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Abstract Background This paper explores the feasibility of establishing a large-scale population-based cohort and biobank in Switzerland by assessing potential participants’ needs, expectations, and concerns about such an infrastructure providing information on health, lifestyle, and exposure trajectories, the development of disease, and risk factors over time. Methods We utilized a scenario-based questionnaire in the Swiss Health Study pilot phase (2020–2021), involving 1349 adults aged 20–69 from the cantons Vaud and Bern. We conducted descriptive statistics supported by R and qualitative content analysis of n = 374 open responses related to attitudes towards research. Results We highlight the benefits and challenges of the scenario-based approach, discuss the sample represented in the pilot phase, and present implications for building a full cohort. We also report on participants’ attitudes towards and previous experience with health research. We analyze references regarding informed consent and feedback, attitudes towards the Swiss Health Study, and recommendations on improving its scope, design, and instruments. Results indicate a high interest (90%) in participating in a national health study, with 85% of a random population sample willing to join a long-term cohort. Only 43% were familiar with biobanks, and 44% preferred general consent. Trust was high for Swiss-based public research but lower for researchers from other countries or private sector. Over 95% expressed willingness to complete online questionnaires, undergo physical examination, and donate biosamples. Almost all participants wanted to know the outcomes of the medical tests (99.5%) and the exposure to environmental stressors (95%) from their study center visit. Preferred tools for monitoring sleep, physical activity, and diet were known smartphone apps with automatic data management. Conclusion Overall, the study reveals a positive attitude towards personalized health research, with a strong willingness to share data and samples. Key insights focus the meaning of informed consent for participation, the relevance of sampling and representativeness, as well as the significance and challenges of personalized feedback, especially regarding environmental health concerns. Findings emphasize participants’ supportive yet reflexive stances, underscoring the importance of aligning research values with individual values in personalized health research. These insights contribute valuable considerations for refining the scope, design, and instruments of future cohort studies.

Objectives: Our study aims to evaluate developments in vaccine uptake and digital proximity tracing app use in a localized context of the SARS-CoV-2 pandemic.Methods: We report findings from two population-based longitudinal cohorts in Switzerland from January to December 2021. Failure time analyses and Cox proportional hazards regression models were conducted to assess vaccine uptake and digital proximity tracing app (SwissCovid) uninstalling outcomes.Results: We observed a dichotomy of individuals who did not use the SwissCovid app and did not get vaccinated, and who used the SwissCovid app and got vaccinated during the study period. Increased vaccine uptake was observed with SwissCovid app use (aHR, 1.51; 95% CI: 1.40–1.62 [CI-DFU]; aHR, 1.79; 95% CI: 1.62–1.99 [CSM]) compared to SwissCovid app non-use. Decreased SwissCovid uninstallation risk was observed for participants who got vaccinated (aHR, 0.55; 95% CI: 0.38–0.81 [CI-DFU]; aHR, 0.45; 95% CI: 0.27–0.78 [CSM]) compared to participants who did not get vaccinated.Conclusion: In evolving epidemic contexts, these findings underscore the need for communication strategies as well as flexible digital proximity tracing app adjustments that accommodate different preventive measures and their anticipated interactions.

Objectives: COVID-19 vaccine hesitancy is a major obstacle in the fight against the pandemic. This study aimed to identify the local determinants of vaccine hesitancy in the context of COVID-19 to better inform future immunization campaigns.Methods: The study, conducted in February 2021, included 1,189 randomly selected inhabitants of the canton of Vaud, Switzerland. Online questionnaires investigated determinants of the intention to vaccinate. Previously validated scores (Cronbach’s alphas >0.70) were applied to our data for inclusion in the ordinal logistic regression model.Results: Individuals were more likely to vaccinate if they were 40 years or older, wealthy, reported a high educational attainment, or reported comorbidities. Doubts regarding vaccine safety and efficacy, mistrust in authorities and a propensity for natural immunity were identified as the main local hindrances to the COVID-19 vaccination.Conclusion: Outreach to people at risk of severe COVID-19 is particularly relevant in the pandemic context to help mitigate vaccine hesitancy in the canton of Vaud, and should take into consideration the level of education. Further investigation is needed to better understand reasons for mistrust in authorities.

