[Patient endangerment due to device diversity? : Discussion of a risk factor based on the results of two surveys of German hospitals]. / Patientengefährdung durch Gerätediversität? : Diskussion eines Risikofaktors anhand der Ergebnisse zweier Befragungen an deutschen Kliniken.

BACKGROUND: The Federal Institute for Drugs and Medical Devices (BfArM) was notified of an event in which it was not possible to sufficiently ventilate a patient suffering a severe asthma attack. It turned out that the ventilation pressures used by the device for pressure-controlled ventilation were below the values set by the user, which the user was not aware of. The ventilation pressures chosen by the user exceeded the preset alarm limits of the ventilator. This pressure and alarm management significantly differed from that of other ventilators used in the hospital. This and similar incident reports suggest that safely operating medical devices for anesthesia and intensive care may be impaired when different models of a device are used within a hospital. If different models are used, more device information needs to be stored in memory. Existing knowledge on human memory suggests that the more individual memory items (e. g. different operating rules) are stored, the greater the risk of memory interference and hence of impaired retrieval, particularly if the different items are associated with overlapping retrieval cues. This is the case when different devices are used for a single functional purpose under identical or similar circumstances. OBJECTIVE: Based on individual incident reports and theoretical knowledge on an association between device diversity and use problems, this study aimed to determine the organizational conditions regarding device diversity that prevail in German hospitals. Additionally, the anesthetists' perspectives and experiences in defined clinical settings were investigated. METHODS: For selected groups of medical devices, the biomedical engineers of German hospitals were surveyed about the different makes used in their hospital. Additionally, questionnaires were sent to a department of anesthesiology of a large University Hospital to investigate the personal experiences of working with different makes and models of a device. RESULTS: Using devices by different manufacturers was particularly frequent for ventilators, but there were also a considerable number of hospitals with syringe pumps and patient monitoring systems from different manufacturers. Almost all participants stated that they work or have worked with different models of a device. The majority of respondents had encountered problems or errors, which they ascribed to the requirement to learn a different method of operation for each device; however, they also listed various benefits, for instance the possibility to optimally address the requirements of specific situations or patient groups. Both biomedical engineers and anesthetists suggested a homogeneous device pool within the hospital and regular and repeated training sessions for each device model used. DISCUSSION: Using different device models for anesthesia and intensive care seems to be common in many German hospitals, particularly for ventilators. An association between device diversity and problems operating a device is plausible, given the functioning of human memory. This topic should be investigated by future studies in order to identify factors that may contribute to such problems and possible solutions for clinical settings. Likewise, the potential benefits of having different device models at one's disposal should be evaluated. To pinpoint the measures that will be most effective given the specific settings of the individual hospital, all underlying clinical and economic considerations must be carefully balanced against the associated potential risks.

Use of a gamma-2 herpesvirus as a vector to deliver antibodies to rhesus monkeys.

The gamma-2 herpesvirus of rhesus monkeys, rhesus monkey rhadinovirus (RRV), persists principally in B cells of its host. We constructed recombinant strains of RRV expressing the rhesus monkey-derived anti-SIV monoclonal antibodies 4L6 and 5L7 and compared the RRV-mediated in vivo delivery of these antibodies in rhesus monkeys with previous studies that utilized intramuscular delivery with an adeno-associated virus (AAV) vector. Recombinant RRV-4L6 and RRV-5L7 were both shown to stably produce the antibodies in persistently infected B-cell lines in culture. Two RRV-negative rhesus monkeys were experimentally infected with recombinant RRV-4L6 and two with recombinant RRV-5L7. Following infection, the appearance of the delivered antibody was readily detected in all four animals. However, the levels of the delivered antibody were considerably lower than what has been typically observed following intramuscular AAV delivery. Furthermore, three of the four monkeys had an antibody response to the delivered antibody as had been observed previously with intramuscular AAV delivery of these same antibodies. We conclude that this recombinant herpesvirus has no inherent advantage over AAV for delivery of potentially therapeutic monoclonal antibodies in a rhesus monkey model.

[Experiences and recommendations of the German Federal Institute for Drugs and Medical Devices (BfArM) concerning clinical investigation of medical devices and the evaluation of serious adverse events (SAE)]. / Erfahrungen und Empfehlungen des BfArM zur Genehmigung klinischer Prüfungen von Medizinprodukten und Bewertung schwerwiegender unerwünschter Ereignisse (SAE).

