Risk factors for long-term invasive mechanical ventilation: a longitudinal study using German health claims data.

BACKGROUND: Long-term invasive mechanical ventilation (IMV) is a major burden for those affected and causes high costs for the health care system. Early risk assessment is a prerequisite for the best possible support of high-risk patients during the weaning process. We aimed to identify risk factors for long-term IMV within 96 h (h) after the onset of IMV. METHODS: The analysis was based on data from one of Germany's largest statutory health insurance funds; patients who received IMV ≥ 96 h and were admitted in January 2015 at the earliest and discharged in December 2017 at the latest were analysed. OPS and ICD codes of IMV patients were considered, including the 365 days before intubation and 30 days after discharge. Long-term IMV was defined as evidence of invasive home mechanical ventilation (HMV), IMV ≥ 500 h, or readmission with (re)prolonged ventilation. RESULTS: In the analysis of 7758 hospitalisations, criteria for long-term IMV were met in 38.3% of cases, of which 13.9% had evidence of HMV, 73.1% received IMV ≥ 500 h and/or 40.3% were re-hospitalised with IMV. Several independent risk factors were identified (p < 0.005 each), including pre-diagnoses such as pneumothorax (OR 2.10), acute pancreatitis (OR 2.64), eating disorders (OR 1.99) or rheumatic mitral valve disease (OR 1.89). Among ICU admissions, previous dependence on an aspirator or respirator (OR 5.13), and previous tracheostomy (OR 2.17) were particularly important, while neurosurgery (OR 2.61), early tracheostomy (OR 3.97) and treatment for severe respiratory failure such as positioning treatment (OR 2.31) and extracorporeal lung support (OR 1.80) were relevant procedures in the first 96 h after intubation. CONCLUSION: This comprehensive analysis of health claims has identified several risk factors for the risk of long-term ventilation. In addition to the known clinical risks, the information obtained may help to identify patients at risk at an early stage. Trial registration The PRiVENT study was retrospectively registered at ClinicalTrials.gov (NCT05260853). Registered at March 2, 2022.

A multidimensional approach to the management of patients in prolonged weaning from mechanical ventilation - the concept of treatable traits - a narrative review.

Background Established structured weaning approaches, which are effective for patients in simple and difficult weaning, are often not appropriate for patients undergoing prolonged weaning. Addressing the complexity of weaning failure requires personalized precision medicine. The therapeutic concept of Treatable Traits (TTs) has been proposed as a new paradigm for the management of chronic respiratory diseases. It is based on a multidimensional assessment of specific characteristics, which can be addressed by specific interventions that go beyond traditional diagnostic criteria. The concept is increasingly adopted for other complex diseases. Summary This is a narrative review and an expert opinion on the development of a concept of TTs for patients undergoing prolonged weaning. The proposed TTs are based on a systematic review of risk factors for prolonged weaning, an analysis of claims data to assess risk factors within 96 hours of IMV onset and data from the WEAN-SAFE study. A multidisciplinary team identified clinically important TTs and determined appropriate interventions. The following TTs have been identified: Airway disorders and complications associated with tracheostomy or intubation, such as airway obstruction, strictures or tracheomalacia, infectious aspects, anxiety, depression, delirium, post-traumatic stress disorder, anemia, pulmonary and cardio-renal disease. The multidimensional holistic approach also includes tailored sedation and pain management, nutritional therapy, early mobilization and physiotherapy. Key message We propose a framework of relevant considerations for a multidimensional approach to the management of patients undergoing prolonged weaning that supports the regain of respiratory capacity, reduces the respiratory load and thus could resolve the respiratory workload imbalance.

E-learning-an interventional element of the PRiVENT project to improve weaning expertise.

