauFor the findings in this study, a circumstance likely linked to the lower socioeconomic group showing a higher likelihood of mobile app adoption is the possession of digital skills. A characteristic of the Dutch population is the high levels of digital skills, with the Netherlands ranking highest in Europe on this scale . An overOverall, the topic of disparities in the use of preventive health services in the existing literature is supported by a general consensus that although the socially disadvantaged segments experience a heavier burden of behavioral risk factors and disease ,49, theyThe realization that mobile app delivery of preventive health programs can increase adoption among the lowest socioeconomic segment of the population has important implications for the future design of health programs. The current digital age is characterized by a higher prevalence of mobile phone use as compared with computer use, a pattern that is especially heightened in low socioeconomic groups ,52, withIn light of the growing health care expenditures and the associated health disparities, it is of importance for health insurance policies to encourage prevention over treatment. Given the higher burden of costs associated with the population segment with the lowest socioeconomic conditions, it is paramount to increase preventive health service use within this segment. Designing future health programs, including the use of mobile apps, can facilitate the increase in the use of such services by the lowest socioeconomic group, thus leading to cost savings and encouraging further investment toward large-scale, web-based prevention services.This study’s setup and analysis methods have several limitations.First, as the adoption of the health program continued beyond the window of observation analyzed in this study, it is not confirmed that the effects observed here would maintain their validity when including the later adopters of the website and the mobile app. To verify whether the later adopters match the pattern discussed in this study, the current analysis can be replicated at a later stage of the health program’s existence.Second, as the data analyzed were retrospective, the analysis was limited to only a few covariates related to the study’s participants. To overcome this restriction, the measure of NSES was used to reflect socioeconomic conditions, with the limitation of missing information on residential moves and not accounting for heterogeneity within neighborhoods. An extension of the current analysis would be to include a measure of individual socioeconomic status and compare the inferences based on the individual-level measure to the ones obtained here based on the neighborhood-level measure.Third, the program analyzed has a particular structure of adoption, with all participants initially adopting the website and subsequently having the choice to adopt the mobile app. Such a structure can potentially lead to conservative estimates, as in this setup, the mobile app adopters are already aware of the program’s existence, having engaged previously with the website. Overcoming this restriction can be achieved by allowing program participants to adopt solely the mobile app, this being a structure toward which the analyzed health program is currently migrating.Fourth, the specific health program analyzed includes solely individuals aged >18 years and from a high-income country. Given that youths worldwide are increasingly using more web-based services, future analyses could include younger individuals and compare web-based health program adoption within a more heterogeneous sample of low- and high-income countries. Although the findings of this study are based on the participants of a specific health program, we believe that the inferences drawn can be applied to the contexts of other health technologies, mainly because of the size and diversity of the data analyzed.Finally, it is important to realize that solely adopting a preventive health program does not contribute to improvements in health. Therefore, as a future extension of this study, the analysis can include the subsequent use of the health program, and its impact on health outcomes, while distinguishing between population groups with different socioeconomic conditions.In this study, a large-scale web-based preventive health program promoted in the Netherlands was analyzed, focusing on its rate of adoption among socioeconomic groups. The mobile app of the health program was identified as a delivery means linked to a higher likelihood of program adoption among the population group with the lowest socioeconomic conditions. This finding suggests that future preventive health interventions can benefit from web-based delivery through mobile apps, especially in the light of the increasing use of mobile phones among the disadvantaged population segments.


