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Introduction Clear cell ovarian cancer (CCOC) is a rare subtype of ovarian cancer. Response rate to first line chemotherapy is only 20%. When disease relapses, chemotherapy response rate is less than 10%. As a result, survival in advanced CCOC is poor and new therapies are urgently required. Upon binding its ligand, Hepatocyte Growth Factor (HGF), the receptor tyrosine kinase c- Met promotes ovarian cancer cell proliferation, survival and motility. c-Met has emerged as a major target and mediator of chemo-resistance in ovarian cancer. c-Met amplification has been demonstrated in 37% of CCOC, compared to 2.6% of epithelial cancers. Recent clinical trials with c-Met inhibitors in ovarian cancer showed response in only 20% of patients. More comprehensive understanding of c-Met signalling in CCOC is necessary to establish optimal therapeutic strategies. We have previously shown that c-Met transmits oncogenic signalling post-endocytosis and endocytosis inhibition reduces c-Met driven tumourigenesis. Consequently, manipulating c-Met endosomal signalling may provide a novel therapeutic approach in cancer treatment. c-Met endocytic trafficking has never previously been analysed in CCOC. Materials /Patients and methods Human tissue sections from CCOC patients were obtained via the Barts/UCLH Gynae Tissue Bank and underwent immunohistochemical staining for c-Met. CCOC cell lines - JHOC-5, JHOC-7, JHOC-9, OVTOKO, OVMANA - were investigated for c- Met expression, activation with exogenous HGF stimulation and downstream signalling via Western blot analysis. The effect of c-Met inhibitor PHA-665752 and siRNA knockdown of c-Met on cell viability was assessed using CellTiter-Glo. Cells were plated on coverslips and stimulated with HGF for 0 and 15 min, fixed and stained for c-Met and the endosomal marker EEA-1. Slides were imaged with fluorescent confocal microscopy. Results c-Met expression was observed in 5/6 patients CCOC patient samples when assessed by immunohistochemistry. Strong c-Met expression was seen at the cell surface of malignant epithelial cells but not in the stroma of these tumours. In our panel of CCOC cell lines, c-Met was found to be expressed with JHOC-5 cells expressing the highest levels. Stimulation of the cell lines with exogenous HGF activated c-Met and the downstream signals ERK1/2 and AKT, followed by degradation of c-Met. This activation was blocked by pre-treatment with c-Met inhibitors. The c-Met inhibitor PHA-665752 and siRNA knockdown significantly reduced the cell's viability (n=3 p<0.001). Exogenous HGF stimulation triggers rapid c-Met endocytosis in our cell panel. Blocking endocytosis with the dynamin inhibitor Dyngo reduced c-Met ERK1/2 and AKT signalling. Conclusion This study confirms c-Met as a therapeutic target in CCOC and illustrates, for the first time, that c-Met is endocytosed in CCOC. Further work is ongoing to unravel these pathways and to identify novel treatment approaches. [ABSTRACT FROM AUTHOR]

Background: Artificial intelligence (AI) has the potential to revolutionize health care by enhancing both clinical outcomes and operational efficiency. However, its clinical adoption has been slower than anticipated, largely due to the absence of comprehensive evaluation frameworks. Existing frameworks remain insufficient and tend to emphasize technical metrics such as accuracy and validation, while overlooking critical real-world factors such as clinical impact, integration, and economic sustainability. This narrow focus prevents AI tools from being effectively implemented, limiting their broader impact and long-term viability in clinical practice., Objective: This study aimed to create a framework for assessing AI in health care, extending beyond technical metrics to incorporate social and organizational dimensions. The framework was developed by systematically reviewing, analyzing, and synthesizing the evaluation criteria necessary for successful implementation, focusing on the long-term real-world impact of AI in clinical practice., Methods: A search was performed in July 2024 across the PubMed, Cochrane, Scopus, and IEEE Xplore databases to identify relevant studies published in English between January 2019 and mid-July 2024, yielding 3528 results, among which 44 studies met the inclusion criteria. The systematic review followed PRISMA (Preferred Reporting Items for Systematic reviews and Meta-Analyses) guidelines and the Cochrane Handbook for Systematic Reviews. Data were analyzed using NVivo through thematic