Objectives: To describe the rationale, organization, and procedures of the Corona Immunitas Digital Follow-Up (CI-DFU) eCohort and to characterize participants at baseline.Methods: Participants of Corona Immunitas, a population-based nationwide SARS-CoV-2 seroprevalence study in Switzerland, were invited to join the CI-DFU eCohort in 11 study centres. Weekly online questonnaires cover health status changes, prevention measures adherence, and social impacts. Monthly questionnaires cover additional prevention adherence, contact tracing apps use, vaccination and vaccine hesitancy, and socio-economic changes.Results: We report data from the 5 centres that enrolled in the CI-DFU between June and October 2020 (covering Basel City/Land, Fribourg, Neuchâtel, Ticino, Zurich). As of February 2021, 4636 participants were enrolled and 85,693 weekly and 27,817 monthly questionnaires were collected. Design-based oversampling led to overrepresentation of individuals aged 65+ years. People with higher education and income were more likely to enroll and be retained.Conclusion: Broad enrolment and robust retention of participants enables scientifically sound monitoring of pandemic impacts, prevention, and vaccination progress. The CI-DFU eCohort demonstrates proof-of-principle for large-scale, federated eCohort study designs based on jointly agreed principles and transparent governance.

BackgroundThe Bland-Altman limits of agreement (LoA) method is almost universally used to compare two measurement methods when the outcome is continuous, despite warnings regarding the often-violated strong underlying statistical assumptions. In settings where only a single measurement per individual has been performed and one of the two measurement methods is exempt (or almost) from any measurement error, the LoA method provides biased results, whereas this is not the case for linear regression.MethodsThus, our goal is to explain why this happens and illustrate the advantage of linear regression in this particular setting. For our illustration, we used two data sets: a sample of simulated data, where the truth is known, and data from a validation study on the accuracy of a smartphone image-based dietary intake assessment tool.ResultsOur results show that when one of the two measurement methods is exempt (or almost) from any measurement errors, the LoA method should not be used as it provides biased results. In contrast, linear regression of the differences on the precise method was unbiased.ConclusionsThe LoA method should be abandoned in favor of linear regression when one of the two measurement methods is exempt (or almost) from measurement errors.

AMP-activated protein kinase (AMPK) is a key regulator of energy homeostasis under conditions of energy stress. Though heart is one of the most energy requiring organs and depends on a perfect match of energy supply with high and fluctuating energy demand to maintain its contractile performance, the role of AMPK in this organ is still not entirely clear, in particular in a non-pathological setting. In this work, we characterized cardiomyocyte-specific, inducible AMPKα1 and α2 knockout mice (KO), where KO was induced at the age of 8 weeks, and assessed their phenotype under physiological conditions. In the heart of KO mice, both AMPKα isoforms were strongly reduced and thus deleted in a large part of cardiomyocytes already 2 weeks after tamoxifen administration, persisting during the entire study period. AMPK KO had no effect on heart function at baseline, but alterations were observed under increased workload induced by dobutamine stress, consistent with lower endurance exercise capacity observed in AMPK KO mice. AMPKα deletion also induced a decrease in basal metabolic rate (oxygen uptake, energy expenditure) together with a trend to lower locomotor activity of AMPK KO mice 12 months after tamoxifen administration. Loss of AMPK resulted in multiple alterations of cardiac mitochondria: reduced respiration with complex I substrates as measured in isolated mitochondria, reduced activity of complexes I and IV, and a shift in mitochondrial cristae morphology from lamellar to mixed lamellar-tubular. A strong tendency to diminished ATP and glycogen level was observed in older animals, 1 year after tamoxifen administration. Our study suggests important roles of cardiac AMPK at increased cardiac workload, potentially limiting exercise performance. This is at least partially due to impaired mitochondrial function and bioenergetics which degrades with age.