An integral part of the conformity assessment process for medical devices is a clinical evaluation based on clinical data. Particularly in the case of implantable devices and products of risk class III clinical trials must be performed. Since March 2010 applications for the authorization of clinical trials as well as for the waiver of the authorization requirement must be submitted centrally in Germany to the appropriate federal authority, the Federal Institute for Drugs and Medical Devices (BfArM) or the Paul Ehrlich Institute (PEI). In addition to authorization, approval by the responsible ethics committee is also required under law in order to begin clinical testing of medical devices in Germany. In this paper, the legal framework for the clinical testing of medical devices as well as those involved and possible procedures including evaluation criteria for the initial application of a trial and subsequent amendments are presented in detail. In addition, the reporting requirements for serious adverse events (SAEs) are explained and possible consequences of the evaluation are presented. Finally, a summary of application and registration numbers for all areas of extensive experience of the BfArM as well as requests and guidance for applicants are presented.

European multidisciplinary consensus statement on the use and monitoring of metal-on-metal bearings for total hip replacement and hip resurfacing.

INTRODUCTION: There is an ongoing debate about the optimal use of metal-on-metal (MoM) bearings in total hip replacement, since there are uncertainties about local and systemic adverse effects due to wear and corrosion of these bearings. Despite various national recommendations, efforts to achieve international harmonization of specific evidence-based recommendations for best practice are still lacking. HYPOTHESIS: An international consensus study group should be able to develop recommendations on the use and monitoring of MoM bearings, preferably at the European level, through a multidisciplinary approach, by integrating the perspectives of various stakeholders. MATERIALS AND METHODS: Twenty-one experts representing three stakeholder groups and eight countries participated in this European consensus study, which consisted of a consensus meeting, subsequent structured discussion, and consensus voting. RESULTS: The current statement defines first of all benefits, local and systemic risks, as well as uncertain issues related to MoM bearings. Safety assessment after implantation of MoM comprises all patients. A closer follow-up is recommended for large head MoM (≥36mm) and resurfacing. In these implants basic follow-up should consist of x-rays and metal ion measurement of cobalt in whole blood, performed with GF-AAS or ICP-MS. Clinical and/or radiographic abnormality as well as elevated ion levels needs additional imaging (ultrasound, CT-scan and/or MARS-MRI). Cobalt values less than 2 µg/L are probably devoid of clinical concern, the threshold value for clinical concern is expected to be within the range of 2-7 µg/L. DISCUSSION: This is the first multinational, interdisciplinary, and multiprofessional approach for developing a recommendation for the use and monitoring of MoM bearings in total hip replacement. The current recommendations are in partial agreement with previous statements regarding the extent of follow-up and imaging techniques. They however differ from previous communications regarding measurement of metal ions and especially the investigated medium, technique, and eventual threshold levels. LEVEL OF EVIDENCE: Level V, expert opinion/agreement conference.

ADCC develops over time during persistent infection with live-attenuated SIV and is associated with complete protection against SIV(mac)251 challenge.

Live-attenuated strains of simian immunodeficiency virus (SIV) routinely confer apparent sterilizing immunity against pathogenic SIV challenge in rhesus macaques. Understanding the mechanisms of protection by live-attenuated SIV may provide important insights into the immune responses needed for protection against HIV-1. Here we investigated the development of antibodies that are functional against neutralization-resistant SIV challenge strains, and tested the hypothesis that these antibodies are associated with protection. In the absence of detectable neutralizing antibodies, Env-specific antibody-dependent cell-mediated cytotoxicity (ADCC) emerged by three weeks after inoculation with SIVΔnef, increased progressively over time, and was proportional to SIVΔnef replication. Persistent infection with SIVΔnef elicited significantly higher ADCC titers than immunization with a non-persistent SIV strain that is limited to a single cycle of infection. ADCC titers were higher against viruses matched to the vaccine strain in Env, but were measurable against viruses expressing heterologous Env proteins. In two separate experiments, which took advantage of either the strain-specificity or the time-dependent maturation of immunity to overcome complete protection against SIV(mac)251 challenge, measures of ADCC activity were higher among the SIVΔnef-inoculated macaques that remained uninfected than among those that became infected. These observations show that features of the antibody response elicited by SIVΔnef are consistent with hallmarks of protection by live-attenuated SIV, and reveal an association between Env-specific antibodies that direct ADCC and apparent sterilizing protection by SIVΔnef.

A large germline deletion in the Chek2 kinase gene is associated with an increased risk of prostate cancer.

BACKGROUND: Germline mutations in the Chek2 kinase gene (CHEK2) have been associated with a range of cancer types. Recently, a large deletion of exons 9 and 10 of CHEK2 was identified in several unrelated patients with breast cancer of Czech or Slovak origin. The geographical and ethnic extent of this founder allele has not yet been determined. PARTICIPANTS AND METHODS: We assayed for the presence of this deletion, and of three other CHEK2 founder mutations, in 1864 patients with prostate cancer and 5496 controls from Poland. RESULTS: The deletion was detected in 24 of 5496 (0.4%) controls from the general population, and is the most common CHEK2 truncating founder allele in Polish patients. The deletion was identified in 15 of 1864 (0.8%) men with unselected prostate cancer (OR 1.9; 95% CI 0.97 to 3.5; p = 0.09) and in 4 of 249 men with familial prostate cancer (OR 3.7; 95% CI 1.3 to 10.8; p = 0.03). These ORs were similar to those associated with the other truncating mutations (IVS2+1G-->A, 1100delC). CONCLUSION: A large deletion of exons 9 and 10 of CHEK2 confers an increased risk of prostate cancer in Polish men. The del5395 founder deletion might be present in other Slavic populations, including Ukraine, Belarus, Russia, Baltic and Balkan countries. It will be of interest to see to what extent this deletion is responsible for the burden of prostate cancer in other populations.

