Small cell transformation in EGFR-mutated non-small cell lung cancer: DLL3 expression and efficacy of immune checkpoint inhibitors or tyrosine kinase inhibitors combined with chemotherapy.

INTRODUCTION: Small cell transformation (SCT) is a typical mechanism of adaptive resistance to third generation epidermal growth factor receptor inhibitors (EGFRi) which have become the standard of care for EGFR-driven non-small cell lung cancer (EGFR+ NSCLC). Little is known about the optimal management of SCT patients. This study aimed to compare outcomes under platinum/etoposide chemotherapy alone (chemo) or in combination with EGFR inhibitors (EGFRi+chemo) or immune checkpoint inhibitors (ICI+chemo). In addition, DLL3 expression was explored as potential novel therapeutic target. METHODS: We conducted a retrospective study on patients with EGFR+ NSCLC and SCT treated at 19 centers in Europe and the United States. A total of 47 patients were included of whom 17 received chemo, 20 ICI+chemo, and 10 EGFRi+chemo. We analyzed DLL3 expression by immunohistochemistry. RESULTS: In the entire cohort, median overall survival (OS) from start of first SCT therapy was 11 months (95 % confidence interval [95 %CI] 9.1-12.9) and median progression-free survival (PFS) was 5 months (95 %CI 4.2-5.8). Median PFS was similar in all three groups (chemo and ICI+chemo 4 months, EGFRi+chemo 6 months), and 12-months PFS was 12 % (95 %CI 2 %-31 %), 13 % (95 %CI 0 %-43 %), and 0 % for ICI+chemo, EGFRi+chemo, and chemo, respectively. Median OS in the ICI+chemo group was 13 months (95 %CI 5.5-20.5) compared to 10 months (95 %CI 7.6-12.4) with chemo and EGFRi+chemo (95 %CI 8.1-11.9), respectively. Before and after SCT, 0 % and 93 % of tumors were DLL3-positive. CONCLUSIONS: Our results suggest that ICI+chemo and DLL3-targeting agents are worth further exploration in EGFR+ NSCLC undergoing SCT. PRESENTED ELSEWHERE: Part of this work has been presented at ESMO annual meeting in Madrid, Spain in October 2023 (Poster 1336 P).

Enhanced oxidative stability of deuterated squalene: the impact of labelling extent on chemical resilience.

The extent to which deuteration affects the oxidative stability of squalene, a nutrient and a commonly-used ingredient in cosmetics and vaccine adjuvants, has been quantified as a function of the extent of labelling. The formation of comedogenic peroxides was inhibited by levels of overall deuteration as low as 19%.

e-VITA study protocol: EU-Japan virtual coach for smart aging.

Aim: The aim of this study is to report a trial protocol for assessing the improvement of older adults' well-being, promoting active and healthy aging, and reducing the risks of social exclusion, using a virtual coach. Background: Increased longevity brings with it reduced autonomy and independence, and it is therefore necessary to act with preventive measures that can promote active and healthy aging. With the development of technology, new tools have appeared, including virtual coaches, which can enable people to lead a healthy lifestyle by identifying individual needs and goals and providing personalized recommendations and advice. However, it is important that these coaches take into consideration the inter-individual and cross-cultural differences of each person. Design: A randomized controlled trial is proposed. Methods: This study will recruit 240 healthy subjects aged 65 years and older. Participants will be assigned to an experimental group that will receive the e-VITA system or to the control group that will receive an information booklet only. The primary outcome measure is the person's quality of life (QoL). Data will be collected at baseline, 3 months after the trial, and at the end of the trial, after 6 months. Discussion: This study will evaluate the effectiveness of the e-VITA system, consisting of a virtual coach, several sensors for monitoring, a smartphone for use at home, and a booklet, in improving the older person's quality of life. The increased perceived well-being will also be linked to improvements in other areas of the person's life, psychological and cognitive status, the area of sociality, nutrition, and eHealth literacy.

Technology-Enabled Senior Living: A Preliminary Report on Stakeholder Perspectives.

BACKGROUND: The integration of stakeholders is crucial in developing smart living technologies to support the autonomy of elderly populations. Despite the clear benefits of these technologies, there remains a significant gap in comprehensive research. METHODS: This study presents the viewpoints of 19 stakeholders from Europe and Japan, focusing on the sustainability of smart living solutions for Active and Healthy Ageing (AHA). Data were gathered through qualitative semi-structured interviews and analysed using a Framework Analysis approach. RESULTS: Analysis of the interviews revealed six key sustainability categories: addressing the unmet needs of older adults, functionalities of the smart living coach, integration within organizations, identified barriers, financial considerations, and the social role of the smart living coach. CONCLUSIONS: This research underscores the importance of evaluating user needs through the involvement of various stakeholders, including the elderly, their caregivers, professionals, technicians, service providers, and government bodies. Collaborative efforts are essential to generate new evidence demonstrating the value of smart living solutions in facilitating Active and Healthy Ageing.

