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.

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.

[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.

Telepresence for surgical assistance and training using eXtended reality during and after pandemic periods.

Existing challenges in surgical education (See one, do one, teach one) as well as the COVID-19 pandemic make it necessary to develop new ways for surgical training. Therefore, this work describes the implementation of a scalable remote solution called "TeleSTAR" using immersive, interactive and augmented reality elements which enhances surgical training in the operating room. The system uses a full digital surgical microscope in the context of Ear-Nose-Throat surgery. The microscope is equipped with a modular software augmented reality interface consisting an interactive annotation mode to mark anatomical landmarks using a touch device, an experimental intraoperative image-based stereo-spectral algorithm unit to measure anatomical details and highlight tissue characteristics. The new educational tool was evaluated and tested during the broadcast of three live XR-based three-dimensional cochlear implant surgeries. The system was able to scale to five different remote locations in parallel with low latency and offering a separate two-dimensional YouTube stream with a higher latency. In total more than 150 persons were trained including healthcare professionals, biomedical engineers and medical students.

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 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.

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.

Digital Live Imaging of Intraoperative Electrocochleography - First Description of Feasibility and Hearing Preservation During Cochlear Implantation.

INTRODUCTION: Intraoperative electrocochleography (ECochG) during cochlear implantation is a promising tool to preserve residual hearing. However, the time gap between insertion of the electrode and acoustic feedback from the audiologist to the surgeon can cause delay and subsequently irreparable damage to cochlear structures. In this feasibility study, for the first time, real-time visualization of intraoperative ECochG via digital microscope display directly to the surgeon was successfully performed in four patients. MATERIALS AND METHODS: Four patients with residual hearing underwent cochlear implantation. Intraoperative electrocochleography responses were collected and direct visualization during the time of electrode insertion into the surgeon's field of view in the binoculars using augmented real-time digital imaging was realized. The time of electrode insertion was recorded. Hearing preservation was determined by testing postoperative changes in behavioral thresholds. RESULTS: Digital live visualization of intraoperative ECochG using image augmentation in a digital microscope was successfully performed in all cases and enabled direct adaptation of the surgeon's insertion behavior. Mean time of electrode insertion was 129.8 seconds. Postoperative behavioral thresholds were comparable to preoperative taken thresholds. Preservation of residual hearing in the low frequency range was possible. DISCUSSION: This study is the first to describe digital visualization of intraoperative electrocochleography as a new method enabling the surgeon to directly react to changes in amplitude of the cochlea microphonics. Our results show that augmentation of the intraoperative live imaging with electrical potentials could add to hearing preservation during cochlear implantation.

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.

Modeling and Bioinformatics Identify Responders to G-CSF in Patients With Amyotrophic Lateral Sclerosis.

Objective: Developing an integrative approach to early treatment response classification using survival modeling and bioinformatics with various biomarkers for early assessment of filgrastim (granulocyte colony stimulating factor) treatment effects in amyotrophic lateral sclerosis (ALS) patients. Filgrastim, a hematopoietic growth factor with excellent safety, routinely applied in oncology and stem cell mobilization, had shown preliminary efficacy in ALS. Methods: We conducted individualized long-term filgrastim treatment in 36 ALS patients. The PRO-ACT database, with outcome data from 23 international clinical ALS trials, served as historical control and mathematical reference for survival modeling. Imaging data as well as cytokine and cellular data from stem cell analysis were processed as biomarkers in a non-linear principal component analysis (NLPCA) to identify individual response. Results: Cox proportional hazard and matched-pair analyses revealed a significant survival benefit for filgrastim-treated patients over PRO-ACT comparators. We generated a model for survival estimation based on patients in the PRO-ACT database and then applied the model to filgrastim-treated patients. Model-identified filgrastim responders displayed less functional decline and impressively longer survival than non-responders. Multimodal biomarkers were then analyzed by PCA in the context of model-defined treatment response, allowing identification of subsequent treatment response as early as within 3 months of therapy. Strong treatment response with a median survival of 3.8 years after start of therapy was associated with younger age, increased hematopoietic stem cell mobilization, less aggressive inflammatory cytokine plasma profiles, and preserved pattern of fractional anisotropy as determined by magnetic resonance diffusion tensor imaging (DTI-MRI). Conclusion: Long-term filgrastim is safe, is well-tolerated, and has significant positive effects on disease progression and survival in a small cohort of ALS patients. Developing and applying a model-based biomarker response classification allows use of multimodal biomarker patterns in full potential. This can identify strong individual treatment responders (here: filgrastim) at a very early stage of therapy and may pave the way to an effective individualized treatment option.