Tobacco mosaic virus (TMV) has served as a model organism for pathbreaking work in plant pathology, virology, biochemistry and applied genetics for more than a century. We were intrigued by a photograph published in Phytopathology in 1934 showing that Tabasco pepper plants responded to TMV infection with localized necrotic lesions, followed by abscission of the inoculated leaves. This dramatic outcome of a biological response to infection observed by Francis O. Holmes, a virologist at the Rockefeller Institute for Medical Research, was used to score plants for resistance to TMV infection. Our objective was to gain a better understanding of early to mid-twentieth century ideas of genetic resistance to viruses in crop plants. We investigated Holmes’ observation as a practical exercise in reworking an experiment, having been inspired by Pamela Smith’s innovative Making and Knowing Project. We had a great deal of difficulty replicating Holmes’ experiment, finding that biological materials and experimental customs change over time, in ways that ideas do not. Using complementary tools plus careful study and interpretation of the original text and figures, we were able to rework, yet only partially replicate, this experiment. Reading peer-reviewed manuscripts that cited Holmes’ 1934 report provided an additional level of insight into the interpretation and replication of this work in the decades that followed. From this, we touch on how experimental reworking can inform our strategies to address the reproducibility “crisis” in twenty-first century science. Phytopathology . Tabasco plants respond to TMV infection within a few days of inoculation, first with localized necrotic lesions (LNLs) on the inoculated leaf. The LNLs are mere pinpoints, oftentimes all but obscured by the damage incurred by rub-inoculation. Leaf abscission occurs a few days after LNLs are observed. This response—to sacrifice an inoculated leaf to rid itself of the virus—is a dramatic outcome. Francis O. Holmes, a virologist at the Rockefeller Institute for Medical Research, used both responses to monitor for the presence of a dominant gene for resistance to TMV infection.1If a photograph is worth a thousand words, then we were taken (in) by an image from a 1934 scientific manuscript in the journal We were interested in replicating this experiment as an exemplar of “practicing virology” within the context of the history of science. Our work, initially inspired by Pamela Smith’s Making and Knowing Project, was fraught with challenges. A seemingly simple experiment belied the complexity and challenges of reworking an experiment from the past. We concluded that some experiments from the past cannot be replicated in full; that complementary methods are oftentimes necessary to interpret experimental results across the decades; that careful and attentive reading and interpretation of text and figures is necessary and essential to rework an experiment; and, identification and reading manuscripts that cite the original work is an extremely useful tool to interpretate historical experiments. Here we discuss our challenges and successes with reference to findings from historians of science who have reworked interesting experiments of the past. We also touch on the role of craft (making) and pitfalls associated with biological materials for historical reworking (knowing). In relation to a perceived “reproducibility crisis” in recent science, we discuss, in light of our experience, potential difficulties in reworking experiments, which includes identifying, replicating, funding and publishing the results. Finally, we hope our experiments will encourage more hands-on reworking as a key component of the historiography of the life sciences because of its informative value.Prior to the rediscovery and wide-spread acceptance of Mendelian genetics, crop improvement was based on observation. Plant pathologists and breeders would survey fields, collecting seeds of plants with desirable traits, such as improved yield, or escape from the ravages of diseases. This seed would be increased and used in subsequent seasons. Another, more focused strategy, evaluated seed from local collections or that provided by the USDA.3Nicotiana glutinosa leaves. The virus was confined within the boundaries of the lesions on the inoculated leaf—this host response was protective, allowing the tobacco plant to complete its lifecycle without detriment. Holmes determined this response was due to N. glutinosa harboring a single dominant gene (N) for resistance to TMV infection  as a first step to develop commercial tobacco lines with field resistance to TMV , finding it more amenable to Mendelian breeding strategies.L, analogous to the N. glutinosa N-gene. With this knowledge, Holmes incorporated the Tabasco gene L into commercial lines of bell pepper, thus protecting the plants from systemic TMV infection.L-gene is found in TMV-resistant bell pepper cultivars. The 1934 publication is important to plant pathology because it was the first demonstration that a resistance gene from one species could be used to protect another species from the ravages of virus infection. As shown by Holmes, Tabasco pepper leaves abscised within days of TMV inoculation, a striking means to visualize a gene-in-action in the pre-molecular biology era.This process was fraught with difficulties in that it took Holmes three years to advance this project Holmes, , 2016. DThe manifest issues of technique, skill, tools, and temporal distance have been addressed by Pamela Smith’s pathbreaking “Making and Knowing Project” at Columbia University. Smith has commented on “how odd