Toward Innovation in Healthcare: An Analysis of the Digital Behavior of Older People in Europe and Japan for the Introduction of a Technological Coaching System.

(1) Background: The increasing older population and demographic shifts highlight the need to understand the digital profiles of older adults, a pivotal factor in developing innovative technologies like the e-VITA virtual coach. This personalized coach provides recommendations for sustainable well-being in a smart home environment. (2) Methods: This study focuses on analyzing the characteristics of older individuals categorized as Internet users (onliners) and non-users (offliners). European Social Survey data from 2021 were utilized for European analysis, determining Internet usage based on frequency. Offliners are defined as users who never use the Internet, and onliners as those who use it, albeit with different frequencies. In Japan, data from the 9th International Comparative Survey on the Lives and Attitudes of the Elderly were employed, based on the responses of 1367 subjects, which defined onliners as individuals using communication devices and offliners as those not utilizing fax machines, cell phones, or the Internet. (3) Results: This paper presents a primary analysis of older end-user context and perspectives, outlining effective strategies for the diffusion of an active and healthy aging coaching system in the market and society. (4) Conclusions: the study emphasizes the importance of analyzing digital behavior in any user-centered design approach to ensure the system's acceptance after deployment.

Intrinsic Capacity and Active and Healthy Aging Domains Supported by Personalized Digital Coaching: Survey Study Among Geriatricians in Europe and Japan on eHealth Opportunities for Older Adults.

BACKGROUND: The worldwide aging trend requires conceptually new prevention, care, and innovative living solutions to support human-based care using smart technology, and this concerns the whole world. Enabling access to active and healthy aging through personalized digital coaching services like physical activity coaching, cognitive training, emotional well-being, and social connection for older adults in real life could offer valuable advantages to both individuals and societies. A starting point might be the analysis of the perspectives of different professionals (eg, geriatricians) on such technologies. The perspectives of experts in the sector may allow the individualization of areas of improvement of clinical interventions, supporting the positive perspective pointed out by the intrinsic capacity framework. OBJECTIVE: The overall aim of this study was to explore the cross-national perspectives and experiences of different professionals in the field of intrinsic capacity, and how it can be supported by eHealth interventions. To our knowledge, this is the first study to explore geriatric care providers' perspectives about technology-based interventions to support intrinsic capacity. METHODS: A survey involving 20 geriatricians or clinical experts in the fields of intrinsic capacity and active and healthy aging was conducted in Italy, France, Germany, and Japan between August and September 2021. RESULTS: The qualitative findings pointed out relevant domains for eHealth interventions and provided examples for successful practices that support subjective well-being under the intrinsic capacity framework (the benefits offered by personalized interventions, especially by promoting health literacy but avoiding intrusiveness). Moreover, eHealth interventions could be used as a bridge that facilitates and enables social engagement; an instrument that facilitates communication between doctors and patients; and a tool to enrich the monitoring actions of medical staff. CONCLUSIONS: There is an unexplored and significant role for such geriatric perspectives to help the development process and evaluate the evidence-based results on the effectiveness of technologies for older people. This is possible only when clinicians collaborate with data scientists, engineers, and developers in order to match the complex daily needs of older adults.

A systematic review of multidomain and lifestyle interventions to support the intrinsic capacity of the older population.

Introduction: The focus on intrinsic capacity (IC) could help clinicians to design interventions to improve the health of the older population. This review aims to map the current state of the art in the field of multi-domain interventions based on the IC framework, to allow health professionals in identifying personalized clinical interventions, oriented to empower the older people with a holistic and positive approach. Methods: A systematic review of the literature was conducted in July 2021 analyzing manuscripts and articles of the last 10.5 years from PubMed, Scopus, Embase, Google Scholar and Elsevier databases. A total of 12 papers were included. Results: The majority of successful interventions are based on a goal setting approach where the older people are involved in the definition of the strategy to follow to remain active and independent. None of the study have used the IC as a framework to design a clinical intervention. Conclusion: To the best of our knowledge, no other reviews are reported in the literature regarding the IC. Our study offers several research directions, which may take the existing debates to the next level.

User Perceptions and Needs Analysis of a Virtual Coach for Active and Healthy Ageing-An International Qualitative Study.