analysis and narrative synthesis to identify key emergent themes in the studies., Results: By synthesizing the included studies, we developed a framework that goes beyond the traditional focus on technical metrics or study-level methodologies. It integrates clinical context and real-world implementation factors, offering a more comprehensive approach to evaluating AI tools. With our focus on assessing the long-term real-world impact of AI technologies in health care, we named the framework AI for IMPACTS. The criteria are organized into seven key clusters, each corresponding to a letter in the acronym: (1) I-integration, interoperability, and workflow; (2) M-monitoring, governance, and accountability; (3) P-performance and quality metrics; (4) A-acceptability, trust, and training; (5) C-cost and economic evaluation; (6) T-technological safety and transparency; and (7) S-scalability and impact. These are further broken down into 28 specific subcriteria., Conclusions: The AI for IMPACTS framework offers a holistic approach to evaluate the long-term real-world impact of AI tools in the heterogeneous and challenging health care context and lays the groundwork for further validation through expert consensus and testing of the framework in real-world health care settings. It is important to emphasize that multidisciplinary expertise is essential for assessment, yet many assessors lack the necessary training. In addition, traditional evaluation methods struggle to keep pace with AI's rapid development. To ensure successful AI integration, flexible, fast-tracked assessment processes and proper assessor training are needed to maintain rigorous standards while adapting to AI's dynamic evolution., Trial Registration: reviewregistry1859; https://tinyurl.com/ysn2d7sh., (©Christine Jacob, Noé Brasier, Emanuele Laurenzi, Sabina Heuss, Stavroula-Georgia Mougiakakou, Arzu Cöltekin, Marc K Peter. Originally published in the Journal of Medical Internet Research (https://www.jmir.org), 05.02.2025.)

There is no multi-country/multi-language study testing a-priori multivariable associations between non-modifiable/modifiable factors and validated wellbeing/multidimensional mental health outcomes before/during the COVID-19 pandemic. Moreover, studies during COVID-19 pandemic generally do not report on representative/weighted non-probability samples. The Collaborative Outcomes study on Health and Functioning during Infection Times (COH-FIT) is a multi-country/multi-language survey conducting multivariable/LASSO-regularized regression models and network analyses to identify modifiable/non-modifiable factors associated with wellbeing (WHO-5)/composite psychopathology (P-score) change. It enrolled general population-representative/weighted-non-probability samples (26/04/2020-19/06/2022). Participants included 121,066 adults (age=42±15.9 years, females=64 %, representative sample=29 %) WHO-5/P-score worsened (SMD=0.53/SMD=0.74), especially initially during the pandemic. We identified 15 modifiable/nine non-modifiable risk and 13 modifiable/three non-modifiable protective factors for WHO-5, 16 modifiable/11 non-modifiable risk and 10 modifiable/six non-modifiable protective factors for P-score. The 12 shared risk/protective factors with highest centrality (network-analysis) were, for non-modifiable factors, country income, ethnicity, age, gender, education, mental disorder history, COVID-19-related restrictions, urbanicity, physical disorder history, household room numbers and green space, and socioeconomic status. For modifiable factors, we identified medications, learning, internet, pet-ownership, working and religion as coping strategies, plus pre-pandemic levels of stress, fear, TV, social media or reading time, and COVID-19 information. In multivariable models, for WHO-5, additional non-modifiable factors with |B|>1 were income loss, COVID-19 deaths. For modifiable factors we identified pre-pandemic levels of social functioning, hobbies, frustration and loneliness, and social interactions as coping strategy. For P-scores, additional non-modifiable/modifiable factors were income loss, pre-pandemic infection fear, and social interactions as coping strategy. COH-FIT identified vulnerable sub-populations and actionable individual/environmental factors to protect well-being/mental health during crisis times. Results inform public health policies, and clinical practice., Competing Interests: Conflict of interest Conflict of interest statements of all authors are detailed in eTable 12., (Copyright © 2024. Published by Elsevier B.V.)