BACKGROUND: PRiVENT (PRevention of invasive VENTilation) is an evaluation of a bundle of interventions aimed at the prevention of long-term invasive mechanical ventilation. One of these elements is an e-learning course for healthcare professionals to improve weaning expertise. The aim of our analysis is to examine the implementation of the course in cooperating intensive care units. METHODS: The course has been developed through a peer review process by pulmonary and critical care physicians in collaboration with respiratory therapists, supported by health services researchers and a professional e-learning agency. The e-learning platform "weLearn" was made available online to participating healthcare professionals. Feedback on the e-learning programme was obtained and discussed in quality circles (QCs). We measured the acceptance and use of the programme through access statistics. RESULTS: The e-learning course "Joint Prevention of Long-Term Ventilation" consists of 7 separate modules with practice-oriented training units as well as a cross-module area and corresponding interactive case studies. Users can receive 23 CME (continuing medical education) credits. The platform was released on July 1, 2021. By June 28, 2023, 214 users from 33 clinics had registered. Most users (77-98%) completed the modules, thus performing well in the test, where 90-100% passed. In the QCs, the users commended the structure and practical relevance of the programme, as well as the opportunity to earn CME credits. CONCLUSION: Especially for medical staff in intensive care units, where continuous training is often a challenge during shift work, e-learning is a useful supplement to existing medical training. TRIAL REGISTRATION: The PRiVENT study is registered at ClinicalTrials.gov (NCT05260853) on 02/03/2022.

[Multidimensional formats of surgical anatomy in otorhinolaryngology student teaching-a comparison of effectivity]. / Multidimensionale Formate chirurgischer Anatomie in der studentischen Ausbildung der HNO-Heilkunde ­ ein Effektivitätsvergleich.

BACKGROUND: Technological change in healthcare and the digital transformation of teaching require innovations in student teaching in medicine. New technologies are needed to enable the delivery and use of diverse teaching and learning formats by educational institutions independent of time and place. The aim of this study is to analyze the effectiveness of different multidimensional formats in student teaching in surgical ENT medical anatomy. MATERIALS AND METHODS: During the summer semester 2022 and winter semester 2022/2023, the digital teaching and learning program was expanded by testing different visualization formats (3D glasses, cardboards, or VR glasses) with students in the context of a highly standardized surgical procedure, namely cochlear implantation. A pre- and post-intervention knowledge assessment was carried out in all groups, followed by an evaluation. RESULTS: Of 183 students, 91 students fully participated in the study. The post-intervention knowledge assessment showed a significant increase in correct answers regardless of visualization format. In a direct comparison, the operating room (OR) group answered correctly significantly more often than the cardboard group (p = 0.0424). The majority of students would like to see 3D teaching as an integral part of the teaching program (87.9%) and more streaming of live surgeries (93.4%). They see the use of the various technologies as a very good addition to conventional surgical teaching (72.5%), as good visualization (89%) increases retention (74.7%) and motivation (81.3%). CONCLUSION: Application and use of new visualization technologies in everyday clinical practice is a promising approach to expanding student training. Mobile, interactive, and personalized technical formats can be adapted to the learning behavior of students. Last but not least, the use of new media influences learning motivation. An expansion of digital teaching and learning formats can be expressly recommended on the basis of this study.

[Interprofessional weaning boards and weaning consults for long-term ventilated patients: A qualitative study of perceived potential for patient care]. / Interprofessionelle Weaning-Boards und Weaning-Konsile für Langzeitbeatmungspatient*innen: Eine qualitative Studie zum wahrgenommenen Potenzial für die Patientenversorgung.