Virtual coaching systems show great potential for meeting the challenges of demographic change. However, the proportion of older users in the field of digital technologies is far behind that of younger people. As part of the e-VITA project, semi-structured interviews were conducted in Japan, France, Italy and Germany with 58 people aged 65 and over, and the content was analyzed with the aim of obtaining information about how older adults organize their everyday lives, also with regard to the COVID-19 pandemic, how they deal with their health, what role digital technologies play in the lives of the interviewees and why they oppose progressive digitization. Second, the survey asked why the older adults oppose a virtual coach, which is to be developed in the e-VITA project to support older adults in healthy and active aging, and what barriers they see in a possible implementation. It was found that older respondents lead active, varied lives and that the COVID-19 pandemic contributed to the increased use of digital solutions. In addition, respondents were consciously addressing their own health. With regard to a virtual coach, barriers were seen primarily in the area of data security and sharing. It can be concluded from this that heterogeneity among older user groups should be taken into account when developing virtual coaches. In addition, aspects of data security and data protection should be presented in a clearly understandable and transparent manner.

Acceptance of truck platooning by professional drivers on German highways. A mixed methods approach.

Truck platoon driving is a current branch of automated driving, which has the potential to radically change the work routine of professional drivers. In a platoon system, one truck (semi-)automatically follows a lead truck with a reduced distance, which produces significant savings in fuel and enables better traffic flow. In a current application of truck platoon driving, the following vehicle operates at level-2 automation. Thus, the driver of the following truck merely has to supervise the semi-automated system, which takes over steering and speed control when engaged. Level-2 truck platoon driving had not been tested with professional drivers in real traffic before. We hypothesized that user acceptance would improve after the experience of platoon driving. Quantitative questionnaires and qualitative interviews were conducted with 10 drivers before and after an extensive Autobahn experience. The results show a clear increase of acceptance after the experience. Platoon driving was evaluated to be more useful, easier to use, and safer after the experience. Besides perceived driving safety, the prestige of truck platooning, the perceived usefulness of the system, and general technology affinity co-determined user acceptance.

Pharmaco-epidemiological research on herbal medicinal products in the paediatric population: data from the PhytoVIS study.

In paediatrics, clinical study data are limited, especially on herbal medicinal products. To address this gap, 2063 datasets from the paediatric population were evaluated in the PhytoVIS data base. By screening for paediatric data, information on indication, gender, treatment, co-medication and tolerability were evaluated. The majority of patients was treated because of common cold, fever, digestive complaints, skin diseases, sleep disturbances and anxiety. The perceived effect of the therapy was rated in 84% of the patients as very good or good without adverse events. The data shed light on a still neglected field of phyto-pharmacotherapy by giving information on the use of herbal medicines in an unselected cohort of paediatric patients. The results confirm the good clinical effects and safety of herbal medicinal products in this patient population and show that they are widely used in Germany.What is Known:• In Germany, about 85% of children receive one or more herbal medicinal products per year.• Despite international initiatives to promote clinical research in paediatrics, there are still many gaps of knowledge in the use of drugs in paediatrics.What is New:• The PhytoVIS project evaluated 2063 data sets from the paediatric population using herbal medicinal products.• The majority of patients was treated because of common cold, fever, digestive complaints, skin diseases, sleep disturbances and anxiety, and 84% of the patients rated the therapy as very good or good without adverse events.

Patterns of structural and sequential ambidexterity in cross-border media management.

Organisational ambidexterity - the ability of a company to successfully link exploitation and exploration - is a fruitful approach for cross-border management. It is a crucial concept for media companies that, because of the dual (cultural and economic) character of their products, need to reconcile strategies of mere expansion with local customisation when engaging across borders. Drawing on semi-structured interviews with international media managers, this article captures patterns of ambidextrous strategising and organising in cross-border media activities. The article focuses on digitisation, which has altered the opportunities for balancing exploration and exploitation in internationalisation. The analysis reveals how, in this context, exploitation takes centre stage and how patterns of ambidexterity differ significantly depending on the media type and the background of the company.

A robust and reproducible animal serum-free culture method for clinical-grade bone marrow-derived mesenchymal stromal cells.

Efficient xenofree expansion methods to replace fetal bovine serum (FBS)-based culture methods are strongly encouraged by the regulators and are needed to facilitate the adoption of mesenchymal stromal cell (MSC)-based therapies. In the current study we established a clinically-compliant and reproducible animal serum-free culture protocol for bone marrow-(BM-) MSCs based on an optimized platelet-derived supplement. Our study compared two different platelet-derived supplements, platelet lysate PL1 versus PL2, produced by two different methods and lysed with different amounts of freeze-thaw cycles. Our study also explored the effect of a low oxygen concentration on BM-MSCs. FBS-supplemented BM-MSC culture served as control. Growth kinetics, differentiation and immunomodulatory potential, morphology, karyotype and immunophenotype was analysed. Growth kinetics in long-term culture was also studied. Based on the initial results, we chose to further process develop the PL1-supplemented culture protocol at 20 % oxygen. The results from 11 individual BM-MSC batches expanded in the chosen condition were consistent, yielding 6.60 × 10(9) ± 4.74 × 10(9) cells from only 20 ml of bone marrow. The cells suppressed T-cell proliferation, displayed normal karyotype and typical MSC differentiation potential and phenotype. The BM-MSCs were, however, consistently HLA-DR positive when cultured in platelet lysate (7.5-66.1 %). We additionally show that culture media antibiotics and sterile filtration of the platelet lysate can be successfully omitted. We present a robust and reproducible clinically-compliant culture method for BM-MSCs based on platelet lysate, which enables high quantities of HLA-DR positive MSCs at a low passage number (p2) and suitable for clinical use.

