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Xiaoyue Song,1,2 Weihong Zhang,2 Cynthia Hallensleben,1 Anke Versluis,1 Rianne van der Kleij,1 Zongliang Jiang,2 Niels H Chavannes,1 Robbert JJ Gobbens3– 5 1Department of Public Health and Primary Care, Leiden University Medical Center, Leiden 2333 ZD, The Netherlands; 2School of Nursing, Zhengzhou University, Zhengzhou, People’s Republic of China; 3Faculty of Health, Sports and Social Work, Inholland University of Applied Sciences, Amsterdam, The Netherlands; 4Zonnehuisgroep Amstelland, Amstelveen, The Netherlands; 5Department of Primary and Interdisciplinary Care, Faculty of Medicine and Health Sciences, University of Antwerp, Antwerp, BelgiumCorrespondence: Xiaoyue SongDepartment of Public Health and Primary Care, Leiden University Medical Center, Hippocratespad 21, Leiden 2333 ZD, The NetherlandsTel +31682817080Email x.song@lumc.nlPurpose: To investigate the prevalence of multidimensional frailty in older people with hypertension and to examine a possible relationship of general obesity and abdominal obesity to frailty in older people with hypertension.Patients and Methods: A sample of 995 community-dwelling older people with hypertension, aged 65 years and older and living in Zhengzhou (China), completed the Tilburg Frailty Indicator (TFI), a validated self-report questionnaire for assessing multidimensional frailty. In addition, socio-demographic and lifestyle characteristics were assessed by self-report, and obesity was determined by measuring waist circumference and calculating the body mass index.Results: The prevalence of multidimensional frailty in this older population with hypertension was 46.5%. Using multiple linear regression analysis, body mass index was significantly associated with physical frailty (p = 0.001), and waist circumference was significantly positively associated with multidimensional frailty and all three frailty domains. Older age was positively associated with multidimensional frailty, physical frailty, and psychological frailty, while gender (woman) was positively associated with multidimensional, psychological, and social frailty. Furthermore, comorbid diseases and being without a partner were positively associated with multidimensional, physical, psychological, and social frailty. Of the lifestyle characteristics, drinking alcohol was positively associated with frailty domains.Conclusion: Multidimensional frailty was highly prevalent among Chinese community-dwelling older people with hypertension. Abdominal obesity could be a concern in physical frailty, psychological frailty, and social frailty, while general obesity was concerning in relation to physical frailty.Keywords: older people, multidimensional frailty, obesity, hypertension

Abstract Background The use of two-dimensional (2D) ultrasound for guiding radiofrequency ablation (RFA) of benign thyroid nodules presents limitations, including the inability to monitor the entire treatment volume and operator dependency in electrode positioning. We compared three-dimensional (3D)-guided RFA using a matrix ultrasound transducer with conventional 2D-ultrasound guidance in an anthropomorphic thyroid nodule phantom incorporated additionally with temperature-sensitive albumin. Methods Twenty-four phantoms with 48 nodules were constructed and ablated by an experienced radiologist using either 2D- or 3D-ultrasound guidance. Postablation T2-weighted magnetic resonance imaging scans were acquired to determine the final ablation temperature distribution in the phantoms. These were used to analyze ablation parameters, such as the nodule ablation percentage. Further, additional procedure parameters, such as dominant/non-dominant hand use, were recorded. Results Nonsignificant trends towards lower ablated volumes for both within (74.4 ± 9.1% (median ± interquartile range) versus 78.8 ± 11.8%) and outside of the nodule (0.35 ± 0.18 mL versus 0.45 ± 0.46 mL), along with lower variances in performance, were noted for the 3D-guided ablation. For the total ablation percentage, 2D-guided dominant hand ablation performed better than 2D-guided non-dominant hand ablation (81.0% versus 73.2%, p = 0.045), while there was no significant effect in the hand comparison for 3D-guided ablation. Conclusion 3D-ultrasound-guided RFA showed no significantly different results compared to 2D guidance, while 3D ultrasound showed a reduced variance in RFA. A significant reduction in operator-ablating hand dependence was observed when using 3D guidance. Further research into the use of 3D ultrasound for RFA is warranted. Relevance statement Using 3D ultrasound for thyroid nodule RFA could improve the clinical outcome. A platform that creates 3D data could be used for thyroid diagnosis, therapy planning, and navigational tools. Key Points Twenty-four in-house-developed thyroid nodule phantoms with 48 nodules were constructed. RFA was performed under 2D- or 3D-ultrasound guidance. 3D- and 2D ultrasound-guided RFAs showed comparable performance. Real-time dual-plane imaging may offer an improved overview of the ablation zone and aid electrode positioning. Dominant and non-dominant hand 3D-ultrasound-guided RFA outcomes were comparable. Graphical Abstract