BACKGROUND: The PRiVENT project aims to improve the care of invasively ventilated patients and to reduce the number of out-of-hospital long-term ventilated patients. PRiVENT offers intensive care units the opportunity to exchange information with experts from specialized weaning centers in interprofessional weaning boards and weaning consults and to exploit the full weaning potential of the patients. In the context of the accompanying process evaluation, the PRiVENT intervention components will be examined for sustainability, scalability and effectiveness, and the interprofessional collaboration between intensive care units and the responsible weaning centers will be investigated in order to identify potentials for the care of invasively managed patients. METHODS: In a qualitative cross-sectional study, semistructured, problem-oriented interviews were conducted with care providers of participating ICUs. The data were digitally recorded, pseudonymized and verbatim transcribed. Data analysis was based on Brown and Clarke's Thematic Analysis and the Consolidated Framework for Implementation Research. MAXQDA 2020 software was used to organize the data. RESULTS: Fourteen interviews were conducted with ICU care providers. The early transfer of patients to a weaning center and the integration of pulmonary expertise into routine care were identified as positively perceived potentials of the weaning boards and weaning consults. Especially in critically ill, multimorbid patients suffering from COVID-19, the expertise of the weaning centers was considered helpful. Due to heavy workloads, nurses were unable to participate in weaning boards and weaning consults. CONCLUSION: Interprofessional collaboration between weaning centers and ICUs in weaning boards and weaning consults can improve the care of invasively ventilated patients. Strategies to promote the involvement of nurses should be discussed and developed.

Prevention of invasive ventilation (PRiVENT)-a prospective, mixed-methods interventional, multicentre study with a parallel comparison group: study protocol.

BACKGROUND: Invasive mechanical ventilation (IMV) is a standard therapy for intensive care patients with respiratory failure. With increasing population age and multimorbidity, the number of patients who cannot be weaned from IMV increases, resulting in impaired quality of life and high costs. In addition, human resources are tied up in the care of these patients. METHODS: The PRiVENT intervention is a prospective, mixed-methods interventional, multicentre study with a parallel comparison group selected from insurance claims data of the health insurer Allgemeine Ortskrankenkasse Baden-Württemberg (AOK-BW) conducted in Baden-Württemberg, Germany, over 24 months. Four weaning centres supervise 40 intensive care units (ICUs), that are responsible for patient recruitment. The primary outcome, successful weaning from IMV, will be evaluated using a mixed logistic regression model. Secondary outcomes will be evaluated using mixed regression models. DISCUSSION: The overall objective of the PRiVENT project is the evaluation of strategies to prevent long-term IMV. Additional objectives aim to improve weaning expertise in and cooperation with the adjacent Intensive Care Units. TRIAL REGISTRATION: This study is registered at ClinicalTrials.gov (NCT05260853).

Risk Factors for Prolonged Mechanical Ventilation and Weaning Failure: A Systematic Review.

INTRODUCTION: Prolonged mechanical ventilation (PMV) and weaning failure are factors associated with prolonged hospital length of stay and increased morbidity and mortality. In addition to the burden these places on patients and their families, it also imposes high costs on the public health system. The aim of this systematic review was to identify risk factors for PMV and weaning failure. METHODS: The study was conducted according to PRISMA guidelines. After a comprehensive search of the COCHRANE Library, CINHAL, Web of Science, MEDLINE, and the LILACS Database a PubMed request was made on June 8, 2020. Studies that examined risk factors for PMV, defined as mechanical ventilation ≥96 h, weaning failure, and prolonged weaning in German and English were considered eligible; reviews, meta-analyses, and studies in very specific patient populations whose results are not necessarily applicable to the majority of ICU patients as well as pediatric studies were excluded from the analysis. This systematic review was registered in the PROSPERO register under the number CRD42021271038. RESULTS: Of 532 articles identified, 23 studies with a total of 23,418 patients met the inclusion criteria. Fourteen studies investigated risk factors of PMV including prolonged weaning, 9 studies analyzed risk factors of weaning failure. The concrete definitions of these outcomes varied considerably between studies. For PMV, a variety of risk factors were identified, including comorbidities, site of intubation, various laboratory or blood gas parameters, ventilator settings, functional parameters, and critical care scoring systems. The risk of weaning failure was mainly related to age, previous home mechanical ventilation (HMV), cause of ventilation, and preexisting underlying diseases. Elevated PaCO2 values during spontaneous breathing trials were indicative of prolonged weaning and weaning failure. CONCLUSION: A direct comparison of risk factors was not possible because of the heterogeneity of the studies. The large number of different definitions and relevant parameters reflects the heterogeneity of patients undergoing PMV and those discharged to HMV after unsuccessful weaning. Multidimensional scores are more likely to reflect the full spectrum of patients ventilated in different ICUs than single risk factors.