Movement Induces the Use of External Spatial Coordinates for Tactile Localization in Congenitally Blind Humans.

To localize touch, the brain integrates spatial information coded in anatomically based and external spatial reference frames. Sighted humans, by default, use both reference frames in tactile localization. In contrast, congenitally blind individuals have been reported to rely exclusively on anatomical coordinates, suggesting a crucial role of the visual system for tactile spatial processing. We tested whether the use of external spatial information in touch can, alternatively, be induced by a movement context. Sighted and congenitally blind humans performed a tactile temporal order judgment task that indexes the use of external coordinates for tactile localization, while they executed bimanual arm movements with uncrossed and crossed start and end postures. In the sighted, start posture and planned end posture of the arm movement modulated tactile localization for stimuli presented before and during movement, indicating automatic, external recoding of touch. Contrary to previous findings, tactile localization of congenitally blind participants, too, was affected by external coordinates, though only for stimuli presented before movement start. Furthermore, only the movement's start posture, but not the planned end posture affected blind individuals' tactile performance. Thus, integration of external coordinates in touch is established without vision, though more selectively than when vision has developed normally, and possibly restricted to movement contexts. The lack of modulation by the planned posture in congenitally blind participants suggests that external coordinates in this group are not mediated by motor efference copy. Instead the task-related frequent posture changes, that is, movement consequences rather than planning, appear to have induced their use of external coordinates.

Tactile-auditory saltation: spatiotemporal integration across sensory modalities.

The perceptual phenomena of sensory saltation involve the systematic displacement of a target stimulus (the attractee) towards a subsequent stimulus (the attractant), which occurs closely in time and space. Here, we demonstrate the existence of cross-modal tactile-auditory saltation. Tactile stimuli were delivered to the forehead and spatially congruent stereoscopic auditory stimuli were presented via headphones to a total of 20 participants. After a reference stimulus at one of five spatial positions, the attractee was presented at a fixed position, followed by the attractant at a different fixed position with a delay of 81, 121, or 181 ms. Participants rated whether the attractee was perceived left or right of the reference in 2 uni-modal and 2 cross-modal (different reference/attractee vs. attractant mode) configurations. Saltation was present in all uni- and cross-modal configurations at an attractee-attractant delay of 81 ms. At delays of 81 ms the overall displacements were stronger than at delays of 121 ms, and tactile attractants generally induced stronger displacements than auditory attractants. The results indicated the existence of cross-modal tactile-auditory saltation, suggesting the application of the saltation phenomenon as a powerful approach for examining multi-modal sensory representations in future studies.

Selective disruption of hippocampus-mediated recognition memory processes after episodes of transient global amnesia.

Transient global amnesia (TGA) is characterized by the abrupt onset of severe amnesia without concomitant focal neurological symptoms. Recent studies revealed that small and punctate MR-signal diffusion-weighted imaging (DWI) lesions can be found within the hippocampus of TGA patients during the post-acute phase. On the basis of dual-process models of recognition memory, the present study examined the hypothesis that hippocampal dysfunction as suggested by these DWI lesions disrupts hippocampus-mediated recollection in patients with TGA, whereas familiarity-based recognition memory that is assumed to be supported by extra-hippocampal brain regions should be unaffected. We administered a recognition memory task for faces and words to eleven TGA patients during the post-acute phase and to eleven matched controls. Receiver operating characteristics (ROCs) were obtained in order to derive estimates of familiarity and recollection by applying a formal dual-process model of recognition memory. Analyses of ROC curves revealed a disruption of recollection in TGA patients' memory for words [t(20)=2.70, p<.05], but no difference in familiarity-based recognition memory between patients and controls [t(20)=-1.10, p=.284]. Post hoc analyses indicated that the deficit in recollection is more pronounced in TGA patients who show visible hippocampal lesions on diffusion-weighted MR imaging compared to those without detectable hippocampal lesions. In conclusion, consistent with recent neuroanatomical dual-process models of recognition memory, hippocampal dysfunction in patients with TGA is associated with a selective effect on specific recognition memory subprocesses.