Commissural axon guidance in the developing spinal cord: from Cajal to the present day.

During neuronal development, the formation of neural circuits requires developing axons to traverse a diverse cellular and molecular environment to establish synaptic contacts with the appropriate postsynaptic partners. Essential to this process is the ability of developing axons to navigate guidance molecules presented by specialized populations of cells. These cells partition the distance traveled by growing axons into shorter intervals by serving as intermediate targets, orchestrating the arrival and departure of axons by providing attractive and repulsive guidance cues. The floor plate in the central nervous system (CNS) is a critical intermediate target during neuronal development, required for the extension of commissural axons across the ventral midline. In this review, we begin by giving a historical overview of the ventral commissure and the evolutionary purpose of decussation. We then review the axon guidance studies that have revealed a diverse assortment of midline guidance cues, as well as genetic and molecular regulatory mechanisms required for coordinating the commissural axon response to these cues. Finally, we examine the contribution of dysfunctional axon guidance to neurological diseases.

Memorandum on the use of information technology to improve medication safety.

BACKGROUND: Information technology in health care has a clear potential to improve the quality and efficiency of health care, especially in the area of medication processes. On the other hand, existing studies show possible adverse effects on patient safety when IT for medication-related processes is developed, introduced or used inappropriately. OBJECTIVES: To summarize definitions and observations on IT usage in pharmacotherapy and to derive recommendations and future research priorities for decision makers and domain experts. METHODS: This memorandum was developed in a consensus-based iterative process that included workshops and e-mail discussions among 21 experts coordinated by the Drug Information Systems Working Group of the German Society for Medical Informatics, Biometry and Epidemiology (GMDS). RESULTS: The recommendations address, among other things, a stepwise and comprehensive strategy for IT usage in medication processes, the integration of contextual information for alert generation, the involvement of patients, the semantic integration of information resources, usability and adaptability of IT solutions, and the need for their continuous evaluation. CONCLUSION: Information technology can help to improve medication safety. However, challenges remain regarding access to information, quality of information, and measurable benefits.

[HeiCare®: a project aiming to improve medication communication across health care sectors]. / HeiCare® : ein Projekt zur Verbesserung der sektorenübergreifenden Arzneimittelkommunikation.

BACKGROUND AND OBJECTIVE: Changes between health care sectors represent a critical phase in long-term pharmacotherapy. The aim of the Hei CARE(®) project was to close the communication gap at the interface between primary care physicians (PCP), hospital physicians and patients, and to improve quality and safety of pharmacotherapy. METHODS: Physicians who enrolled patients with long-term pharmacotherapy were able to participate in the Hei CARE(®) project. After enrolment the patient's medication was entered in the internet-based medication knowledge data base AiD PRAXIS and checked for medication interactions and optimized if necessary. At hospitalisation medication was transferred electronically to the hospital (AiD KLINIK(®)) and on discharge integrated in the discharge letter and faxed to the primary care physician (PCP). The project was evaluated using quantitative and qualitative methods. Hei CARE(®) -cases, in which medication was transferred electronically as planned, were compared with the other cases. PCPs' experiences were collected in focus groups. RESULTS: One thousand and three chronically ill patients of 56 primary care practices participated. 259 patients were hospitalized between October 2005 and March 2009 of which entrance and discharge medication were transferred both ways via the electronic prescribing platform in 67 cases. The number of changes in medication was reduced in comparison to the other cases. Participating PCPs reported positive changes through Hei CARE(®) as well as further potential for optimizing communication across health care sectors. CONCLUSION: Use of a common internet-based medication knowledge data base (Hei CARE(®) ) in both health care sectors reduced the number of changes in pharmacotherapy. Seamless care in chronically ill patients was thereby improved. The project also demonstrated that improving communication across health care sectors is a slow process.

[Prerequisites for electronic systems evaluating safe and effective drug therapy. A contribution to the Action Plan of the Federal Health Ministry]. / Voraussetzungen für elektronische Systeme zur Prüfung auf Arzneimitteltherapiesicherheit (AMTS). Ein Beitrag zum Aktionsplan des Bundesministeriums für Gesundheit.

Evaluation of effective and safe drug therapy assisted by electronic systems is based on certain prerequisites, including structured data of drugs and from patients. These prerequisites were identified in a workshop within the scope of the National Action Plan and have been reported in a 7+1-point plan: medicinal product data must be correct and up-to-date based on the summary of product characteristics approved by the responsible authorities. Product data must be available in an agreed textual structure and must use defined semantic elements within this structure. Identifiers must be allocated to all drugs and substances in order to enable unique identification and exchange across systems. Semantic structures of the product data, on the one hand, and of patient data, on the other, must be defined across system boundaries and for the whole German national health care system, and be available to every stakeholder, up-to-date, and preferably freely accessible. This consensus regarding content and structural conventions is a prerequisite for other scenarios in the health care system, such as transmitting individual case safety reports without system and media discontinuity, and is currently of great importance with respect to the European legislation on pharmacovigilance, which will be implemented nationally.