Interactive live-stream surgery contributes to surgical education in the context of contact restrictions.

BACKGROUND: Attendance teaching is the predominant teaching method at universities but needs to be questioned in the context of digital transformation. This study establishes and evaluates a method to accomplish electronic learning to supplement traditional attendance courses. MATERIALS AND METHODS: Surgery was transmitted in real-time conditions via an online live stream from the surgical theater. Visualization was transferred from a fully digital surgical microscope, an endoscope or an environmental camera in high definition quality. Students were able to participate at home from their personal computer. After following the surgery, they participated in an online-evaluation. RESULTS: A total of 65 students participated in the live stream. The majority of students (61.54%) indicated a significant subjective increase in knowledge after participation. The majority of students (53.85%) indicated that live surgeries should be offered as a permanent component in addition to classroom teaching. Likewise, a broader offer was desired by many students (63.08%). CONCLUSIONS: Live streaming of surgery is a promising approach as an alternative or supplement to traditional attendance teaching. An expansion of digital teaching can be explicitly supported on the basis of this study.

[Interactive intraoperative annotation of surgical landmarks in student education to support learning efficiency and motivation]. / Interaktive intraoperative Annotation chirurgischer Anatomie in der studentischen Ausbildung zur Unterstützung der Lerneffizienz und -motivation.

BACKGROUND: The development of technological innovations has not only changed social life and the healthcare system, but also affects medical education. The aim of this pilot study was to evaluate whether students, when observing a microsurgical procedure of the temporal bone, gain an additional understanding of the anatomical structures and surgical site when visualization is used that provides identical views for the surgeon and viewer in 3D. MATERIALS AND METHODS: During regular attendance tutorials, students were randomly assigned to three different groups: control group, 2D group, or 3D group. Evaluation questionnaires and intraoperative student annotation of the surgical view were used to assess the subjective didactic value of different visualization formats and resultant learning experiences for the students. RESULTS: A total of 47 students were included in the investigations during conventional attendance tutorials. The majority indicated a high added value of the 3D visualization in terms of method (70%) and vividness (80%) compared to the 2D group and self-study; 69% of the students fully agreed with the statement that 2D and 3D visualization increases learning motivation and is a very good way to improve recognition of anatomical topography and structures. CONCLUSION: New interactive visualization options in teaching promote learning efficiency and motivation among students. Especially 3D visualization and intraoperative annotation of the surgical view by the student is a useful didactic tool and increases the quality of clinical teaching. It supports the perception of anatomical topography and enables more focused surgical training.

Reversible Edema in the Penumbra Correlates With Severity of Hypoperfusion.