Abstract Functionalized monodisperse microbubbles have the potential to boost the sensitivity and efficacy of molecular ultrasound imaging and targeted drug delivery using bubbles and ultrasound. Monodisperse bubbles can be produced in a microfluidic flow focusing device. However, their functionalization and sequential use require removal of the excess lipids from the bubble suspension to minimize the use of expensive ligands and to avoid competitive binding and blocking of the receptor molecules. To date, excess lipid removal is performed by centrifugation, which is labor intensive and challenging to automate. More importantly, as we show, the increased hydrostatic pressure during centrifugation can reduce bubble monodispersity. Here, we introduce a novel automated microfluidic ’washing’ method. First, bubbles are injected in a microfluidic chamber 1 mm in height where they are left to float against the top wall. Second, lipid-free medium is pumped through the chamber to remove excess lipids while the bubbles remain located at the top wall. Third, the washed bubbles are resuspended and removed from the device into a collection vial. We demonstrate that the present method can (i) reduce the excess lipid concentration by 4 orders of magnitude, (ii) be fully automated, and (iii) be performed in minutes while the size distribution, functionality, and acoustic response of the bubbles remain unaffected. Thus, the presented method is a gateway to the fully automated production of functionalized monodisperse microbubbles.

Abstract The FRESHAIR4Life study aims to reduce the non-communicable disease (NCD) burden by implementing preventive interventions targeting adolescents’ exposure to tobacco use and air pollution (AP) worldwide. This paper presents the FRESHAIR4Life methodology and initial rapid review results. The rapid review, using various databases and PubMed, aimed to guide decision-making on risk factor focus, target areas, and populations. It showed variable NCD mortality rates related to tobacco use and AP across the participating countries, with tobacco as the main risk factor in the Kyrgyz Republic, Greece, and Romania, and AP prevailing in Pakistan and Uganda. Adolescent exposure levels, sources, and correlates varied. The study will continue with an in-depth situational analysis to guide the selection, adaptation, and integration of evidence-based interventions into the FRESHAIR4Life prevention package. This package will be implemented, evaluated, assessed for cost-effectiveness, and iteratively refined. The research places a strong emphasis on co-creation, capacity building, and comprehensive communication and dissemination.

Abstract Randomized controlled trials (RCTs) are the gold standard to establish the benefit-risk ratio of novel drugs. However, the evaluation of mature results often takes many years. We hypothesized that the addition of Bayesian inference methods at interim analysis time points might accelerate and enforce the knowledge that such trials may generate. In order to test that hypothesis, we retrospectively applied a Bayesian approach to the HOVON 132 trial, in which 800 newly diagnosed AML patients aged 18 to 65 years were randomly assigned to a “7 + 3” induction with or without lenalidomide. Five years after the first patient was recruited, the trial was negative for its primary endpoint with no difference in event-free survival (EFS) between experimental and control groups (hazard ratio [HR] 0.99, p = 0.96) in the final conventional analysis. We retrospectively simulated interim analyses after the inclusion of 150, 300, 450, and 600 patients using a Bayesian methodology to detect early lack of efficacy signals. The HR for EFS comparing the lenalidomide arm with the control treatment arm was 1.21 (95% CI 0.81–1.69), 1.05 (95% CI 0.86–1.30), 1.00 (95% CI 0.84–1.19), and 1.02 (95% CI 0.87–1.19) at interim analysis 1, 2, 3 and 4, respectively. Complete remission rates were lower in the lenalidomide arm, and early deaths more frequent. A Bayesian approach identified that the probability of a clinically relevant benefit for EFS (HR