Patient-specific electronic decision support reduces prescription of excessive doses.

OBJECTIVES: Prescription of excessive doses is the most common prescription error, provoking dose-dependent adverse drug reactions. Clinical decision support systems (CDSS) can prevent prescription errors especially when mainly clinically relevant warnings are issued. We have built and evaluated a CDSS providing upper dose limits personalised to individual patient characteristics thus guaranteeing for specific warnings. METHODS: For 170 compounds, detailed information on upper dose limits (according to the drug label) was compiled. A comprehensive software-algorithm extracted relevant patient information from the electronic chart (eg, age, renal function, comedication). The CDSS was integrated into the local prescribing platform for outpatients and patients at discharge, providing immediate dosage feedback. Its impact was evaluated in a 90-day intervention study (phase 1: baseline; phase 2: intervention). Outcome measures were frequency of excessive doses before and after intervention considering potential induction of new medication errors. Moreover, predictors for alert adherence were analysed. RESULTS: In phase 1, 552 of 12,197 (4.5%) prescriptions exceeded upper dose limits. In phase 2, initially 559 warnings were triggered (4.8%, p=0.37). Physicians were responsive to one in four warnings mostly adjusting dosages. Thus, the final prescription rate of excessive doses was reduced to 3.6%, with 20% less excessive doses compared with baseline (p<0.001). No new manifest prescription errors were induced. Physicians' alert adherence correlated with patients' age, prescribed drug class, and reason for the alert. CONCLUSION: During the 90-day study, implementation of a highly specific algorithm-based CDSS substantially improved prescribing quality with a high acceptance rate compared with previous studies.

[Patient safety based on computer-assisted drug therapy. Electronic check-up of the patient]. / Patientensicherheit durch computerbasierte Arzneimittelinformationen. Der Patient im elektronischen Check-up.

Patients in internal medicine frequently experience adverse drug events. Many of those events, however, are avoidable because they are caused by medication errors, which are particularly frequent in drug prescribing. Therefore, practical concepts are needed to make the rapidly growing knowledge on drugs available already during prescription. But also when deviations from standards are intended access to up-to-date information is required. Computer-based systems can offer support for prescribing clinicians to meet these claims and thus improve the quality of pharmacotherapy. To reach this goal, such systems have to be interlinked among each other and with systems of primary, secondary, and tertiary care. They must be based on scientific published evidence and should consider as many factors as possible for individualization of drug therapy. Individualization and focusing on relevant information are prerequisites to prevent inappropriate alerts (over-alerting) and thus to increase acceptance in practical use.

[Medical problems and risks of switching drugs according to legal requirements of drug discount contracts in Germany]. / Medizinische Probleme und Risiken bei der rabattvertragsgerechten Umstellung von Medikationen in Deutschland.

INTRODUCTION: Since 2007 German health insurance funds may conclude discount contracts with pharmaceutical companies for individual drugs. According to German legislation pharmacies are liable to preferentially dispense these drugs to patients of the respective funds if the prescribed drug is identical regarding active ingredient, strength, package size, and route of administration, and is approved for the same indication. We aimed to assess the number and nature of clinically relevant differences between prescribed drug and its legal alternatives. METHODS: Using databases and expert systems of the drug information system AiD KLINIK we evaluated all 258 412 exchangeable drug pairs of the German market currently regulated by discount contracts. RESULTS: 15,7 % of the drug pairs differed in dosage, in one quarter each colour or shape was significantly different, and in roughly 3 % the size of the substituted drug differed by more than 50 %. In 9,43 % splitting characteristics of solid oral doses differed and in 1,87 % the substituted drug contained additives with allergenic potential not present in the primarily selected drug. On average 0,44 clinically relevant differences could be calculated in each substitution. CONCLUSION: This study has revealed that current legal provision ignore important medical criteria of the substitution process including individual risks (e. g. allergies). Patients will have to change the drug application process and will therefore need appropriate information and training. All these differences between substitutional drug pairs should already be known when prescribing so as to maintain patient safety in the face of this merely cost-saving measure.

Detection and prevention of prescriptions with excessive doses in electronic prescribing systems.