Background and Purpose: We aimed to investigate fluid-attenuated inversion recovery changes in the penumbra. Methods: We determined core and perfusion lesions in subjects from the WAKE-UP trial (Efficacy and Safety of MRI-Based Thrombolysis in Wake-Up Stroke) and AXIS 2 trial (Granulocyte Colony-Stimulating Factor in Patients With Acute Ischemic Stroke) with perfusion- and diffusion-weighted imaging at baseline. Only subjects with a mismatch volume >15 mL and ratio >1.2 were included. We created voxel-based relative fluid-attenuated inversion recovery signal intensity (rFLAIR SI) maps at baseline and follow-up. We studied rFLAIR SI in 2 regions of interest: baseline penumbra (baseline perfusion lesion−[core lesion+voxels with apparent diffusion coefficient <620 10−6 mm2/s]) and noninfarcted penumbra (baseline perfusion lesion−follow-up fluid-attenuated inversion recovery lesion) at 24 hours (WAKE-UP) or 30 days (AXIS 2). We analyzed the association between rFLAIR SI and severity of hypoperfusion, defined as time to maximum of the residue function. Results: In the baseline penumbra, rFLAIR SI was elevated (ratio, 1.04; P=1.7×10−13; n=126) and correlated with severity of hypoperfusion (Pearson r, 0.03; P<1.0×10−4; n=126). In WAKE-UP, imaging at 24 hours revealed a further increase of rFLAIR SI in the noninfarcted penumbra (ratio, 1.05 at 24 hours versus 1.03 at baseline; P=7.1×10−3; n=43). In AXIS 2, imaging at 30 days identified reversibility of the rFLAIR SI (ratio, 1.02 at 30 days versus 1.04 at baseline; P=1.5×10−3; n=26) since it was no longer different from 1 (ratio, 1.01 at 30 days; P=0.099; n=26). Conclusions: Penumbral rFLAIR SI increases appear early after stroke onset, correlate with severity of hypoperfusion, further increase at 24 hours, and are reversible by 30 days. Registration: URL: https://clinicaltrials.gov; Unique identifier: NCT01525290. URL: https://clinicaltrials.gov; Unique identifier: NCT00927836.

Automated detection of electrically evoked stapedius reflexes (eSR) during cochlear implantation.

INTRODUCTION: In cochlear implantation, objective fitting methods are needed to optimize audiological results in small children or patients with poor compliance. Intraoperatively measured electrically evoked stapedius reflexes (eSR) can be used as a marker for the patient's discomfort level. The aim of this study was to develop and evaluate an automated detection method for eSR and to compare it to the detection rate of the surgeon and independent observers. METHODS: Cochlear implantation using a fully digital surgical microscope was performed. Movements of the stapedius tendon were recorded and analyzed by means of computer vision technique. Differences in eSR elicited by stimulating electrodes at different cochlear locations (basal, middle and apical) were analyzed. The eSR detection rate of the image processing algorithm was compared to the surgeon's detection rate and to those of two less experienced observers. RESULTS: A total of 387 electrically impulses were applied. The stimulation of middle turn electrodes showed significantly higher detection rates (50.4%) compared to the basal (40.0%; p = 0.001) and apical (43.6%; p = 0.03) turn. The software identified significantly more of the applied stimuli (58.4%) compared to the surgeon (46.3%; p = 0.0007), the intermediate observer (37.7%; p < 0.0001) and the unexperienced observer (41.3%; p < 0.0001). CONCLUSION: The feasibility of an automated intraoperative software-based detection of eSR is demonstrated. By improving the eSR detection methods and their clinical applicability, their utility in objective cochlear implant fitting may be substantially increased.

Evaluating the didactic value of 3D visualization in otosurgery.

INTRODUCTION: Improvements of surgical visualization add value to the quality of clinical routine and offer the opportunity to improve surgical education of medical staff. The aim of this study was to determine whether otorhinolaryngology trainees gain additional comprehension of the anatomical structures and the surgical site when 3D visualization is used. METHODS: Data were collected from ENT trainees of microsurgical courses of the middle ear, inner ear and lateral skull base at four university ENT departments (Charité (Berlin), Martin Luther University Halle-Wittenberg (Halle/Saale), Ludwig Maximilian University (Munich) and Rostock University Medical Center). Participants were asked to complete a questionnaire assessing the subjective value of identical surgical field visualization in 3D for surgeon and observer. RESULTS: A total of 112 participants completed the questionnaire. The majority of participants stated a high additional value of 3D visualization compared to 2D visualization, with 75% fully agreeing to the statement that 3D visualization of the surgical field is superior to perceive the anatomical topography and structures compared to 2D representation. Participants encouraged the storage of data in online learning platforms. CONCLUSION: The results show that 3D visualization with identical imaging for surgeon and observer is a useful tool in teaching of microsurgery. It addresses perception of anatomical topography and structures as well as conception of the surgical workflow.

Infarct volume-based subgroup selection in acute ischemic stroke trials.