International studies measuring wellbeing/multidimensional mental health before/ during the COVID-19 pandemic, including representative samples for >2 years, identifying risk groups and coping strategies are lacking. COH-FIT is an online, international, anonymous survey measuring changes in well-being (WHO-5) and a composite psychopathology P-score, and their associations with COVID-19 deaths/restrictions, 12 a-priori defined risk individual/cumulative factors, and coping strategies during COVID-19 pandemic (26/04/2020-26/06/2022) in 30 languages (representative, weighted non-representative, adults). T-test, χ 2 , penalized cubic splines, linear regression, correlation analyses were conducted. Analyzing 121,066/142,364 initiated surveys, WHO-5/P-score worsened intra-pandemic by 11.1±21.1/13.2±17.9 points (effect size d=0.50/0.60) (comparable results in representative/weighted non-probability samples). Persons with WHO-5 scores indicative of depression screening (<50, 13% to 32%) and major depression (<29, 3% to 12%) significantly increased. WHO-5 worsened from those with mental disorders, female sex, COVID-19-related loss, low-income country location, physical disorders, healthcare worker occupations, large city location, COVID-19 infection, unemployment, first-generation immigration, to age=18-29 with a cumulative effect. Similar findings emerged for P-score. Changes were significantly but minimally related to COVID-19 deaths, returning to near-pre-pandemic values after >2 years. The most subjectively effective coping strategies were exercise and walking, internet use, social contacts. Identified risk groups, coping strategies and outcome trajectories can inform global public health strategies., Competing Interests: Declaration of competing interest Conflict of interest statements of all authors are detailed in eTable 8., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Objective: To identify the COVID-19 pandemic impact on well-being/mental health, coping strategies, and risk factors in adolescents worldwide., Method: This study was based on an anonymous online multi-national/multi-language survey in the general population (representative/weighted non-representative samples, 14-17 years of age), measuring change in well-being (World Health Organization-Five Well-Being Index [WHO-5]/range = 0-100) and psychopathology (validated composite P-score/range = 0-100), WHO-5 <50 and <29, pre- vs during COVID-19 pandemic (April 26, 2020-June 26, 2022). Coping strategies and 9 a priori- defined individual/cumulative risk factors were measured. A χ 2 , penalized cubic splines, linear regression, and correlation analyses were conducted., Results: Analyzing 8,115 of 8,762 initiated surveys (representative = 75.1%), the pre-pandemic WHO-5 and P-score remained stable during the study (excluding relevant recall bias/drift), but worsened during the pandemic by 5.55 ± 17.13 (SD) and 6.74 ± 16.06 points, respectively (effect size d = 0.27 and d = 0.28). The proportion of adolescents with WHO-5 scores suggesting depression screening (<50) and major depression (<29) increased from 9% to 17% and 2% to 6%. WHO-5 worsened (descending magnitude, with cumulative effect) in adolescents with a mental or physical disorder, female gender, and with school closure. Results were similar for the P-score, with the exception of school closure (not significant) and living in a low-income country, as well as not living in a large city (significant). Changes were significantly but minimally related to COVID-19 deaths/restrictions, returning to near-pre-pandemic values after >2 years. The 3 most subjectively effective coping strategies were Internet use, exercise/walking, and social contacts., Conclusion: Overall, well-being/mental health worsened (small effect sizes) during the early stages of the COVID-19 pandemic, especially in vulnerable subpopulations. Identified at-risk groups, association with pandemic-related measures, and coping strategies can inform individual behaviors and global public health strategies., Study Preregistration Information: Physical and mental health impact of COVID-19 on children, adolescents, and their families: The Collaborative Outcomes study on Health and Functioning during Infection Times - Children and Adolescents (COH-FIT-C&A); https://doi.org/10.1016/j.jad.2021.09.090 DIVERSITY & INCLUSION STATEMENT: We worked to ensure sex and gender balance in the recruitment of human participants. We worked to ensure race, ethnic, and/or other types of diversity in the recruitment of human participants. We worked to ensure that the study questionnaires were prepared in an inclusive way. The author list of this paper includes contributors from the location and/or community where the research was conducted who participated in the data collection, design, analysis, and/or interpretation of the work. We actively worked to promote inclusion of historically underrepresented racial and/or ethnic groups in science in our author group. We actively worked to promote sex and gender balance in our author group. One or more of the authors of this paper self-identifies as a member of one or more historically underrepresented racial and/or ethnic groups in science., (Copyright © 2024 American Academy of Child and Adolescent Psychiatry. Published by Elsevier Inc. All rights reserved.)