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.

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.

Intrathecal Application of a Fluorescent Dye for the Identification of Cerebrospinal Fluid Leaks in Cochlear Malformation.

In cases of cerebrospinal fluid (CSF) leaks, reliable detection of their origins is needed to seal the leak sufficiently and prevent complications, such as meningitis. A method is presented here using intrathecal administered fluorescein in a clinical case of bilateral congenital ear malformation. A fluorescent dye is administered intrathecally to achieve intraoperative visualization of CSF leaks. The dye is applied 20 min before surgery, and concentration of 5% is used. Per every 10 kg of body weight, 0.1 mL of the fluid is applied intrathecally. The fluorescein is visualized using a fully digital microscope. The origin of the fluid leak is identified in the stapes footplate. During primary surgery, it is sealed, and cochlea implantation is performed for hearing restoration. In this specific case, 6 weeks later, the implant was explanted due to acute meningitis, and the electrode array was left as a spacer. Postoperatively, in the aural smear, ß-transferrin was detected. During a revision mastoidectomy, dislocated coverage of the leak was found. The stapes was removed and oval window sealed. Five days after revision surgery, no ß-transferrin was detected in the aural smear. During the revision of cochlea implantation 6 months later, intact coverage of the oval niche was observed. Thus, intrathecal fluorescein application proves to be a reliable tool for the detection of CSF leaks. It facilitates the orientation in malformations and complicated or unknown surgical situs. In the literature, its use is described for CSF fistulas in endonasal surgery but is rarely described in skull base and mastoid surgeries. The method has been used successfully in several cases with CSF leaks, and the results confirm the feasibility of safely accessing the origin of the leak.

Biomarker Supervised G-CSF (Filgrastim) Response in ALS Patients.

Objective: To evaluate safety, tolerability and feasibility of long-term treatment with Granulocyte-colony stimulating factor (G-CSF), a well-known hematopoietic stem cell factor, guided by assessment of mobilized bone marrow derived stem cells and cytokines in the serum of patients with amyotrophic lateral sclerosis (ALS) treated on a named patient basis. Methods: 36 ALS patients were treated with subcutaneous injections of G-CSF on a named patient basis and in an outpatient setting. Drug was dosed by individual application schemes (mean 464 Mio IU/month, range 90-2160 Mio IU/month) over a median of 13.7 months (range from 2.7 to 73.8 months). Safety, tolerability, survival and change in ALSFRS-R were observed. Hematopoietic stem cells were monitored by flow cytometry analysis of circulating CD34+ and CD34+CD38- cells, and peripheral cytokines were assessed by electrochemoluminescence throughout the intervention period. Analysis of immunological and hematological markers was conducted. Results: Long term and individually adapted treatment with G-CSF was well tolerated and safe. G-CSF led to a significant mobilization of hematopoietic stem cells into the peripheral blood. Higher mobilization capacity was associated with prolonged survival. Initial levels of serum cytokines, such as MDC, TNF-beta, IL-7, IL-16, and Tie-2 were significantly associated with survival. Continued application of G-CSF led to persistent alterations in serum cytokines and ongoing measurements revealed the multifaceted effects of G-CSF. Conclusions: G-CSF treatment is feasible and safe for ALS patients. It may exert its beneficial effects through neuroprotective and -regenerative activities, mobilization of hematopoietic stem cells and regulation of pro- and anti-inflammatory cytokines as well as angiogenic factors. These cytokines may serve as prognostic markers when measured at the time of diagnosis. Hematopoietic stem cell numbers and cytokine levels are altered by ongoing G-CSF application and may potentially serve as treatment biomarkers for early monitoring of G-CSF treatment efficacy in ALS in future clinical trials.

