Large variety in a panel of human colon cancer organoids in response to EZH2 inhibition

EZH2 inhibitors have gained great interest for their use as anti-cancer therapeutics. However, most research has focused on EZH2 mutant cancers and recently adverse effects of EZH2 inactivation have come to light. To determine whether colorectal cancer cells respond to EZH2 inhibition and to explore which factors influence the degree of response, we treated a panel of 20 organoid lines derived from human colon tumors with different concentrations of the EZH2 inhibitor GSK126. The resulting responses were associated with mutation status, gene expression and responses to other drugs. We found that the response to GSK126 treatment greatly varied between organoid lines. Response associated with the mutation status of ATRX and PAX2, and correlated with BIK expression. It also correlated well with response to Nutlin-3a which inhibits MDM2-p53 interaction thereby activating p53 signaling. Sensitivity to EZH2 ablation depended on the presence of wild type p53, as tumor organoids became resistant when p53 was mutated or knocked down. Our exploratory study provides insight into which genetic factors predict sensitivity to EZH2 inhibition. In addition, we show that the response to EZH2 inhibition requires wild type p53. We conclude that a subset of colorectal cancer patients may benefit from EZH2-targeting therapies

Recruitment through media and general practitioners resulted in comparable samples in an RCT on incontinence

Objectives: The objective of the study was to assess the impact of recruitment strategy on the baseline characteristics of patients recruited in a randomized controlled trial for treating women with urinary incontinence. Study Design and Setting: We conducted a cross-sectional analysis of baseline data from an earlier trial. Women were recruited through the media (including social media) or from participating general practices. Baseline characteristics were compared by univariate testing. Logistic regression analysis was performed to study the association between recruitment type and multiple baseline characteristics. Results: The only differences between recruitment methods were in patient age, with those recruited through the media being significantly older than those recruited through general practice. The mean age difference was 5.0 years (95% confidence interval: 2.2–7.9). Conclusion: Samples recruited through the media and through case identification were largely comparable. Therefore, recruitment through the media may be a viable alternative to recruitment through primary care. This may be especially relevant for research on eHealth treatment for conditions with which patients experience barriers when seeking health care

Perspective of Dutch healthcare professionals on care for female urinary incontinence:A mixed-methods study

Introduction and hypothesis : Health care professionals (HCP) can reveal practical recommendations to improve processes and address challenges in the care of women with urinary incontinence (UI) in the Netherlands.Methods : We conducted an exploratory, sequential, mixed-methods study among HCPs, using the outcomes of six focus group sessions (30 HCPs) to inform a subsequent survey. HCPs included general practitioners (GPs), practice assistants (PAs), pelvic physiotherapists (PPTs), and urologists and gynecologists (UGs).Results : The main themes arising from the six focus group sessions (with 6 GPs, 7 PAs, 6 (resident) UGs, 8 PPTs, and 7 PPTs) were “identification of UI,” “current state of care,” and “guiding patients through the healthcare system.” The survey respondents included 351 PAs, 124 GPs, 75 PPTs, and 183 UGs. Of these 741 respondents, 72.8% (strongly) agreed that the identification of UI in general practice required improvement and 60% confirmed the need for further education on this topic. Most HCPs (83.1%) found it useful to offer women a patient information leaflet when buying incontinence products, but less useful to ask about UI routinely in specific scenarios, and most (75%) agreed that a multidisciplinary guideline could improve healthcare. Interestingly, 86% of PPTs and 21% of UGs advocated referral to a PPT before referral to a specialist, while 87% of PPTs wanted primary care services to offer a UI consultation hour and 36% of the GPs (strongly) disagreed.Conclusion : Poor UI identification in primary care and a lack of patient guidance through the health care system hamper continence care provision

Care provider views on app-based treatment for female urinary incontinence:A mixed-methods study

Objective: To explore the views and preferences of care providers on app use for the treatment of UI and to identify the anticipated barriers to, and facilitators of, implementation.Patients and Methods: We performed an exploratory, two-phase, sequential mixed-methods study. In phase 1, the views of care providers were explored through five focus group sessions with care providers involved in UI: general practitioners (GPs), practice assistants (PAs), pelvic physical therapists (PPTs), and urologists and (uro)gynecologists (UGs). In phase 2, the identified themes and subthemes were quantified in an online survey distributed among different care providers matching these groups.Results: In the focus group sessions, 30 female and two male care providers participated. Survey participants included 351 PAs and 76 PPTs (all females) next to 124 GPs and 183 UGs (70% females). Caregivers generally considered UI treatment apps as having a supportive role, being less convinced about their advantages in the absence of a care provider. Whereas most PPTs (89%) and the majority of participants overall (56%) agreed that app use should be supervised, most GPs considered apps to be suitable alternatives for women who do not visit a care provider. Additionally, caregivers required that the effectiveness of an app should be proven first, and that privacy and safety should be ensured. Contrasting with other research, lack of time and financial compensation were not considered important barriers to implementation. Although care providers shared a positive view of app use for UI treatment, most never to seldom referred their patients to existing tools.Conclusion: Our results add to the existing knowledge about eHealth-related barriers and facilitators. These findings can be used to optimize implementation strategies for other apps and to enhance the uptake of app-based treatment for UI in The Netherlands