Objectives: This paper about social media platforms of Swiss hospitals refers to the period between 10 February 2020 and 6 July 2020. The study included in-depth insights into the use of platforms, content analyses of posts and resonance of the posts. The study's objective was to get insights into social media post creation by and corresponding resonance in pandemic crisis., Study Design: This study included collection and analyses of posts created by a selection of Swiss hospitals during the period of study. All university hospitals and a variety of private and regional hospitals in all regions of Switzerland are represented. The data collection started before the official shutdown in Switzerland., Methods: This study used mixed method approach and content analysis to evaluate 2,326 posts during the study period related to the COVID-19 pandemic., Results: During the first phase of the pandemic, hospitals used social media platforms more frequently than normal. Especially in the first month, the number of posts rose disproportionally. The numbers dropped back to the initial situation after only 4 months into the COVID-19 pandemic. Most hospitals used Facebook and Twitter, whereas Instagram and YouTube's use were marginal. University hospitals used social media platforms differently than regional hospitals., Conclusion: Most posts generated only a very low response with a median of 2. Hospitals were therefore not able to create engagement of their followers. However, hospitals that publish actively were able to build a more active community. Only a small number of posts led to heated discussions in the comments. These viral posts shared information on the illness, the vaccination, children and COVID-19., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Objective: With the rapid advancement of digital technology due to COVID-19, the health care field is embracing the use of digital technologies for learning, which presents an opportunity for teaching methods such as serious games to be developed and improved. Technology offers more options for these educational approaches. The goal of this study was to assess health care workers' experiences, attitudes, and knowledge regarding serious games in training., Methods: The convenience sample consisted of 223 participants from the specialties of internal medicine and psychiatry who responded to questions regarding sociodemographic data, experience, attitudes, and knowledge regarding serious games. This study used an ordinal regression model to analyze the relationship between knowledge, attitudes, and experiences and the idea or wish to implement serious games., Results: The majority of healthcare workers were not familiar with serious games or gamification. The results show gender and age differences regarding familiarity and willingness to use serious games. With increasing age, the respondents preferred conventional and traditional learning methods to playful teaching elements; younger generations were significantly more motivated than older generations when envisioning using elements of serious games in the future., Conclusions: The COVID-19 pandemic has encouraged the use of new technologies and digitalization. This study describes positive attitudes toward serious games, mainly in younger people working in health care. Serious games present an opportunity to develop new approaches for postgraduate medical teachings and continuing medical education., (© 2023. The Author(s), under exclusive licence to American Association of Chairs of Departments of Psychiatry, American Association of Directors of Psychiatric Residency Training, Association for Academic Psychiatry and Association of Directors of Medical Student Education in Psychiatry.)