TruePrime is a novel method for whole-genome amplification from single cells based on TthPrimPol.

Sequencing of a single-cell genome requires DNA amplification, a process prone to introducing bias and errors into the amplified genome. Here we introduce a novel multiple displacement amplification (MDA) method based on the unique DNA primase features of Thermus thermophilus (Tth) PrimPol. TthPrimPol displays a potent primase activity preferring dNTPs as substrates unlike conventional primases. A combination of TthPrimPol's unique ability to synthesize DNA primers with the highly processive Phi29 DNA polymerase (Φ29DNApol) enables near-complete whole genome amplification from single cells. This novel method demonstrates superior breadth and evenness of genome coverage, high reproducibility, excellent single-nucleotide variant (SNV) detection rates with low allelic dropout (ADO) and low chimera formation as exemplified by sequencing HEK293 cells. Moreover, copy number variant (CNV) calling yields superior results compared with random primer-based MDA methods. The advantages of this method, which we named TruePrime, promise to facilitate and improve single-cell genomic analysis.

Magnetic resonance imaging-based endovascular versus medical stroke treatment for symptom onset up to 12 h.

BACKGROUND: Recent trials have shown a clear benefit of endovascular therapy for stroke patients presenting within 6 h after stroke onset. Imaging-based selection may identify a cohort with a favorable response to endovascular therapy, in an even later time window. AIMS: We performed an indirect comparison between outcomes seen in DEFUSE 2, a prospective cohort study of patients who received a baseline MRI before endovascular therapy, and a control group from AXIS 2 receiving standard medical care up to 12 h after symptom onset. METHODS: Patients from AXIS 2 with a confirmed large vessel occlusion were selected as a control group for DEFUSE 2-patients. The primary endpoint was good functional outcome at day 90 (Modified Rankin Score 0-2). We performed a stratified analysis based on the presence of the target mismatch for both studies and reperfusion status in DEFUSE 2. RESULTS: We compared good functional outcome in 108 patients from AXIS 2 and 99 patients from DEFUSE 2. In DEFUSE 2-patients with the target mismatch profile in whom reperfusion was achieved, the rate of good functional outcome was increased compared to target mismatch patients in AXIS 2, 54% versus 29% (OR 3.2, 95% CI 1.1-9.4). In target mismatch patients treated between 6 and 12 h after stroke onset, this association between study and good functional outcome remained present (OR 9.0, 95% CI 1.1-75.8). CONCLUSIONS: This indirect comparison suggests that endovascular treatment resulting in substantial reperfusion is associated with improved outcome in target mismatch patients even beyond 6 h after stroke onset. Confirmation is needed from future clinical trials that randomize patients beyond the 6 h time window.

Erythropoietin Stimulates Tumor Growth via EphB4.

While recombinant human erythropoietin (rhEpo) has been widely used to treat anemia in cancer patients, concerns about its adverse effects on patient survival have emerged. A lack of correlation between expression of the canonical EpoR and rhEpo's effects on cancer cells prompted us to consider the existence of an alternative Epo receptor. Here, we identified EphB4 as an Epo receptor that triggers downstream signaling via STAT3 and promotes rhEpo-induced tumor growth and progression. In human ovarian and breast cancer samples, expression of EphB4 rather than the canonical EpoR correlated with decreased disease-specific survival in rhEpo-treated patients. These results identify EphB4 as a critical mediator of erythropoietin-induced tumor progression and further provide clinically significant dimension to the biology of erythropoietin.