Gunnar O. Klein

Electronic health records: new opportunities for clinical research

Clinical research is on the threshold of a new era in which electronic health records (EHRs) are gaining an important novel supporting role. Whilst EHRs used for routine clinical care have some limitations at present, as discussed in this review, new improved systems and emerging research infrastructures are being developed to ensure that EHRs can be used for secondary purposes such as clinical research, including the design and execution of clinical trials for new medicines. EHR systems should be able to exchange information through the use of recently published international standards for their interoperability and clinically validated information structures (such as archetypes and international health terminologies), to ensure consistent and more complete recording and sharing of data for various patient groups. Such systems will counteract the obstacles of differing clinical languages and styles of documentation as well as the recognized incompleteness of routine records. Here, we discuss some of the legal and ethical concerns of clinical research data reuse and technical security measures that can enable such research while protecting privacy. In the emerging research landscape, cooperation infrastructures are being built where research projects can utilize the availability of patient data from federated EHR systems from many different sites, as well as in international multilingual settings. Amongst several initiatives described, the EHR4CR project offers a promising method for clinical research. One of the first achievements of this project was the development of a protocol feasibility prototype which is used for finding patients eligible for clinical trials from multiple sources.

H-2 associated control of natural cytotoxicity and hybrid resistance against rbl-5.

Abstract(C57B1 × DBA)F1 hybrids were more resistant to the inoculation of 103 Rauscher virus-induced, serially propagated RBL-5 cells than syngeneic C57Bl recipients. Resistance was linked toH-2di in the C57Bl backcross. Spleen cells from nonimmune (C57Bl × DBA)F1 hybrids were significantly more reactive against RBL-5 in the natural killer (NK) cytotoxicity test in vitro than were C57Bl spleen cells. In the C57Bl backcross,H-2dH 2b heterozygotes were more cytotoxic than theH- 2B homozygotes. Along with RBL-5, they were also more cytotoxic to the Moloney virus-induced YAC lymphoma (of strain A origin) and to the human ALL-derived MOLT-4 line.

Archetype-based conversion of EHR content models: pilot experience with a regional EHR system

BackgroundExchange of Electronic Health Record (EHR) data between systems from different suppliers is a major challenge. EHR communication based on archetype methodology has been developed by openEHR and CEN/ISO. The experience of using archetypes in deployed EHR systems is quite limited today. Currently deployed EHR systems with large user bases have their own proprietary way of representing clinical content using various models. This study was designed to investigate the feasibility of representing EHR content models from a regional EHR system as openEHR archetypes and inversely to convert archetypes to the proprietary format.MethodsThe openEHR EHR Reference Model (RM) and Archetype Model (AM) specifications were used. The template model of the Cambio COSMIC, a regional EHR product from Sweden, was analyzed and compared to the openEHR RM and AM. This study was focused on the convertibility of the EHR semantic models. A semantic mapping between the openEHR RM/AM and the COSMIC template model was produced and used as the basis for developing prototype software that performs automated bi-directional conversion between openEHR archetypes and COSMIC templates.ResultsAutomated bi-directional conversion between openEHR archetype format and COSMIC template format has been achieved. Several archetypes from the openEHR Clinical Knowledge Repository have been imported into COSMIC, preserving most of the structural and terminology related constraints. COSMIC templates from a large regional installation were successfully converted into the openEHR archetype format. The conversion from the COSMIC templates into archetype format preserves nearly all structural and semantic definitions of the original content models. A strategy of gradually adding archetype support to legacy EHR systems was formulated in order to allow sharing of clinical content models defined using different formats.ConclusionThe openEHR RM and AM are expressive enough to represent the existing clinical content models from the template based EHR system tested and legacy content models can automatically be converted to archetype format for sharing of knowledge. With some limitations, internationally available archetypes could be converted to the legacy EHR models. Archetype support can be added to legacy EHR systems in an incremental way allowing a migration path to interoperability based on standards.