Purpose: Both cardiomyocytes and cardiac fibroblasts (CF) play essential roles in cardiac development, function, and remodeling. Properties of 3D co-cultures are incompletely understood. Hence, 3D co-culture of cardiomyocytes and CF was characterized, and selected features compared with single-type and 2D culture conditions.Methods: Human cardiomyocytes derived from induced-pluripotent stem cells (hiPSC-CMs) were obtained from Cellular Dynamics or Ncardia, and primary human cardiac fibroblasts from ScienCell. Cardiac spheroids were investigated using cryosections and whole-mount confocal microscopy, video motion analysis, scanning-, and transmission-electron microscopy (SEM, TEM), action potential recording, and quantitative PCR (qPCR).Results: Spheroids formed in hanging drops or in non-adhesive wells showed spontaneous contractions for at least 1 month with frequent media changes. SEM of mechanically opened spheroids revealed a dense inner structure and no signs of blebbing. TEM of co-culture spheroids at 1 month showed myofibrils, intercalated disc-like structures and mitochondria. Ultrastructural features were comparable to fetal human myocardium. We then assessed immunostained 2D cultures, cryosections of spheroids, and whole-mount preparations by confocal microscopy. CF in co-culture spheroids assumed a small size and shape similar to the situation in ventricular tissue. Spheroids made only of CF and cultured for 3 weeks showed no stress fibers and strongly reduced amounts of alpha smooth muscle actin compared to early spheroids and 2D cultures as shown by confocal microscopy, western blotting, and qPCR. The addition of CF to cardiac spheroids did not lead to arrhythmogenic effects as measured by sharp-electrode electrophysiology. Video motion analysis showed a faster spontaneous contraction rate in co-culture spheroids compared to pure hiPSC-CMs, but similar contraction amplitudes and kinetics. Spontaneous contraction rates were not dependent on spheroid size. Applying increasing pacing frequencies resulted in decreasing contraction amplitudes without positive staircase effect. Gene expression analysis of selected cytoskeleton and myofibrillar proteins showed more tissue-like expression patterns in co-culture spheroids than with cardiomyocytes alone or in 2D culture.Conclusion: We demonstrate that the use of 3D co-culture of hiPSC-CMs and CF is superior over 2D culture conditions for co-culture models and more closely mimicking the native state of the myocardium with relevance to drug development as well as for personalized medicine.

Digital dietary assessment devices could help overcome the limitations of traditional tools to assess dietary intake in clinical and/or epidemiological studies. We evaluated the accuracy of the automated dietary app MyFoodRepo (MFR) against controlled reference values from weighted food diaries (WFD). MFR’s capability to identify, classify and analyze the content of 189 different records was assessed using Cohen and uniform kappa coefficients and linear regressions. MFR identified 98.0% ± 1.5 of all edible components and was not affected by increasing numbers of ingredients. Linear regression analysis showed wide limits of agreement between MFR and WFD methods to estimate energy, carbohydrates, fat, proteins, fiber and alcohol contents of all records and a constant overestimation of proteins, likely reflecting the overestimation of portion sizes for meat, fish and seafood. The MFR mean portion size error was 9.2% ± 48.1 with individual errors ranging between −88.5% and +242.5% compared to true values. Beverages were impacted by the app’s difficulty in correctly identifying the nature of liquids (41.9% ± 17.7 of composed beverages correctly classified). Fair estimations of portion size by MFR, along with its strong segmentation and classification capabilities, resulted in a generally good agreement between MFR and WFD which would be suited for the identification of dietary patterns, eating habits and regime types.

Nutritional habits can have a significant impact on cardiovascular health and disease. This may also apply to cardiotoxicity caused as a frequent side effect of chemotherapeutic drugs, such as doxorubicin (DXR). The aim of this work was to analyze if diet, in particular creatine (Cr) supplementation, can modulate cardiac biochemical (energy status, oxidative damage and antioxidant capacity, DNA integrity, cell signaling) and functional parameters at baseline and upon DXR treatment. Here, male Wistar rats were fed for 4 weeks with either standard rodent diet (NORMAL), soy-based diet (SOY), or Cr-supplemented soy-based diet (SOY + Cr). Hearts were either freeze-clamped in situ or following ex vivo Langendorff perfusion without or with 25 μM DXR and after recording cardiac function. The diets had distinct cardiac effects. Soy-based diet (SOY vs. NORMAL) did not alter cardiac performance but increased phosphorylation of acetyl-CoA carboxylase (ACC), indicating activation of rather pro-catabolic AMP-activated protein kinase (AMPK) signaling, consistent with increased ADP/ATP ratios and lower lipid peroxidation. Creatine addition to the soy-based diet (SOY + Cr vs. SOY) slightly increased left ventricular developed pressure (LVDP) and contractility dp/dt, as measured at baseline in perfused heart, and resulted in activation of the rather pro-anabolic protein kinases Akt and ERK. Challenging perfused heart with DXR, as analyzed across all nutritional regimens, deteriorated most cardiac functional parameters and also altered activation of the AMPK, ERK, and Akt signaling pathways. Despite partial reprogramming of cell signaling and metabolism in the rat heart, diet did not modify the functional response to supraclinical DXR concentrations in the used acute cardiotoxicity model. However, the long-term effect of these diets on cardiac sensitivity to chronic and clinically relevant DXR doses remains to be established.

