Translational Medicine and Patient Safety in Europe:TRANSFoRm - Architecture for the Learning Health System in Europe

The Learning Health System (LHS) describes linking routine healthcare systems directly with both research translation and knowledge translation as an extension of the evidence-based medicine paradigm, taking advantage of the ubiquitous use of electronic health record (EHR) systems. TRANSFoRm is an EU FP7 project that seeks to develop an infrastructure for the LHS in European primary care. Methods. The project is based on three clinical use cases, a genotype-phenotype study in diabetes, a randomised controlled trial with gastroesophageal reflux disease, and a diagnostic decision support system for chest pain, abdominal pain, and shortness of breath. Results. Four models were developed (clinical research, clinical data, provenance, and diagnosis) that form the basis of the projects approach to interoperability. These models are maintained as ontologies with binding of terms to define precise data elements. CDISC ODM and SDM standards are extended using an archetype approach to enable a two-level model of individual data elements, representing both research content and clinical content. Separate configurations of the TRANSFoRm tools serve each use case. Conclusions. The project has been successful in using ontologies and archetypes to develop a highly flexible solution to the problem of heterogeneity of data sources presented by the LHS

Advancing a MEMS-Based 3D Cell Culture System for in vitro Neuro-Electrophysiological Recordings

In this work we present advances in three dimensional (3D) neuronal cell culture systems based on a reversible assembly of a microbioreactor with a microelectrode array (MEA) to create a MEMS-based 3D cell culture system for in vitro neuro-electrophysiological recordings. A batch of six molds were milled in poly (methyl methacrylate). The molds were used for soft lithography of polydimethylsiloxane (PDMS). In the center of the PDMS shape, a porous polyethersulfone (PES) cylindrical tube was press-fitted to form a growth barrier between the culture chamber inside the PES tube and the microfluidic channel surrounding the PES tube. A thin layer of partially cured PDMS was used to seal the bottom of the microbioreactor and provide reversible adhesion with the glass surface of a MEA. SH-SY5Y cells were successfully differentiated inside the microbioreactors in Matrigel and demonstrated extended neuronal networks over a height of at least 184 micrometers within the system. In previous microbioreactor designs visibility was limited due to the closed top with the dispensing holes. The new open top design allows for a better evaluation of the cell culture by optical detection methods during the experiment. Electrophysiological activity was recorded within the microbioreactor using human induced pluripotent stem cell-derived cortical neurons cultured in Matrigel, in 3D, up until 21 days in vitro. In summary, we present advances made in the design, the fabrication process and integration of microbioreactors with MEAs. Optical imaging capabilities improved significantly with an open top and the culture time was further extended from 7 to 21 DIV without leakage or degradation thanks to introducing PES as a barrier material and an enhanced assembly procedure. The latter facilitated a sufficient long-term culture for neurons to mature in an environment free from flow-induced stress and provided a proof of principle for the recording of electrophysiological activity of cortical neurons cultured in 3D

The inclusion of pregnant women in vaccine clinical trials : an overview of late-stage clinical trials' records between 2018 and 2023

Abstract: Pregnant women are generally excluded from clinical research over safety concerns. However, demands to include them in clinical vaccine development have intensified after recent COVID-19, Ebola, and Lassa fever outbreaks given the disproportionate effect of these diseases on pregnant women and/or their foetuses. Numerous studies highlighted the scarcity of safety data for therapeutic interventions in pregnant women. Nevertheless, only a small number have assessed the number of vaccine trials including this population. Therefore, we searched for phase 3 and 4 vaccine clinical trials in healthy populations registered between 2018 and 2023 in clinicaltrials.gov and the International Clinical Trial Registry Platform. Out of 400 registered vaccine trials matching our inclusion criteria, 217 (54 %) were industry-sponsored, and 222 (56 %) had COVID-19 as a target. We found 22 studies (6 %) that either were designed for pregnant women or included them as part of a larger population. Out of these 22 trials, 13 were designed specifically for pregnant women; seven of these were maternal vaccines aiming at protecting the foetus, namely pertussis (3), Respiratory Syncytial Virus (RSV) (3), and meningitis plus tetanus (1) vaccines, and six others targeted either flu (3), COVID-19 (2) or Ebola (1). Only the RSV and Ebola vaccine trials were industry-sponsored. We also found that nine studies targeting the general population included pregnant women. These focused on COVID-19 (3), flu (2), COVID-19 + flu (2), Ebola (1), and Hepatitis B (1). None of these studies was industry-sponsored. Our findings show that a gap still exists in terms of pregnant women's inclusion in vaccine trials. Such a gap needs to be tackled urgently to minimise the devastating effects that a future infectious disease outbreak could have on this population. This study can inform future demands for increased inclusion, especially in industry-sponsored trials, as it provides an overview of the current vaccine trials scene