Barriers and Facilitators Associated With App-Based Treatment for Female Urinary Incontinence:Mixed Methods Evaluation

BACKGROUND: App-based treatment for urinary incontinence is a proven effective and cost-effective alternative to care as usual, but successful implementation requires that we identify and address the barriers and facilitators associated with app use. OBJECTIVE: The goal of the research was to explore the factors influencing app-based treatment for urinary incontinence and identify which barriers or facilitators are associated with treatment success or failure. METHODS: We used a sequential explanatory mixed methods design to connect the results of a randomized controlled trial with data from semistructured interviews. This previous RCT had shown the noninferiority of app-based treatment compared with care as usual for urinary incontinence over 4 months. Participants who reported success or failure with app-based treatment, as measured by the change in International Consultation on Incontinence Modular Questionnaire Urinary Incontinence Short Form symptom score, were selected for telephone interview by purposive sampling (n=17). This study reports mainly on the qualitative component of our mixed methods study. Qualitative analyses were conducted in two ways. First, we analyzed the qualitative data of all interviewed participants and discussed the relationships between the main themes. Second, the experiences between the success (n=9) and failure group (n=8) were compared and contrasted to explore factors that were positively or negatively associated with the quantitative effect of app-based treatment. These factors were then interpreted as barriers to and facilitators of successful app-based treatment. RESULTS: Four interrelated themes were identified as affecting the app based treatment effect: adherence, personal factors, app factors, and awareness. Qualitative analyses of the relationships between the themes showed that adherence-related factors directly influenced treatment effect in both a positive and negative matter. In turn, adherence was also positively and negatively influenced by the other 3 themes. Additionally, awareness was positively influenced by the treatment effect. Within these themes, several factors were identified that acted as barriers (eg, unrealistic expectation of time investment and interfering personal circumstances), facilitators (eg, strict integration of exercises and prior pelvic floor muscle therapy), or both (eg, personality traits and increased awareness of symptoms). CONCLUSIONS: This study shows that the effect of app-based treatment for urinary incontinence is mainly influenced by adherence, which in turn is affected by personal factors, app-based factors, and awareness. The identified factors could function as both facilitators and barriers depending on the user and interaction with other themes. Insight into these facilitators and barriers could lead to improved implementation and increased treatment effectiveness by targeting women most likely to benefit and through further development of the app. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): RR2-10.1002/nau.2350

One year effectiveness of an app-based treatment for urinary incontinence in comparison to care as usual in Dutch general practice:A pragmatic randomised controlled trial over 12 months

OBJECTIVE: To assess the long-term effectiveness of app-based treatment for female stress, urgency, or mixed urinary incontinence (UI) compared to care-as-usual in primary care. DESIGN: A pragmatic, randomised controlled, superiority trial. SETTING: Primary care in the Netherlands from 2015 to 2018, follow-up at 12 months. POPULATION: Women with ≥2 UI-episodes per week, access to mobile apps, wanting treatment. 262 women randomised equally to app or care-as-usual; 89 (68%) and 83 (63%) attended one year follow-up. INTERVENTIONS: The standalone app included conservative management for UI with motivation aids (e.g., reminders). Care-as-usual delivered according to the Dutch GP guideline for UI. MAIN OUTCOME MEASURES: Effectiveness assessed by the change in symptom severity score (ICIQ-UI-SF) and the change in quality of life (ICIQ-LUTS-QoL) with linear regression on an intention-to-treat basis. RESULTS: Clinically relevant improvement of UI severity for both app (-2.17 ± 2.81) and care-as-usual (-3.43 ± 3.6), with a non-significant mean difference of 0.903 (-0.66 to 1.871). CONCLUSION: App-based treatment is a viable alternative to care-as-usual for UI in primary care in terms of effectiveness after one year

Cost-effectiveness of an app-based treatment for urinary incontinence in comparison with care-as-usual in Dutch general practice:a pragmatic randomised controlled trial over 12 months