BACKGROUND AND PURPOSE: We investigated whether hyperintensities with a diameter of at least 3, 3.5, and 4 cm and visible on at least 3 slices on diffusion-weighted imaging enables patient selection with an infarct volume of ≥15 mL. METHODS: Consecutive acute stroke patients were screened for the AXIS2 trial and examined according to a standardized magnetic resonance imaging protocol in 65 sites. Diffusion-weighted lesion diameters were measured and compared with volumetric assessments. RESULTS: Out of 238 patients, 86.2% (N=206) had infarct diameter of at least 3 cm. Volumetric assessments showed infarct volume of ≥15 mL in 157 patients. A cut-off value of 3 cm led to 96.8% sensitivity and 33.3% specificity for predicting lesion volume of ≥15 mL. Analogously, a 3.5 cm cut-off led to 96.8% sensitivity and 50.6% specificity and a 4 cm cut-off led to 91.7% sensitivity and 61.7% specificity. CONCLUSIONS: Lesion diameter measures may enable multicentric patient recruitment with a prespecified minimal infarct volume. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00927836.

What Do We Really Need? Visions of an Ideal Human-Machine Interface for NOTES Mechatronic Support Systems From the View of Surgeons, Gastroenterologists, and Medical Engineers.

PURPOSE: To investigate why natural orifice translumenal endoscopic surgery (NOTES) has not yet become widely accepted and to prove whether the main reason is still the lack of appropriate platforms due to the deficiency of applicable interfaces. METHODS: To assess expectations of a suitable interface design, we performed a survey on human-machine interfaces for NOTES mechatronic support systems among surgeons, gastroenterologists, and medical engineers. Of 120 distributed questionnaires, each consisting of 14 distinct questions, 100 (83%) were eligible for analysis. RESULTS: A mechatronic platform for NOTES was considered "important" by 71% of surgeons, 83% of gastroenterologist,s and 56% of medical engineers. "Intuitivity" and "simple to use" were the most favored aspects (33% to 51%). Haptic feedback was considered "important" by 70% of participants. In all, 53% of surgeons, 50% of gastroenterologists, and 33% of medical engineers already had experience with NOTES platforms or other surgical robots; however, current interfaces only met expectations in just more than 50%. Whereas surgeons did not favor a certain working posture, gastroenterologists and medical engineers preferred a sitting position. Three-dimensional visualization was generally considered "nice to have" (67% to 72%); however, for 26% of surgeons, 17% of gastroenterologists, and 7% of medical engineers it did not matter (P = 0.018). CONCLUSION: Requests and expectations of human-machine interfaces for NOTES seem to be generally similar for surgeons, gastroenterologist, and medical engineers. Consensus exists on the importance of developing interfaces that should be both intuitive and simple to use, are similar to preexisting familiar instruments, and exceed current available systems.

Design of a test system for the development of advanced video chips and software algorithms.

BACKGROUND: Visual deterioration is a crucial point in minimally invasive surgery impeding surgical performance. Modern image processing technologies appear to be promising approaches for further image optimization by digital elimination of disturbing particles. To make them mature for clinical application, an experimental test environment for evaluation of possible image interferences would be most helpful. METHODS: After a comprehensive review of the literature (MEDLINE, IEEE, Google Scholar), a test bed for generation of artificial surgical smoke and mist was evolved. Smoke was generated by a fog machine and mist produced by a nebulizer. The size of resulting droplets was measured microscopically and compared with biological smoke (electrocautery) and mist (ultrasound dissection) emerging during minimally invasive surgical procedures. RESULTS: The particles resulting from artificial generation are in the range of the size of biological droplets. For surgical smoke, the droplet dimension produced by the fog machine was 4.19 µm compared with 4.65 µm generated by electrocautery during a surgical procedure. The size of artificial mist produced by the nebulizer ranged between 45.38 and 48.04 µm compared with the range between 30.80 and 56.27 µm that was generated during minimally invasive ultrasonic dissection. CONCLUSION: A suitable test bed for artificial smoke and mist generation was developed revealing almost identical droplet characteristics as produced during minimally invasive surgical procedures. The possibility to generate image interferences comparable to those occurring during laparoscopy (electrocautery and ultrasound dissection) provides a basis for the future development of image processing technologies for clinical applications.