INTRODUCTION: Dose dependent adverse drug reactions are often caused by prescribing errors ignoring upper dose limits. Thus, computerised physician order entry incorporating maximum recommended therapeutic doses (MRTDs) might reduce prescriptions of excessive doses. We evaluated the suitability of MRTD information as published in the Summary of Product Characteristics (SPC) (MRTD(SPC)) or by the US Food and Drug Administration (MRTD(FDA)) and the value of Defined Daily Doses (DDD, World Health Organisation) as knowledge bases for an alerting system. METHODS: In a large set of critical-dose drugs (N = 140) we compared MRTD(FDA) and DDD values with the corresponding German MRTD(SPC). We then retrospectively assessed a set of 633 electronically prescribed drugs (EPDs) issued at a university hospital and calculated prescription rates of excessive doses. RESULTS: MRTD(FDA) was similar to MRTD(SPC) in 37% (N = 140), higher in 32%, and lower in 31% of drugs. On average, available DDD values (N = 129) were 1.6 times lower than MRTD(SPC), with 64% being lower, 33% similar, and 3% larger than MRTD(SPC). Prescription rates of excessive doses according to MRTD(FDA) were 2.5-fold higher (6.1%) than according to MRTD(SPC) (2.5%) (p < 0.01). However, only one in four EPDs categorised as overdosed according to MRTD(FDA) exceeded MRTD(SPC), and MRTD(FDA) values were available only for 67% of all assessed EPDs. CONCLUSION: Our study revealed a remarkable number of prescriptions with doses exceeding approved limits. Their prevention appears feasible but the choice of an appropriate database for MRTDs is essential, and differences between available information sources are large.

Standardized documentation of drug recommendations in discharge letters--a contribution to quality management in cooperative care.

OBJECTIVES: To analyze the necessity and potential usefulness of a computerized physician order entry (CPOE) system in supporting the writing of pharmacotherapeutic recommendations in discharge letters. METHODS: Systematic analysis of drug recommendations in discharge letters of a hospital providing tertiary care, structured interviews with in-hospital prescribers, and focus groups with general practitioners who admit patients to this hospital. RESULTS: We analyzed 1800 randomly selected discharge letters, 1205 of which contained pharmacotherapeutic recommendations. The frequencies, structure, and quality of these recommendations varied considerably between departments. Nearly 16% of the recommendations contained both proprietary (brand) and non-proprietary names (active ingredient). Interviewed clinicians expressed interest in CPOE systems that check for contraindications and interactions between drugs, suggest cheaper products, and automatically insert active ingredients when omitted. The focus group sessions confirmed that the pharmacotherapeutic recommendations in current discharge letters do not effectively support daily clinical practice. CONCLUSIONS: Documenting active ingredients as well as brand names in drug therapy recommendations is currently not part of clinical practice. Computerized decision support can help to optimise the structure and communication of therapeutic information across interfaces and can be a quality factor with considerable influence on process quality, outcome quality, and costs of cooperative patient care.

Frizzled regulates localization of cell-fate determinants and mitotic spindle rotation during asymmetric cell division.

Cell-fate diversity is generated in part by the unequal segregation of cell-fate determinants during asymmetric cell divisions. In the Drosophila pupa, the pI sense organ precursor cell is polarized along the anterior-posterior axis of the fly and divides asymmetrically to generate a posterior pIIa cell and an anterior pIIb cell. The anterior pIIb cell specifically inherits the determinant Numb and the adaptor protein Partner of Numb (Pon). By labelling both the Pon crescent and the microtubules in living pupae, we show that determinants localize at the anterior cortex before mitotic-spindle formation, and that the spindle forms with random orientation and rotates to line up with the Pon crescent. By imaging living frizzled (fz) mutant pupae we show that Fz regulates the orientation of the polarity axis of pI, the initiation of spindle rotation and the unequal partitioning of determinants. We conclude that Fz participates in establishing the polarity of pI.

Rotation and asymmetry of the mitotic spindle direct asymmetric cell division in the developing central nervous system.

The asymmetric segregation of cell-fate determinants and the generation of daughter cells of different sizes rely on the correct orientation and position of the mitotic spindle. In the Drosophila embryo, the determinant Prospero is localized basally and is segregated equally to daughters of similar cell size during epidermal cell division. In contrast, during neuroblast division Prospero is segregated asymmetrically to the smaller daughter cell. This simple switch between symmetric and asymmetric segregation is achieved by changing the orientation of cell division: neural cells divide in a plane perpendicular to that of epidermoblast division. Here, by labelling mitotic spindles in living Drosophila embryos, we show that neuroblast spindles are initially formed in the same axis as epidermal cells, but rotate before cell division. We find that daughter cells of different sizes arise because the spindle itself becomes asymmetric at anaphase: apical microtubules elongate, basal microtubules shorten, and the midbody moves basally until it is positioned asymmetrically between the two spindle poles. This observation contradicts the widely held hypothesis that the cleavage furrow is always placed midway between the two centrosomes.