OBJECTIVE: To assess the cost-effectiveness of app-based treatment for female stress, urgency, or mixed urinary incontinence (UI) compared to care-as-usual in Dutch primary care. DESIGN: A pragmatic, randomised controlled, superiority trial. SETTING: Primary care in the Netherlands from 2015 to 2018, follow-up at 12 months. POPULATION: Women with ≥2 UI-episodes per week, access to mobile apps, wanting treatment. INTERVENTIONS: The standalone app included conservative management for UI with motivation aids (e.g., reminders). Care-as-usual delivered according to the Dutch GP guideline for UI. MAIN OUTCOME MEASURES: Costs and cost-effectiveness and -utility were assessed from a societal perspective, based on Incontinence Impact Adjusted Life Years (IIALYs), Quality Adjusted Life years (QALYs) and medical, non-medical and productivity costs. Information on costs was obtained with the iMCQ and iPCQ questionnaires (Medical Consumption and Productivity Cost Questionnaires). RESULTS: 262 women randomised equally to app or care-as-usual; 89 (68%) and 83 (63%) attended follow-up. Costs were lower for app-based treatment with €-161 (95%CI: -180 to -151) per year. Cost-effectiveness showed small mean differences in effect for IIALY (0.04) and QALY (-0.03) and thus larger ICER (-€3,696) and ICUR (€6,379) (Incremental Cost-Effectiveness and Cost-utility Ratios). CONCLUSION: App-based treatment is a cost-effective alternative to care-as-usual for women with UI in Dutch primary care

App-Based Treatment in Primary Care for Urinary Incontinence:A Pragmatic, Randomized Controlled Trial

PURPOSE: Electronic application (app)-based treatment is promising for common diseases with good conservative management options, such as urinary incontinence (UI) in women, but its effectiveness compared with usual care is unclear. This study set out to determine if app-based treatment for women with stress, urgency, or mixed UI was noninferior to usual care in the primary care setting. METHODS: The URinControl trial is a pragmatic, noninferiority randomized controlled trial in Dutch primary care including adult women with 2 episodes of UI per week. From July 2015 to July 2018, we screened 350 women for eligibility. A stand-alone app-based treatment with pelvic floor muscle and bladder training (URinControl) was compared with usual care according to the Dutch general practitioner guideline for UI treatment. Outcomes measured were change in symptom severity score from baseline to 4 months (primary outcome), impact on disease-specific quality of life, patient-perceived improvement, and number of UI episodes. Noninferiority (<1.5 points) was assessed with linear regression analysis. RESULTS: A total of 262 eligible women were randomized equally; 195 of them had follow-up through 4 months. The change in symptom severity with app-based treatment (-2.16 points; 95% CI, -2.67 to -1.65) was noninferior to that with usual care (-2.56 points; 95% CI, -3.28 to -1.84), with a mean difference of 0.058 points (95% CI, -0.776 to 0.891) between groups. Neither treatment was superior to the other, and both groups showed improvements in outcome measures after treatment. CONCLUSIONS: App-based treatment for women with UI was at least as effective as usual care in the primary care setting. As such, app-based treatments, with their potential advantages of privacy, accessibility, and lower cost, may provide women with a good alternative to consultation

Impact of infection on proteome-wide glycosylation revealed by distinct signatures for bacterial and viral pathogens

Mechanisms of infection and pathogenesis have predominantly been studied based on differential gene or protein expression. Less is known about posttranslational modifications, which are essential for protein functional diversity. We applied an innovative glycoproteomics method to study the systemic proteome-wide glycosylation in response to infection. The protein site-specific glycosylation was characterized in plasma derived from well-defined controls and patients. We found 3862 unique features, of which we identified 463 distinct intact glycopeptides, that could be mapped to more than 30 different proteins. Statistical analyses were used to derive a glycopeptide signature that enabled significant differentiation between patients with a bacterial or viral infection. Furthermore, supported by a machine learning algorithm, we demonstrated the ability to identify the causative pathogens based on the distinctive host blood plasma glycopeptide signatures. These results illustrate that glycoproteomics holds enormous potential as an innovative approach to improve the interpretation of relevant biological changes in response to infection

Recruitment through media and general practitioners resulted in comparable samples in an RCT on incontinence

Objectives: The objective of the study was to assess the impact of recruitment strategy on the baseline characteristics of patients recruited in a randomized controlled trial for treating women with urinary incontinence. Study Design and Setting: We conducted a cross-sectional analysis of baseline data from an earlier trial. Women were recruited through the media (including social media) or from participating general practices. Baseline characteristics were compared by univariate testing. Logistic regression analysis was performed to study the association between recruitment type and multiple baseline characteristics. Results: The only differences between recruitment methods were in patient age, with those recruited through the media being significantly older than those recruited through general practice. The mean age difference was 5.0 years (95% confidence interval: 2.2–7.9). Conclusion: Samples recruited through the media and through case identification were largely comparable. Therefore, recruitment through the media may be a viable alternative to recruitment through primary care. This may be especially relevant for research on eHealth treatment for conditions with which patients experience barriers when seeking health care.</p