Elevated antibody titers to Epstein-Barr virus and low natural killer cell activity in patients with Chediak-Higashi syndrome

Four Venezuelan patients with the autosomal recessive Chediak-Higashi syndrome (CHS) were studied. The results confirm the severe reduction in natural killer (NK) cell activity, as previously described and showed also a decline in the activity of cells involved in antibody-dependent cellular cytotoxicity (ADCC). No defect was found in the production of immunoglobulins and of specific antibodies to measles, varicella, herpes simplex, and cytomegalo viruses. Two of the patients had extremely high antibody titers to the Epstein-Barr virus (EBV) specific viral capsid antigen (VCA), to the restricted (R) component of the EBV-induced early antigen complex, and to the EBV-associated nuclear antigen (EBNA). These two patients had enlarged livers, spleens, and lymph nodes indicative of the lymphoproliferative phase. The other two patients were initially negative for all EBV-associated antibodies but seroconverted subsequently and, in the course of a year, also developed high antibody titers to VCA and R. In one of these patients the primary infection was accompanied by moderate signs of infectious mononucleosis (IM) followed after more than 6 months by persistent hepatosplenomegaly. The other patient also developed signs of a lymphoproliferative syndrome with hepatosplenomegaly and jaundice and died 8 months later. Such high anti-R titers are seen frequently in Burkitts lymphoma, but rarely in other conditions. It is likely that the high antibody titers reflect an increased production of VCA and R due to defective NK and ADCC cell activities so that productively infected B lymphocytes are no longer eliminated before they have synthesized maximal amounts of antigens. The high anti-EBNA titers suggest normal T lymphocyte function. The possibility that the accelerated, lymphoma-like phase of the CHS involves EBV-transformed cells is discussed.

'hybrid Resistance' against parental tumors. One or several genetic patterns?

A spectrum of lymphomas, sarcomas, and carcinomas were tested for F1 hybrid resistance after s.c. inoculation of small numbers of cells into syngeneic and F1 hybrid mice. Significant F1 resistance was demonstrated against all tumors tested except one. Backcross and/or congenic inoculation tests showed significantH-2 linkage of hybrid resistance against all lymphomas and leukemias tested. There was no linkage betweenH-2 and hybrid resistance within the more limited group of carcinomas and sarcomas. DifferentH-2-linked resistance genes were shown to act against different lymphomas, including some that were induced by the same agent. Some lymphomas induced by different agents in the same strain were also found to differ in their sensitivity to the sameH-2-linked resistance factor. These data suggest the existence of a polymorphic system, probably pseudoallelic, rather than simply allelic in nature.

Julius – a template based supplementary electronic health record system

BackgroundEHR systems are widely used in hospitals and primary care centres but it is usually difficult to share information and to collect patient data for clinical research. This is partly due to the different proprietary information models and inconsistent data quality. Our objective was to provide a more flexible solution enabling the clinicians to define which data to be recorded and shared for both routine documentation and clinical studies. The data should be possible to reuse through a common set of variable definitions providing a consistent nomenclature and validation of data. Another objective was that the templates used for the data entry and presentation should be possible to use in combination with the existing EHR systems.MethodsWe have designed and developed a template based system (called Julius) that was integrated with existing EHR systems. The system is driven by the medical domain knowledge defined by clinicians in the form of templates and variable definitions stored in a common data repository. The system architecture consists of three layers. The presentation layer is purely web-based, which facilitates integration with existing EHR products. The domain layer consists of the template design system, a variable/clinical concept definition system, the transformation and validation logic all implemented in Java. The data source layer utilizes an object relational mapping tool and a relational database.ResultsThe Julius system has been implemented, tested and deployed to three health care units in Stockholm, Sweden. The initial responses from the pilot users were positive. The template system facilitates patient data collection in many ways. The experience of using the template system suggests that enabling the clinicians to be in control of the system, is a good way to add supplementary functionality to the present EHR systems.ConclusionThe approach of the template system in combination with various local EHR systems can facilitate the sharing and reuse of validated clinical information from different health care units. However, future system developments for these purposes should consider using the openEHR/CEN models with shareable archetypes.

THE GENETIC REGULATION OF NK‐ACTIVITY: STUDIES ON CONGENIC MICE WITH B10 OR AKR BACKGROUND

Mouse strains differ widely in their natural killer(NK)‐cell activity. In the (A X B6) X A backcross, high reactivity was linked to H‐2b, although non‐H‐2‐linked genes were also demonstrated (Petranyi et al., 1975). Harmon et al. (1977) demonstrated an H‐2Dd‐associated reactivity gene (1977). In the present study, we have tested eleven B10 congenic strains for NK activity. The H‐2Dd strains B10.A, B10.T(6R), B10.S(7R), B10.HTT and B10.D2 were more highly reactive than B10, B10.S, B10.G, B10.A(2R) and B10.BR, which do not carry the d allele at the H‐2D locus. While this confirms the H‐2Dd association of a reactivity gene, an exception was found in the B10.A(5R) strain that was low reactive in spite of the fact that it carries H‐2Dd. This suggests the possibility that the H‐2Dd‐associated gene is outside H‐2, to the right of Tla.

