Basic models to advanced systems: harnessing the power of organoids-based microphysiological models of the human brain.

Understanding the complexities of the human brain's function in health and disease is a formidable challenge in neuroscience. While traditional models like animals offer valuable insights, they often fall short in accurately mirroring human biology and drug responses. Moreover, recent legislation has underscored the need for more predictive models that more accurately represent human physiology. To address this requirement, human-derived cell cultures have emerged as a crucial alternative for biomedical research. However, traditional static cell culture models lack the dynamic tissue microenvironment that governs human tissue function. Advancedin vitrosystems, such as organoids and microphysiological systems (MPSs), bridge this gap by offering more accurate representations of human biology. Organoids, which are three-dimensional miniaturized organ-like structures derived from stem cells, exhibit physiological responses akin to native tissues, but lack essential tissue-specific components such as functional vascular structures and immune cells. Recent endeavors have focused on incorporating endothelial cells and immune cells into organoids to enhance vascularization, maturation, and disease modeling. MPS, including organ-on-chip technologies, integrate diverse cell types and vascularization under dynamic culture conditions, revolutionizing brain research by bridging the gap betweenin vitroandin vivomodels. In this review, we delve into the evolution of MPS, with a particular focus on highlighting the significance of vascularization in enhancing the viability, functionality, and disease modeling potential of organoids. By examining the interplay of vasculature and neuronal cells within organoids, we can uncover novel therapeutic targets and gain valuable insights into disease mechanisms, offering the promise of significant advancements in neuroscience and improved patient outcomes.

Clinical-scientist-led transoesophageal echocardiography (TOE): using extended roles to improve the service.

At the North West Anglia NHS Foundation Trust, we perform transoesophageal echocardiography (TOE), a semi-invasive diagnostic test using ultrasound for high-quality heart imaging. TOE allows accurate diagnosis of serious heart problems to support high-quality clinical decision-making about treatment pathways. The procedure can be lengthy and is traditionally performed by a consultant cardiologist, who typically has multiple commitments. This constrains patient access to TOE, leading to waits from referral to test, delaying treatment decisions.In this quality improvement project, we improved access by redesigning workforce roles. The clinical scientist, who had been supporting the consultant during TOE clinics, took on performing the procedure as the main operator. We used the Model for Improvement to develop this clinical-scientist-led service-delivery model, and then test and refine it. This increased capacity and frequency of TOE clinics, reducing waits and releasing around 2 days per month of consultant time.Over five plan-do-study-act cycles, we tested six changes/refinements. Our targets were to reduce the maximum waiting time for TOE to 3 working days for inpatients and to 14 working days for outpatients. We succeeded, achieving reductions in mean waiting times from 7.7 days to 3.0 days for inpatients and from 33.2 days to 8.3 days for outpatients.TOE requires intubation; when this fails, TOE is abandoned. We believe light (rather than heavy) sedation is helpful for this intubation. We reduced sedation levels (from a median of 3 mg of midazolam to 1.5 mg) and, as a secondary outcome of this project, reduced the intubation failure rate from 13% to 0% (over 32 postchange patients).Following this project, our TOE service is usually performed by a clinical scientist in echocardiography who has British Society of Echocardiography TOE accreditation and advanced training. We have sustained the improved performance and demonstrated the value of enhanced roles for clinical scientists.

The information distortion bias: implications for medical decisions.

CONTEXT: Every diagnosis involves an act of decision making, which requires proper evaluation of information. However, even seemingly objective information can require interpretation, often without our conscious awareness. In this cross-cutting edge article we describe the phenomenon of leader-driven information distortion (ID) and its implications for medical education. INFORMATION DISTORTION: Recent research indicates that one threat to good decisions is a biased interpretation of information to favour one alternative course of action over another. Once an alternative emerges as a leader during a decision there is a strong tendency to evaluate subsequent information as supporting that option. This can occur when deciding between two competing diagnoses. It is particularly a concern if diagnostic tests provide potentially ambiguous results. This leader-driven ID is pre-decisional in nature, in that it develops during a decision and involves the interpretation of information available prior to the final decision or diagnosis, with different interpretations possible depending on whichever alternative is the leader. Studies reveal that the distortion bias is pervasive in decisions, and that awareness of the act of distortion is low in decision makers. APPLICATION TO MEDICAL EDUCATION: Empirical research has confirmed the presence of leader-driven ID in hypothetical diagnoses made by physicians. ID creates two threats to medical decisions: First, it can make a diagnosis sticky in that it is resistant to being overturned by contradictory information. Second, it can promote unwarranted certainty in a diagnosis. The outcome may be premature closure, unnecessary testing or incorrect treatment, resulting in delayed or missed diagnoses. METHODS: This paper summarises research related to leader-driven ID in medical and professional decisions and discusses various approaches directed towards reducing ID. A framework and language are provided for thinking about and discussing ID in medical decisions and medical education. Courses of action for mitigating the effects of ID are suggested.

Identification of the cytochromes P450 that catalyze coumarin 3,4-epoxidation and 3-hydroxylation.

Coumarin, a widely used fragrance ingredient, is a rat liver and mouse lung toxicant. Species differences in toxicity are metabolism-dependent, with injury resulting from the cytochrome P450-mediated formation of coumarin 3,4-epoxide (CE). In this study, the enzymes responsible for coumarin activation in liver and lung were determined. Recombinant human and rat CYP1A forms and recombinant human CYP2E1 readily catalyzed CE production. Coinhibition with CYP1A1/2 and CYP2E1 antibodies blocked CE formation by 38, 84, and 67 to 92% (n = 3 individual samples) in mouse, rat, and human hepatic microsomes, respectively. Although CYP1A and 2E forms seem to be the most active catalysts of CE formation in liver, studies conducted with the mechanism-based inhibitor 5-phenyl-pentyne demonstrated that CYP2F2 is responsible for up to 67% of CE formation in whole mouse lung microsomes. In contrast to the CE pathway, coumarin 3-hydroxylation is a minor product of coumarin in liver microsomes from mice, rats, and humans and is catalyzed predominately by CYP3A and CYP1A forms, confirming that CE and 3-hydroxycoumarin are formed via distinct metabolic pathways.