The "Iceberg Phenomenon": As Soon as One Technological Problem in NOTES Is Solved, the Next One Appears!

PURPOSE: Though already proclaimed about 7 years ago, natural orifice transluminal endoscopic surgery (NOTES) is still in its early stages. A multidisciplinary working team tried to analyze the technical obstacles and identify potential solutions. METHODS: After a comprehensive review of the literature, a group of 3 surgeons, 1 gastroenterologist, 10 engineers, and 1 representative of biomedical industry defined the most important deficiencies within the system and then compiled as well as evaluated innovative technologies that could be used to help overcome these problems. These technologies were classified with regard to the time needed for their implementation and associated hindrances, where priority is based on the level of impact and significance that it would make. RESULTS: Both visualization and actuation require significant improvement. Advanced illumination, mist elimination, image stabilization, view extension, 3-dimensional stereoscopy, and augmented reality are feasible options and could optimize visual information. Advanced mechatronic platforms with miniaturized, powerful actuators, and intuitive human-machine interfaces could optimize dexterity, as long as enabling technologies are used. The latter include depth maps in real time, precise navigation, fast pattern recognition, partial autonomy, and cognition systems. CONCLUSION: The majority of functional deficiencies that still exist in NOTES platforms could be overcome by a broad range of already existing or emerging enabling technologies. To combine them in an optimal manner, a permanent dialogue between researchers and clinicians is mandatory.

KIBRA (KIdney/BRAin protein) regulates learning and memory and stabilizes Protein kinase Mζ.

The WWC1 gene has been genetically associated with human episodic memory performance, and its product KIdney/BRAin protein (KIBRA) has been shown to interact with the atypical protein kinase protein kinase M ζ (PKMζ). Although recently challenged, PKMζ remains a candidate postsynaptic regulator of memory maintenance. Here, we show that PKMζ is subject to rapid proteasomal degradation and that KIBRA is both necessary and sufficient to counteract this process, thus stabilizing the kinase and maintaining its function for a prolonged time. We define the binding sequence on KIBRA, a short amino acid motif near the C-terminus. Both hippocampal knock-down of KIBRA in rats and KIBRA knock-out in mice result in decreased learning and memory performance in spatial memory tasks supporting the notion that KIBRA is a player in episodic memory. Interestingly, decreased memory performance is accompanied by decreased PKMζ protein levels. We speculate that the stabilization of synaptic PKMζ protein levels by KIBRA may be one mechanism by which KIBRA acts in memory maintenance. KIBRA/WWC1 has been genetically associated with human episodic memory. KIBRA has been shown to be post-synaptically localized, but its function remained obscure. Here, we show that KIBRA shields PKMζ, a kinase previously linked to memory maintenance, from proteasomal degradation via direct interaction. KIBRA levels in the rodent hippocampus correlate closely both to spatial memory performance in rodents and to PKMζ levels. Our findings support a role for KIBRA in memory, and unveil a novel function for this protein.

Granulocyte-colony stimulating factor: a new player for the enteric nervous system.

The enteric nervous system (ENS) controls and modulates gut motility and responds to food intake and to internal and external stimuli such as toxins or inflammation. Its plasticity is maintained throughout life by neural progenitor cells within the enteric stem cell niche. Granulocyte-colony stimulating factor (G-CSF) is known to act not only on cells of the immune system but also on neurons and neural progenitors in the central nervous system (CNS). Here, we demonstrate, for the first time, that G-CSF receptor is present on enteric neurons and progenitors and that G-CSF plays a role in the expansion and differentiation of enteric neural progenitor cells. Cultured mouse ENS-neurospheres show increased expansion with increased G-CSF concentrations, in contrast to CNS-derived spheres. In cultures from differentiated ENS- and CNS-neurospheres, neurite outgrowth density is enhanced depending on the amount of G-CSF in the culture. G-CSF might be an important factor in the regeneration and differentiation of the ENS and might be a useful tool for the investigation and treatment of ENS disorders.