Analysis of surgical management of calvarial tumours and first results of a newly designed robotic trepanation system.

This study was performed to evaluate the surgical strategy in patients with calvarial tumours, in order to design and modify a robot-assisted trepanation system. A total of 75 patients underwent craniectomy for the treatment of calvarial tumours during the 10-year period from 1993 to 2002. The patients' complaints, the size, location and histology of the tumour, and the various cranioplasty techniques used were analysed retrospectively. In a second procedure several craniectomies at typical locations according to the study's results were performed in a laboratory setting using a hexapod robotic tool, constructed at the Helmholtz-Institute, RWTH Aachen University, and plastic model heads. The workflow was documented and the reproducibility and the accuracy of the procedure were registered. A total of 83 surgical procedures were performed on 75 patients. The majority (87 %) of lesions treated surgically were located in the frontal, temporal and anterior parts of the parietal region. Histological examination revealed benign lesions in 66 % of the patients and dural involvement in 46 %. According to these results craniectomies were performed using the robotic system. Mean positioning accuracy of the robotic system while milling was 0.24 mm, with a standard deviation of 0.04 mm, and maximum error under 1 mm. Craniectomies leaving a 1-mm layer of the tabula interna intact to ensure a healthy dura were performed in several regions successfully. The majority of calvarial tumours, requiring surgical treatment in our patients, were located in cosmetically relevant areas in which drilling can be carried out with the robotic trepanation system. Consequently, the surgical approach had to be planned carefully in order to achieve a good cosmetic outcome.

Robot- and computer-assisted craniotomy: resection planning, implant modelling and robot safety.

BACKGROUND: In cases of cranial tumour, manual resection of the cancerous tissue can be very stressful and time-consuming, due to the adhesion of the subjacent dura mater. Computer-assisted planning, navigation and robotic craniotomy, with optional skull reconstruction using customized implants, are of increasing clinical interest in craniofacial and neurosurgery. METHODS: Using preoperative computed tomography (CT) images, an automatic segmentation of the tumour is performed, followed by resection planning. The skull reconstruction is performed using computer-assisted implant modeling and manufacturing. Risk analysis of the robot-guided intervention led to the development of a new hexapod robot system. RESULTS: Results from registration and robot accuracy on plastic and Anatomical skull are shown. The concept of a stand-alone safety system is presented to supervise the robot during the intervention. The entire process from preoperative CT scan to intraoperative robot assisted removal of tumourous bone is shown in laboratory and anatomical trials. CONCLUSION: The laboratory and anatomy studies conducted so far provided a substantial basis for further improvement of the system's integration in the surgical workflow and the final approval of the system for initial clinical studies.

Identification of milling parameters for manual cutting of bicortical bone structures.

Within the framework of the development of a new neurosurgical robot system, parameters of conventional manual neurosurgical bone milling had to be determined. These results were used as a reference for the design and validation of the robotic versus manual milling task. Bovine scapulae were used for the tests because their bicortical structure is similar to the bone structure of the skull. The exercise was to cut defined geometries that had been registered on the bone prior to the start of the milling operation. The geometries had to be milled with a depth of 3 mm, which corresponded to the radius of the ball of the cutter. Different parameters like tool position, rotary speed, temperature, forces and time were registered. Eleven experienced neurosurgeons with practical experience of 80-1200 skull operations participated in this study. First results show a large variation in depth along the line. The lateral deviation was up to 5 mm, the depth error up to 2.5 mm, the tool temperature was 22 degrees C to 65 degrees C, and rotary speed varied from 15,000 to 80,000 rpm. Registered forces had maxima of 16 N in the feed direction and 21 N normal to the surface; average forces were approximately 1-2 N.

[Development of a compact, semi-robotic platform for an electronic surgical microscope]. / Entwicklung einer kompakten, teilrobotischen Trägerplattform für ein elektronisches OP-Mikroskop.

In the context of the development of a new, electronic microscope for surgical interventions a semirobotic motion platform for the spatial placement and fixation of a stereoscopic camera is currently being developed. Based on an inquiry about the medical, technical and user-requirements, different phases and characteristics concerning frequency, workspace, speed and accuracy of camera movement during an intervention have been specified. To meet these requirements, a differentiated concept for the platform has been developed including a serial structure for manual pre-positioning, a parallel robot for motor-movement during surgical work and different user-interfaces for suitable robot-control.