Background: The Collaborative Outcome study on Health and Functioning during Infection Times (COH-FIT; www.coh-fit.com) is an anonymous and global online survey measuring health and functioning during the COVID-19 pandemic. The aim of this study was to test concurrently the validity of COH-FIT items and the internal validity of the co-primary outcome, a composite psychopathology "P-score"., Methods: The COH-FIT survey has been translated into 30 languages (two blind forward-translations, consensus, one independent English back-translation, final harmonization). To measure mental health, 1-4 items ("COH-FIT items") were extracted from validated questionnaires (e.g. Patient Health Questionnaire 9). COH-FIT items measured anxiety, depressive, post-traumatic, obsessive-compulsive, bipolar and psychotic symptoms, as well as stress, sleep and concentration. COH-FIT Items which correlated r ≥ 0.5 with validated companion questionnaires, were initially retained. A P-score factor structure was then identified from these items using exploratory factor analysis (EFA) and confirmatory factor analyses (CFA) on data split into training and validation sets. Consistency of results across languages, gender and age was assessed., Results: From >150,000 adult responses by May 6th, 2022, a subset of 22,456 completed both COH-FIT items and validated questionnaires. Concurrent validity was consistently demonstrated across different languages for COH-FIT items. CFA confirmed EFA results of five first-order factors (anxiety, depression, post-traumatic, psychotic, psychophysiologic symptoms) and revealed a single second-order factor P-score, with high internal reliability (ω = 0.95). Factor structure was consistent across age and sex., Conclusions: COH-FIT is a valid instrument to globally measure mental health during infection times. The P-score is a valid measure of multidimensional mental health., Competing Interests: Conflict of interest Conflict of interest statements of all authors are detailed in Supplementary Table 7., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Background: Technological advancements have opened the path for many technology providers to easily develop and introduce eHealth tools to the public. The use of these tools is increasingly recognized as a critical quality driver in health care; however, choosing a quality tool from the myriad of tools available for a specific health need does not come without challenges., Objective: This review aimed to systematically investigate the literature to understand the different approaches and criteria used to assess the quality and impact of eHealth tools by considering sociotechnical factors (from technical, social, and organizational perspectives)., Methods: A structured search was completed following the participants, intervention, comparators, and outcomes framework. We searched the PubMed, Cochrane, Web of Science, Scopus, and ProQuest databases for studies published between January 2012 and January 2022 in English, which yielded 675 results, of which 40 (5.9%) studies met the inclusion criteria. The PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines and the Cochrane Handbook for Systematic Reviews of Interventions were followed to ensure a systematic process. Extracted data were analyzed using NVivo (QSR International), with a thematic analysis and narrative synthesis of emergent themes., Results: Similar measures from the different papers, frameworks, and initiatives were aggregated into 36 unique criteria grouped into 13 clusters. Using the sociotechnical approach, we classified the relevant criteria into technical, social, and organizational assessment criteria. Technical assessment criteria were grouped into 5 clusters: technical aspects, functionality, content, data management, and design. Social assessment criteria were grouped into 4 clusters: human centricity, health outcomes, visible popularity metrics, and social aspects. Organizational assessment criteria were grouped into 4 clusters: sustainability and scalability, health care organization, health care context, and developer., Conclusions: This review builds on the growing body of research that investigates the criteria used to assess the quality and impact of eHealth tools and highlights the complexity and challenges facing these initiatives. It demonstrates that there is no single framework that is used uniformly to assess the quality and impact of eHealth tools. It also highlights the need for a more comprehensive approach that balances the social, organizational, and technical assessment criteria in a way that reflects the complexity and interdependence of the health care ecosystem and is aligned with the factors affecting users' adoption to ensure uptake and adherence in the long term., (©Christine Jacob, Johan Lindeque, Alexander Klein, Chris Ivory, Sabina Heuss, Marc K Peter. Originally published in JMIR Human Factors (https://humanfactors.jmir.org), 23.03.2023.)