The goal of the study was to develop a method for segmentation of the thyroid, carotid artery (CA), and jugular vein (JV) using 3D ultrasound data. This method forms the basis for a computer-assisted needle-based intervention for thyroid nodules and thyroid volume estimation accuracy. Two datasets were used: the first was acquired using a tracked 2D sweep and the second with a 3D matrix transducer. A 2D and 3D U-Net model were trained on the full data set with different strategies (2D, majority vote in 2.5D and 3D). The 2D model achieved the best results for the tracked 2D sweep data set in terms of median Dice Score Coefficient (DSC) (0.934, 0.924, 0.897) and Hausdorff distance at the 95 percentile (HD95) (1.206, 0.588, 1.571 mm) for the thyroid, CA, and JV, respectively. For the matrix data set, the 3D model gave overall the best results in its median DSC (0.869, 0.930, 0.856) and HD95 (1.814, 0.606, 1.405 mm) for the thyroid, CA, and JV, respectively, showing comparable results in vessel segmentation but inferior results in thyroid segmentation compared to the tracked sweep data set. The model demonstrated lower median volume estimation errors in the tracked sweep data set (4.45 %) compared to the matrix data set (7.40 %) and the ellipsoid formula (13.84 %) for thyroid volume estimation. This work shows that automatic segmentation in 3D ultrasound of the human neck is best performed with 3D ultrasound. Improving the quality of the 3D data is important for the development of a planning and navigation method to be used with needle-based interventions for thyroid nodules.

BackgroundType 2 diabetes (T2D) tremendously affects patient health and health care globally. Changing lifestyle behaviors can help curb the burden of T2D. However, health behavior change is a complex interplay of medical, behavioral, and psychological factors. Personalized lifestyle advice and promotion of self-management can help patients change their health behavior and improve glucose regulation. Digital tools are effective in areas of self-management and have great potential to support patient self-management due to low costs, 24/7 availability, and the option of dynamic automated feedback. To develop successful eHealth solutions, it is important to include stakeholders throughout the development and use a structured approach to guide the development team in planning, coordinating, and executing the development process. ObjectiveThe aim of this study is to develop an integrated, eHealth-supported, educational care pathway for patients with T2D. MethodsThe educational care pathway was developed using the first 3 phases of the Center for eHealth and Wellbeing Research roadmap: the contextual inquiry, the value specification, and the design phase. Following this roadmap, we used a scoping review about diabetes self-management education and eHealth, past experiences of eHealth practices in our hospital, focus groups with health care professionals (HCPs), and a patient panel to develop a prototype of an educational care pathway. This care pathway is called the Diabetes Box (Leiden University Medical Center) and consists of personalized education, digital educational material, self-measurements of glucose, blood pressure, activity, and sleep, and a smartphone app to bring it all together. ResultsThe scoping review highlights the importance of self-management education and the potential of telemonitoring and mobile apps for blood glucose regulation in patients with T2D. Focus groups with HCPs revealed the importance of including all relevant lifestyle factors, using a tailored approach, and using digital consultations. The contextual inquiry led to a set of values that stakeholders found important to include in the educational care pathway. All values were specified in biweekly meetings with key stakeholders, and a prototype was designed. This prototype was evaluated in a patient panel that revealed an overall positive impression of the care pathway but stressed that the number of apps should be restricted to one, that there should be no delay in glucose value visualization, and that insulin use should be incorporated into the app. Both patients and HCPs stressed the importance of direct automated feedback in the Diabetes Box. ConclusionsAfter developing the Diabetes Box prototype using the Center for eHealth and Wellbeing Research roadmap, all stakeholders believe that the concept of the Diabetes Box is useful and feasible and that direct automated feedback and education on stress and sleep are essential. A pilot study is planned to assess feasibility, acceptability, and usefulness in more detail.