[Technical principles for removal of femoral bone cements in hip prosthesis implant revision]. / Technische Prinzipien zur Entfernung femoralen Knochenzements in der Revisionshüftendoprothetik.

As the removal of femoral bone cement is one of the most challenging tasks in cemented total Hip Revision, a lot of different technical devices have been developed to aid the surgeon. All of their pros and cons are partly consequences of the specific system-design but mainly arise from the basic physical principles used. The known methods and devices as well as their data-handling have therefore been analysed, reduced to their principles according to the criteria of systematic engineering design and systematized in order to provide a better comparability and starting point for the development of new devices.

Detex for detection of Escherichia coli O157 in raw ground beef and raw ground poultry.

A method for detection of Escherichia coli O157 in beef and poultry is presented. The method is antibody-based and uses a patented antibody-specific metal-plating procedure for the detection of E. coli O157 in enriched meat samples. Both raw ground beef and raw ground poultry were tested as matrixes for the organism. The sensitivity and specificity of the assay were 98 and 90%, respectively. The accuracy of the assay was 96%. Overall, the method agreement between the E. coli O157 Detex assay and the U.S. Department of Agriculture/Food Safety Inspection Service method was 96%. Sample temperature upon loading of the apparatus was critical to the observed false-positive rate of the system.

Denver Potable Water Reuse Demonstration Project: comprehensive chronic rat study.

The health effects testing program for the Denver Water Department's Potable Water Reuse Demonstration Project was designed to evaluate the relative health effects of highly treated reclaimed water derived from secondary wastewater in comparison with Denver's present high-quality drinking water. The 1 x 10(6) gal/day treatment plant provided 500-fold concentrates of water that had been treated by multiple processes to remove microbial and chemical contaminants. Fischer 344 rats were exposed to the complex mixture solutions for up to 2 yr to evaluate chronic toxicity and oncogenicity effects. The following parameters were evaluated: clinical observations, survival rate, growth, food and water consumption, haematology, clinical chemistry, urinalysis, organ weights, gross autopsy and histopathological examination of all lesions, major tissues and organs. Clinical pathology, gross pathology, and microscopic pathology conducted at wk 26 and 65 and at the end of the study did not reveal any findings that could be considered to be treatment related. Administration of drinking water concentrates at up to 500 times the original concentration in the original water samples to F344 rats for up to 104 wk did not result in any overt toxicological or carcinogenic effects.

Comprehensive Health Effects Testing Program for Denver's Potable Water Reuse Demonstration Project.

The Comprehensive Health Effects Testing Program for the Denver Water Department's Potable Water Reuse Demonstration Project is designed to evaluate the relative health effects of highly treated reclaimed water derived from secondary wastewater compared to Denver's present high-quality drinking water. The 1 million gallon per day (1 mgd) demonstration plant provides water to be evaluated in the studies treating unchlorinated secondary treated wastewater with the following additional processes: high pH lime clarification, recarbonation, filtration, ultraviolet irradiation, activated carbon adsorption, reverse osmosis, air stripping, ozonation, and chloramination. An additional sample is obtained from the identical treatment process substituting ultrafiltration for reverse osmosis. The toxicology tests to evaluate the possible long-term health effects are chronic toxicity and oncogenicity studies in Fischer 344 rats and B6C3F1 mice and reproductive/teratology in Sprague-Dawley rats. The results of these evaluations will be correlated with microbiological, chemical, and physical test results to establish the relative quality of reclaimed water compared to all established health standards as well as Denver's pristine drinking water.

Primary structure of the gene for the murine Ia antigen-associated invariant chains (Ii). An alternatively spliced exon encodes a cysteine-rich domain highly homologous to a repetitive sequence of thyroglobulin.

The gene for murine Ia-associated invariant (Ii) chains (Ii31 and Ii41) was characterized by sequence analysis. The gene extends over approximately 9 kb and is organized in nine exons. Exon 1 encodes the 5' untranslated region and the cytoplasmic segment, exon 2 the membrane spanning segment and adjacent amino acids and exons 3-8 the extracytoplasmic portion of Ii31. Putative promoter sequences were found upstream of the start of the coding sequence. Between exons 6 and 7 an additional, alternatively spliced exon 6b has been identified. This exon is spliced into the mRNA coding for the Ii-related Ii41 protein. Exon 6b encodes a cysteine-rich domain of 64 amino acids. It shows a remarkably high homology to the repetitive elements in thyroglobulin, a precursor for thyroid hormone. Based on this homology, it is suggested that this domain (TgR) in Tg and in Ii41 may play a role either in hormone formation or as a carrier in the transport of molecules (thyroid hormone or processed antigen respectively) between intracellular compartments.