Background: Research has shown that patient engagement is most commonly done at the beginning of research or to test readily available prototypes and less commonly done in other phases such as the execution phases. Previous studies have reported that patients are usually assigned a consultative rather than a decision-making role in health service planning and evaluation., Objective: This study had 2 objectives: to better understand the challenges and opportunities in the inclusion of patients in the development of eHealth technologies and ideas on how to overcome the identified gaps and to create a research-based end-to-end practical blueprint that can guide the relevant stakeholders to successfully engage patients as cocreators in all human-centered design phases rather than mere testers of preplanned prototypes., Methods: Key informant interviews were conducted using in-depth semistructured interviews with 20 participants from 6 countries across Europe. This was followed by a focus group to validate the initial findings. Participants encompassed all the relevant stakeholder groups including patient experts, eHealth experts, health technology providers, clinicians, pharma executives, and health insurance experts., Results: This study shows that engaging patients in eHealth development can help provide different types of value; namely, identifying unmet needs, better usability and desirability, better fit into the patient journey, better adoption and stickiness, better health outcomes, advocacy and trust, a sense of purpose, and better health equity and access. However, the participants agreed that patients are usually engaged too late in the development process, mostly assuming a sounding role in testing a ready-made prototype. The justification for these gaps in engagement is driven by some prominent barriers, notably compliance risks, patient-related factors, power dynamics, patient engagement as lip service, poor value perception, lack of resources, mistrust, and inflexibility. On the positive side, the participants also reflected on facilitators for better patient engagement; for instance, engaging through engagement partners, novel approaches such as the rise of professional patient experts, embedding patients in development teams, expectation management, and professional moderation services., Conclusions: Overcoming the current gaps in patient engagement in eHealth development requires consolidated efforts from all stakeholders in a complex health care ecosystem. The shift toward more patient-driven eHealth development requires education and awareness; frameworks to monitor and evaluate the value of patient engagement; regulatory clarity and simplification; platforms to facilitate patient access and identification; patient incentivization, transparency, and trust; and a mindset shift toward value-based health care., (©Christine Jacob, Steven Bourke, Sabina Heuss. Originally published in JMIR Human Factors (https://humanfactors.jmir.org), 06.10.2022.)

Lung cancer classification has been radically transformed in recent years as genomic profiling has identified multiple novel therapeutic targets including MET exon 14 (METex14) alterations and MET amplification. Utilizing targeted therapies in patients with molecularly-defined NSCLC leads to remarkable objective response rates and improved progression-free survival. However, acquired resistance is inevitable. Several recent phase II trials have confirmed that METex14 NSCLC can be treated effectively with MET kinase inhibitors, such as crizotinib, capmatinib, tepotinib, and savolitinib. However, response rates for many MET TKIs are modest relative to the activity of targeted therapy in other oncogene-driven lung cancers, where ORRs are more consistently greater than 60%. In spite of significant gains in the field of MET inhibition in NSCLC, challenges remain: the landscape of resistance mechanisms to MET TKIs is not yet well characterized, and there may be intrinsic and acquired resistance mechanisms that require further characterization to enable increased MET TKI activity. In this review, we overview MET pathway dysregulation in lung cancer, methods of detection in the clinic, recent clinical trial data, and discuss current mechanisms of TKI resistance, exploring emerging strategies to overcome resistance., (Copyright © 2022 Elsevier B.V. All rights reserved.)

The Notch pathway is involved in cell-cell signaling during development and adulthood from invertebrates to higher eukaryotes. Activation of the Notch receptor by its ligands relies upon a multi-step processing. The extracellular part of the receptor is removed by a metalloprotease of the ADAM family and the remaining fragment is cleaved within its transmembrane domain by a presenilin-dependent γ-secretase activity. γ-Secretase processing of Notch has been shown to depend upon monoubiquitination as well as clathrin-mediated endocytosis (CME). We show here that AAK1, the adaptor-associated kinase 1, directly interacts with the membrane-tethered active form of Notch released by metalloprotease cleavage. Active AAK1 acts upstream of the γ-secretase cleavage by stabilizing both the membrane-tethered activated form of Notch and its monoubiquitinated counterpart. We propose that AAK1 acts as an adaptor for Notch interaction with components of the clathrin-mediated pathway such as Eps15b. Moreover, transfected AAK1 increases the localization of activated Notch to Rab5-positive endocytic vesicles, while AAK1 depletion or overexpression of Numb, an inhibitor of the pathway, interferes with this localization. These results suggest that after ligand-induced activation of Notch, the membrane-tethered form can be directed to different endocytic pathways leading to distinct fates.