Uncontrolled hypertension in Uganda : a comparative cross-sectional study

In a community survey, 4432 persons aged 15 years and older in two districts in Uganda were studied. Blood pressure was measured and predictors for subtypes of uncontrolled hypertension (HTN) were assessed using bivariate and multivariate logistic regression modeling. Prevalence of uncontrolled HTN was 20.2% and the subgroups of isolated systolic HTN (ISH), isolated diastolic HTN (IDH), and systolic‐diastolic HTN (SDH) were 7.2%, 4.2%, and 8.8%, respectively. No difference was observed between the sexes. For all HTN subtypes, middle (35–49 years) and older age (50+) groups had a higher prevalence compared with younger subjects (15–34 years) (all P<.001). IDH prevalence in older age was not higher compared with younger age (P=.417). After multivariate analysis, middle age predicted all subtypes of HTN and old age predicted ISH and SDH. Alcohol consumption predicted IDH and SDH. Uncontrolled HTN in this population increases in the order IDH, ISH, and SDH, with more than 1 in 5 having uncontrolled HTN

Exploiting nanogroove-induced cell culture anisotropy to advance in vitro brain models

A new generation of in vitro human brain models is vital to surpass the limitations of current cell culture platforms and animal cell lines in studying brain function and diseases. Brain-on-chip technology can generate well-defined and reproducible platforms to control the cellular microenvironment for in vivo-like, organized brain cell cultures. Previously, the authors investigated differentiation and network organization of the neuroblastoma SH-SY5Y cell line on nanogrooved substrates, showing that nanogroove guidance of neuronal outgrowths is dependent on nanogroove dimensions. Further, increased orientation of neurites was positively correlated to the differentiation of SH-SY5Y cells. However, as mimicking brain structure alone is insufficient, here, the function of the neuronal cell network as dependent on surface topography and material stiffness is investigated. A generalized replication protocol was developed to create similar nanogrooved patterns in cell culture substrates from different materials, specifically polydimethylsiloxane (PDMS) and Ostemer. Experiments using calcium imaging, where calcium fluxes across membranes are visualized as an indication of action potentials in neuronal cells, were performed with differentiated SH-SY5Y cells and human induced pluripotent stem cell-derived neuronal cells (hiPSCNs) on flat versus nanogrooved substrates to study the network function. Calcium live-imaging was performed and results for experiments with SH-SY5Y cells and hiPSCNs showed that nanogrooved PDMS substrates trended toward increased cellular activity and neuronal cell network connectivity. For future investigation of compatible substrate materials in combination with the effect of material stiffness on the cells, nanogrooved Ostemer substrates were demonstrated to faithfully replicate for use in neuronal cell cultures using nanogrooved substrates. First experiments into the neuronal cell function using stem cells described here aid toward elucidating the effect of nanotopographical and mechanical properties and their benefits toward advancing in vitro neuronal cell models both in form and function. Overall, the results indicate, in conjunction with the previous findings on neuronal outgrowth guidance, that anisotropy as introduced by nanogrooved substrates can have a controllable and potentially beneficial influence on neuronal cell cultures