Three-dimensional (3D) cell culture is often mentioned in the context of regenerative medicine, for example, for the replacement of ischemic myocardium with tissue-engineered muscle constructs. Additionally, 3D cell culture is used, although less commonly, in basic research, toxicology, and drug development. These applications have recently benefited from innovations in stem cell technologies allowing the mass-production of hiPSC-derived cardiomyocytes or other cardiovascular cells, and from new culturing methods including organ-on-chip and bioprinting technologies. On the analysis side, improved sensors, computer-assisted image analysis, and data collection techniques have lowered the bar for switching to 3D cell culture models. Nevertheless, 3D cell culture is not as widespread or standardized as traditional cell culture methods using monolayers of cells on flat surfaces. The many possibilities of 3D cell culture, but also its limitations, drawbacks and methodological pitfalls, are less well-known. This article reviews currently used cardiovascular 3D cell culture production methods and analysis techniques for the investigation of cardiotoxicity, in drug development and for disease modeling.

Cardiac fibrosis represents a serious clinical problem. Development of novel treatment strategies is currently restricted by the lack of the relevant experimental models in a human genetic context. In this study, we fabricated self-aggregating, scaffold-free, 3D cardiac microtissues using human inducible pluripotent stem cell (iPSC)-derived cardiomyocytes and human cardiac fibroblasts. Fibrotic condition was obtained by treatment of cardiac microtissues with profibrotic cytokine transforming growth factor β1 (TGF-β1), preactivation of foetal cardiac fibroblasts with TGF-β1, or by the use of cardiac fibroblasts obtained from heart failure patients. In our model, TGF-β1 effectively induced profibrotic changes in cardiac fibroblasts and in cardiac microtissues. Fibrotic phenotype of cardiac microtissues was inhibited by treatment with TGF-β-receptor type 1 inhibitor SD208 in a dose-dependent manner. We observed that fibrotic cardiac microtissues substantially increased the spontaneous beating rate by shortening the relaxation phase and showed a lower contraction amplitude. Instead, no changes in action potential profile were detected. Furthermore, we demonstrated that contraction of human cardiac microtissues could be modulated by direct electrical stimulation or treatment with the β-adrenergic receptor agonist isoproterenol. However, in the absence of exogenous agonists, the β-adrenoreceptor blocker nadolol decreased beating rate of fibrotic cardiac microtissues by prolonging relaxation time. Thus, our data suggest that in fibrosis, activated cardiac fibroblasts could promote cardiac contraction rate by a direct stimulation of β-adrenoreceptor signalling. In conclusion, a model of fibrotic cardiac microtissues can be used as a high-throughput model for drug testing and to study cellular and molecular mechanisms of cardiac fibrosis.

Recent innovations in stem cell technologies and the availability of human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) have opened new possibilities for studies and drug testing on human cardiomyocytes in vitro. Still, there are concerns about the precise nature of such ‘reprogrammed’ cells. We have performed an investigation using immunocytochemistry and confocal microscopy on several cellular features using commercially available hiPSC-CMs. For some selected developmentally regulated or cardiac chamber-specific proteins, we have compared the results from hiPSC-derived cardiomyocytes with freshly isolated, ventricular cardiomyocytes from adult rats. The results show that all typical cardiac proteins are expressed in these hiPSC-CMs. Furthermore, intercalated disc-like structures, calcium cycling proteins, and myofibrils are present. However, some of these proteins are only known from early developmental stages of the ventricular myocardium or the diseased adult heart. A heterogeneous expression pattern in the cell population was noted for some muscle proteins, such as for myosin light chains, or incomplete organization in sarcomeres, such as for telethonin. These observations indicate that hiPSC-CMs can be considered genuine human cardiomyocytes of an early developmental state. The here described marker proteins of maturation may become instrumental in future studies attempting the improvement of cardiomyocyte in vitro models.