A probe-based electromagnetic navigation system to integrate computed tomography during upper gastrointestinal endoscopy.

BACKGROUND AND STUDY AIMS: For preoperative work-up, an examination tool that visualizes separately compiled diagnostics in augmented reality would be desirable. We developed a probe-based electromagnetic navigation system, which can be passed through the working channel of an endoscope, to integrate computed tomography (CT) information during upper gastrointestinal endoscopy. PATIENTS AND METHODS: The target registration error (TRE) of the system was evaluated experimentally and clinically. A total of 24 study patients with upper gastrointestinal cancer were included in the study. The cancerous lesion was endoscopically located (mean duration 8.4 minutes, range 7.1 - 23.2) and the TRE (coronal, transverse, sagittal layer) was measured by comparing the distance between the navigation probe (at the tip of the endoscope) and the target lesion shown on the corresponding CT cross section. RESULTS: Experimental evaluations showed an accuracy in line with the system's inherent failure rate, with a median TRE of 2.8 mm (IQR 1.8 - 4.3), 2.2 mm (0.4 - 3.7), and 2.8 mm (1.1 - 5.9) in the coronal, transverse, and sagittal planes, respectively. Clinical evaluation revealed a median TRE of 4.8 mm (1.9 - 10.1), 3.9 mm (0.7 - 7.1), and 4.2 mm (0.9 - 8.9), respectively. No complications occurred during navigated endoscopy. CONCLUSIONS: The probe-based electromagnetic navigation system revealed high accuracy (TRE < 5 mm), facilitating improved interpretation of endoluminal imaging.

Granulocyte colony-stimulating factor in patients with acute ischemic stroke: results of the AX200 for Ischemic Stroke trial.

BACKGROUND AND PURPOSE: Granulocyte colony-stimulating factor (G-CSF; AX200; Filgrastim) is a stroke drug candidate with excellent preclinical evidence for efficacy. A previous phase IIa dose-escalation study suggested potential efficacy in humans. The present large phase IIb trial was powered to detect clinical efficacy in acute ischemic stroke patients. METHODS: G-CSF (135 µg/kg body weight intravenous over 72 hours) was tested against placebo in 328 patients in a multinational, multicenter, randomized, and placebo-controlled trial (NCT00927836; www.clinicaltrial.gov). Main inclusion criteria were ≤9-hour time window after stroke onset, infarct localization in the middle cerebral artery territory, baseline National Institutes of Health Stroke Scale score range of 6 to 22, and baseline diffusion-weighted imaging lesion size ≥15 mL. Primary and secondary end points were the modified Rankin scale score and the National Institutes of Health Stroke Scale score at day 90, respectively. Data were analyzed using a prespecified model that adjusted for age, National Institutes of Health Stroke Scale score at baseline, and initial infarct volume (diffusion-weighted imaging). RESULTS: G-CSF treatment failed to meet the primary and secondary end points of the trial. For additional end points such as mortality, Barthel index, or infarct size at day 30, G-CSF did not show efficacy either. There was, however, a trend for reduced infarct growth in the G-CSF group. G-CSF showed the expected peripheral pharmacokinetic and pharmacodynamic profiles, with a strong increase in leukocytes and monocytes. In parallel, the cytokine profile showed a significant decrease of interleukin-1. CONCLUSIONS: G-CSF, a novel and promising drug candidate with a comprehensive preclinical and clinical package, did not provide any significant benefit with respect to either clinical outcome or imaging biomarkers. CLINICAL TRIAL REGISTRATION URL: http://www.clinicaltrials.gov. Unique identifier: NCT00927836.