Abstract Background We recently reported results of the prospective, open‐label HOVON‐100 trial in 334 adult patients with acute lymphoblastic leukemia (ALL) randomized to first‐line treatment with or without clofarabine (CLO). No improvement of event‐free survival (EFS) was observed, while a higher proportion of patients receiving CLO obtained minimal residual disease (MRD) negativity. Aim In order to investigate the effects of CLO in more depth, two multi‐state models were developed to identify why CLO did not show a long‐term survival benefit despite more MRD‐negativity. Methods The first model evaluated the effect of CLO on going off‐protocol (not due to refractory disease/relapse, completion or death) as a proxy of severe treatment‐related toxicity, while the second model evaluated the effect of CLO on obtaining MRD negativity. The subsequent impact of these intermediate events on death or relapsed/refractory disease was assessed in both models. Results Overall, patients receiving CLO went off‐protocol more frequently than control patients (35/168 [21%] vs. 18/166 [11%], p = 0.019; HR 2.00 [1.13–3.52], p = 0.02), especially during maintenance (13/44 [30%] vs. 6/56 [11%]; HR 2.85 [95%CI 1.08–7.50], p = 0.035). Going off‐protocol was, however, not associated with more relapse or death. Patients in the CLO arm showed a trend towards an increased rate of MRD‐negativity compared with control patients (HR MRD‐negativity: 1.35 [0.95–1.91], p = 0.10), which did not translate into a significant survival benefit. Conclusion We conclude that the intermediate states, i.e., going off‐protocol and MRD‐negativity, were affected by adding CLO, but these transitions were not associated with subsequent survival estimates, suggesting relatively modest antileukemic activity in ALL.

BackgroundHealth care lags in digital transformation, despite the potential of technology to improve the well-being of individuals. The COVID-19 pandemic has accelerated the uptake of technology in health care and increased individuals’ willingness to perform self-management using technology. A web-based service, Directlab Online, provides consumers with direct digital access to diagnostic test packages, which can digitally support the self-management of health. ObjectiveThis study aims to identify the facilitators, barriers, and needs of Directlab Online, a self-management service for web-based access to diagnostic testing. MethodsA qualitative method was used from a potential user’s perspective. The needs and future needs for, facilitators of, and barriers to the use of Directlab Online were evaluated. Semistructured focus group meetings were conducted in 2022. Two focus groups were focused on sexually transmitted infection test packages and 2 were focused on prevention test packages. Data analysis was performed according to the principles of the Framework Method. The Consolidated Framework for Implementation Research was used to categorize the facilitators and barriers. ResultsIn total, 19 participants, with a mean age of 34.32 (SD 14.70) years, participated in the focus groups. Important barriers were a lack of privacy information, too much and difficult information, and a commercial appearance. Important facilitators were the right amount of information, the right kind of tests, and the involvement of a health care professional. The need for a service such as Directlab Online was to ensure its availability for users’ health and to maintain their health. ConclusionsAccording to the participants, facilitators and barriers were comprehension of the information, the goal of the website, and the overall appearance of the service. Although the service was developed in cocreation with health care professionals and users, the needs did not align. The users preferred understandable and adequate, but not excessive, information. In addition, they preferred other types of tests to be available on the service. For future research, it would be beneficial to focus on cocreation between the involved medical professionals and users to develop, improve, and implement a service such as Directlab Online.

Abstract Background Ethiopia has scaled up medical education to improve access to healthcare which presented challenges to maintaining training quality. We conducted a study to assess the clinical competence of graduating medical students and the associated factors. Methods and materials A pretest assessment of a quasi-experimental study was conducted in 10 medical schools with a sample size of 240 students. We randomly selected 24 students per school. Clinical competence was assessed in a 12-station objective structured clinical examination. The clinical learning environment (CLE), simulation training, and practice exposure were self-rated. Mean scores for clinical competence, and satisfaction in the CLE and simulation training were calculated. Proportions of students with practice exposure, and who agreed on CLE and simulation items were done. Independent t-tests were used to look at competence differences among subgroups. Bivariate and multiple linear regression models were fitted for the outcome variable: competence score. A 95% statistical confidence interval and p-value