it is that historians whose object of study is historical materials and techniques … have generally not considered engagement with the materials of their historical topics as an essential part of their training and research” Smith, , p. 9. H7In his TEA set paper Harry Collins addressed the difficulty of replication across physical distance, even for those expert in their area of practice and craft Collins, .8 CollinHere, we provide an example of reproducing knowledge at a temporal distance, using a biological experiment. We encountered many of the same problems mentioned in the TEA set paper as we worked to reproduce an experiment from a written document. Collins indicated that “written sources … as the sole source of information” are inadequate and the ability to reproduce an experiment or build a piece of equipment or “reinvent it” indicates that the (naïve) group “knows as much” as the reporter Collins, , p. 176.Several scholars have been at the forefront in engaging in the “experimental history of science”  using maize kernels 1). Our oN. tabacum cv. Turk and N. benthamiana (commonly used for laboratory experiments), were cultivated from our laboratory seed stock.12We purchased Tabasco and Heirloom California Wonder (sweet bell pepper) seeds from W. Atlee Burpee & Co. Two TMV-susceptible tobacco lines, C. frutescens) it is not possible to definitively state that the plant is identical to Holmes’ Tabasco; almost certainly it is not the same.L-gene in peppers provides an effective form of resistance” to “all tested strains of TMV from tobacco and tomato” . For example, a genetic analysis of ten lines of California Wonder showed the plants could be grouped into 5 classes, based on genetic polymorphisms identified by PCR amplification with a series of primer sets to randomly sample the genome , using a mortar and pestle. The negative control experiment, or mock-inoculation utilizes healthy leaves. Two or three lower leaves of a plant are rubbed gently with the sap extract following dusting with an abrasive powder (carborundum or Celite) to slightly injury the leaf, allowing virus ingress  inoculation Holmes, , 1931  gene (TMV-GFP)  was maintained on hod Fig. . UnfortuFP) Fig. A. TMV-GFFP) Fig. .17 TMV-Gopportunities for better historical understanding” . Our first estimation of plant age was based on plant height and the approximate leaf size , are both considered straightforward “ubiquitous practice”  exposed to cooler growing temperatures may experience premature leaf abscission  practice” . The choices we and Holmes made were not trivial or insignificant. As discussed by Jordan and Lynch in their analysis of the standardized protocol for plasmid preps: “For practitioners at the bench, these distinctions [choices] do not easy resolve such issues as what to include or exclude from a procedure, what to do now, and what to do next”  interpretation is integral to science practice. For example, Staffan Müller-Wille and Giuditta Parolini inspected copies of Mendel’s pea breeding manuscript, finding that readers “actively engaged with the text” by “rehearsing calculations and by employing Mendel’s notation system”  plants maintained at 23ºC developed “local necrotic lesions on mature and nearly mature leaves … and these leaves eventually absciss”  affected our ability to make and learn from Holmes. This has ramifications for scientists and historians who decide to replicate key experiments in their field. As we show here, and as discussed by Jordan and Lynch for plasmid preps, success with a particular protocol belies the depth of required experience and expertise by the users. Our difficulty in recapitulating Holmes’ work was difficult and interesting, and we learned a few things:L-gene pepper plants or developing new commercial varieties.1. We became better readers and observers. As noted by Pamela Smith and others, we too stumbled on the processual research, providing us with the opportunity (and necessity) of studying processes rather than discrete events, to carefully read the materials and methods, and then assemble the needed reagents and tools. This extends into the need for carefully reading the protocols following failed attempts. In the early stages, the process of re-investigation seemed straightforward. Yet it quickly became evident that we were missing or unable to identify the materials used by Holmes. We interpreted what we expected to observe; that is, we anticipated ‘seeing’ the exact outcomes shown in Fig. 2. Side projects are projects. The TMV-pepper experiment was piggy-backed onto ‘normal’ experiments in our molecular virology laboratory. We do not often perform experiments unrelated to our primary research interests. “What is typical, rather, are extended series of experiments which communicate among each other with different intensity and constitute an experimental texture,” as noted by Hans-Jorg Rheinberger , may have strong feelings “over just what sorts of variations are tolerable, trivial, or significant”  is equivalent to discovery-based research. Which experiments will be tested for reproducibility? For a specific example, which of 200,000 COVID-19 manuscripts published the past 18 months should be replicated?Of papers subjected to replication, how one approaches an experiment is predicated on many parameters, including biased approaches and interpretations.In their exploration of allosteric regulation, Angela Creager and Jean-Paul Gaudillière focused on the role of local knowledge and the co-evolution of meaning and experiments within individual locations  “marveled at the length of time it took to acquire experiential knowledge”(Smith,