Coding variants identified in patients with diabetes alter PICK1 BAR domain function in insulin granule biogenesis.

Bin/amphiphysin/Rvs (BAR) domains are positively charged crescent-shaped modules that mediate curvature of negatively charged lipid membranes during remodeling processes. The BAR domain proteins PICK1, ICA69, and the arfaptins have recently been demonstrated to coordinate the budding and formation of immature secretory granules (ISGs) at the trans-Golgi network. Here, we identify 4 coding variants in the PICK1 gene from a whole-exome screening of Danish patients with diabetes that each involve a change in positively charged residues in the PICK1 BAR domain. All 4 coding variants failed to rescue insulin content in INS-1E cells upon knock down of endogenous PICK1. Moreover, 2 variants showed dominant-negative properties. In vitro assays addressing BAR domain function suggested that the coding variants compromised BAR domain function but increased the capacity to cause fission of liposomes. Live confocal microscopy and super-resolution microscopy further revealed that PICK1 resides transiently on ISGs before egress via vesicular budding events. Interestingly, this egress of PICK1 was accelerated in the coding variants. We propose that PICK1 assists in or complements the removal of excess membrane and generic membrane trafficking proteins, and possibly also insulin, from ISGs during the maturation process; and that the coding variants may cause premature budding, possibly explaining their dominant-negative function.

Development of methods for usability evaluations of EHR systems.

Developing electronic health record (EHR) systems in Denmark is an on going, iterative process, where also a maturation process for clinical use should be considered. Convincing methodology for collecting and incorporating in the soft- and hardware knowledge and robustness for the clinical environments is not on hand. A way to involve the clinicians in the development process is conducting usability evaluations. The complexity of the clinical use of the systems is difficult to transmit to a usability laboratory, and due to ethical issues a traditional field study can be impossible to carry out. The aim of this study has been to investigate how it is possible to identify usability problems in an EHR system by combining methods from laboratory tests and field studies. The methods selected for the test design are: the think aloud method, video and screen recording, debriefing, a scenario based on an authentic patient record, and testing on the normal production system. The reliability and validity of the results is increased due to the application of method- and data-triangulation. The results of the usability evaluation include problems in the categories: system response time, GUI-design, functionality, procedures, and error messages. The problems were classified as cosmetic, severe, or critical according to a rating scale. The experience with each method is discussed. It is concluded that combining methods from laboratory test and field study makes it possible to identify usability problems. There are indications that some of the usability problems only occurred due to the establishment of an authentic scenario.

Comparing different approaches to two-level modelling of electronic health records.

Electronic Health Record (EHR) systems are being developed to improve the communication of patient data. The health care domain includes many different types of data and concepts, of which some are constantly changing, and some are more lasting. This makes the development of an EHR a complex task. In order to improve the handling of this complexity, a new two-level modelling approach in EHR system development has emerged, using a concept of archetypes as the pivot in the representation of the health care knowledge. The key issue in this approach involves dividing the problem field into two separate models: A generic information model and a domain knowledge model. By analysis of how this layering has been carried out in two different two-level EHR systems - the OpenEHR (formerly the Australian GEHR, Good Electronic Health Record) and the EHR project of Aarhus County, Denmark. We have identified critical meta model parameters influencing the ability of the modelling paradigm to meet the expectation for easy handling of the development process (flexibility) and the capability to manage changing models (dynamics). The OpenEHR has defined the division line in such a way that it makes the generic model small and the domain model large. The opposite is the case of the Aarhus EHR system, where the information model is large, and the knowledge model is small. A small information model and a large knowledge model make more of the system changeable, but it also makes it less flexible to develop. The opposite is the case for a large information model and a small knowledge model.