Hybrid resistance against a natural killer (NK) cell-resistant lymphoma (YWA) is mediated by a T cell-dependent mechanism.

Rejection of the Moloney virus-induced YAC lymphoma of strain A origin by semisynegeneic F1 hybrids has previously been shown to correlate with the levels of natural killer (NK) cell activity in the same F1 hybrids against this target cell line in vitro. In the present study, YAC and another Moloney virus-induced lymphoma,, YWA, derived from the A congenic A.SW strain, were tested for F1 hybrid resistance after s.c. inoculation of small numbers of cells into syngeneic and semisyngeneic F1 mice. While YAC cells invariably grew progressively once they formed a palpable tumor, regression of YWA tumors was frequently observed in both susceptible and resistant genotypes. The hybrid resistance pattern for YAC and YWA differed in one important respect: outcross of the syngeneic host to the A-congenic A.BY strain introduced a strong H-2b-associated resistance factor against YWA, but not against YAC. Compared to YAC, which is highly NK-sensitive and rapidly eliminated from mice with high NK activity, YWA was insensitive to NK-mediated lysis in vitro and [125I] UdR-labelled YWA cells were not eliminated more efficiently from the highly resistant (A.SW X A.BY) F1 then from the parental strain in short-term (4-18h) in vivo rejection assays. It was therefore concluded that the H-2b-associated resistance against YWA was independent of NK cells or other rapidly acting effector mechanisms. Moreover, thymectomy, followed by irradiation and fetal liver reconstitution, completely abolished the resistance against YWA but left the resistance against YAC virtually intact. These data suggest that two lymphomas induced by the same agent can be rejected by different effectors. The NK-resistant YWA lymphoma is rejected by a T-dependent mechanism, while the resistance against the inoculation of the highly NK-sensitive YAC line is T-independent and, in all probability, mediated by NK cells.

Mobile health treatment support intervention for HIV and tuberculosis in Mozambique: Perspectives of patients and healthcare workers.

Background Studies have been conducted in developing countries using SMS to communicate with patients to reduce the number of missed appointments and improve retention in treatment, however; very few have been scaled up. One possible reason for this could be that patients or staff are dissatisfied with the method in some way. This paper reports a study of patients’ and healthcare workers’ (HCW) views on an mHealth intervention aiming to support retention in antiretroviral therapy (ART) and tuberculosis (TB) treatment in Mozambique. Methods The study was conducted at five healthcare centres in Mozambique. Automated SMS health promotions and reminders were sent to patients in a RCT. A total of 141 patients and 40 HCWs were interviewed. Respondents rated usefulness, perceived benefits, ease of use, satisfaction, and risks of the SMS system using a Likert scale questionnaire. A semi-structured interview guide was followed. Interviews were transcribed and thematic analysis was conducted. Results Both patients and HCW found the SMS system useful and reliable. Most highly rated positive effects were reducing the number of failures to collect medication and avoiding missing appointments. Patients’ confidence in the system was high. Most perceived the system to improve communication between health-care provider and patient and assist in education and motivation. The automatic recognition of questions from patients and the provision of appropriate answers (a unique feature of this system) was especially appreciated. A majority would recommend the system to other patients or healthcare centres. Risks also were mentioned, mostly by HCW, of unintentional disclosure of health status in cases where patients use shared phones. Conclusions The results suggest that SMS technology for HIV and TB should be used to transmit reminders for appointments, medications, motivational texts, and health education to increase retention in care. Measures must be taken to reduce risks of privacy intrusion, but these are not a main obstacle for scaling up systems of this kind.

Using mobile information technology to build a database for anesthesia quality control and to provide clinical guidelines.

The paper describes a mobile information system to collect patient information for anaesthesia quality control. In this system we use handheld computers, to collect patient data at the bedside with a daily synchronization of the data of the anaesthesiologists handheld with the anaesthesia database center, later used for quality control analysis. Further, we design mobile clinical guidelines to be used on the same handhelds.