Analyse der Zytokinsynthese-Kapazität von Monozyten polytraumatisierter Patienten

Die Destabilisierung des humanen Immunsystems stellt für polytraumatisierte Patienten ein relevantes Problem dar und manifestiert sich auf der Ebene von Organfunktionsstörungen mit nach wie vor erheblicher Letalität. Zahlreiche Untersuchungen der jüngsten Vergangenheit haben klare Hinweise dafür gegeben, daß den zellulären Komponenten des Immunsystems eine zentrale Rolle für die Ausbildung und Ausprägung des posttraumatischen Multi-Organ-Dysfunktions-Syndroms (MODS) und des Multi-Organ-Versagens (Multiple Organ Failure, MOF) zukommt. Dabei hat sich die Fähigkeit monozytärer Zellen auf einen pathologischen Stimulus reagieren zu können, als einer der kritischen Funktionsparameter des menschlichen Immunsystems gezeigt. Die umfangreichen Untersuchungen der jüngsten Vergangenheit konnten jedoch die Frage nach der Dynamik dieser Funktionsstörung bislang nur unzureichend beantworten. Darüber blieb die tatsächliche Synthese-Kapazität relevanter Botenstoffe, wie z.B. von Zytokinen auf intrazellulärem Niveau weitgehend uncharakterisiert. Ziel der vorliegenden Untersuchung war es daher: i) Die intrazelluläre Zytokinsynthese-Kapazität von Monozyten polytraumatisierter Patienten in der direkten posttraumatischen Phase mittels Durchflußzytometrie zu quantifizieren ii) Zu analysieren, ob es einen Zusammenhang zwischen der intrazellulären Aktivierung der Zytokinsynthese-Kapazität und der Änderung der systemischen Zytokin-Konzentration gibt iii) Die dabei gewonnenen Ergebnisse in Vergleich zu klinischen Parametern zu setzen Da es bislang keine validen Versuchsprotokolle für die durchflußzytometrische Analyse der intrazellulären Zytokinsynthese-Kapazität von Monozyten gab, wurden in der ersten Stufe der vorliegenden Studie die Kulturbedingungen für die Stimulation, Sekretionsblockade und Stimulationszeit von Monozyten erarbeitet. Es zeigte sich, daß im Hinblick auf die weitere Fragestellung die Stimulation mit Lipopolysaccharid über 4 Stunden unter einer Sekretionsblockade mit Monensin valide Ergebnisse erbringt. In der zweiten Stufe der Studie wurde erstmalig mittels intrazellulärer single cell Analyse die Synthese-Kapazität von Entzündungs-relevanten Mediatoren (TNF-, Il-1, Il-6 und Il-8) bei polytraumatisierten Patienten untersucht. Gemäß einem seriellen Protokoll wurde zu den Zeitpunkten „Aufnahme in den Schockraum“, 6 Stunden, 12 Stunden, 24 Stunden, 48 Stunden und 72 Stunden nach Trauma bei 13 polytraumatisierten Patienten (ISS >16 Punkte, zwölf überlebt, einer verstorben) jeweils die Zytokinsynthese-Kapazität analysiert. Für TNF- beträgt sie bei Aufnahme 78±5%, für Il-1 ergab sich mit 73±6% ebenso wie für Il-6 mit 58±4%bereits bei Aufnahme eine signifikante Reduktion im Vergleich zur Kontrollgruppe. Es konnte gezeigt werden, daß die Synthese-Kapazität für diese essentiellen proinflammatorischen Zytokine zwischen 12 und 48 Stunden nach Trauma mit 49±5% für TNF-, 53±7% für Il-1, 36,7% für Il-6 und 77,3% für Il-8 signifikant im Vergleich zu den Werten bei Aufnahme reduziert ist. Die vorliegende Untersuchung demonstriert somit eine engmaschige Analyse und Quantifizierung der monozytären Zytokinsynthese-Kapazität für TNF-, Il-6, Il-1 und Il-8 nach Polytrauma. Bezüglich der Analyse, ob ein Zusammenhang zwischen intrazellulärer Aktivierung der Zytokinsynthese-Kapazität und der Änderung der systemischen Zytokin-Konzentration besteht, konnten wir mittels ELISA in der systemischen Zirkulation zwar tendenzielle Veränderungen der einzelnen Faktoren beobachten, jedoch fand sich auf Grund der niedrigen Sensitivität der ELISA-Methode keine signifikante Korrelation zu den hoch-sensitiven intrazellulären Ergebnissen. Bezüglich des Einflusses klinischer Faktoren auf die intrazelluläre Zytokinsynthese-Kapazität ließ sich nachweisen, daß Patienten mit schwerer Verletzung (ISS ≥34) im Zeitraum zwischen 24 Stunden und 72 Stunden nach Trauma eine signifikant niedrigere Zytokinsynthese-Kapazität aufweisen als weniger schwer verletzte Patienten (ISS <34). So beträgt die Kapazität für TNF- in der Schwerer-Verletzten-Gruppe 72 Stunden nach Trauma 62±11% vs. 80±6% in der Leichter-Verletzten-Gruppe. Ähnliche Beobachtungen ließen sich auch für Il-1 und Il-6 machen. Lediglich für die Synthese-Kapazität von Il-8 ließ sich nach 72 Stunden kein Unterschied mehr zwischen den Gruppen feststellen. Die vorliegende Arbeit zeigt somit, daß das, in der Literatur beschriebene Phänomen der posttraumatischen Immundysfunktion bei Monozyten bereits 12 Stunden nach Trauma auftritt, deutlich früher also als bisher in der Literatur anhand von Messungen in Überständen isolierter MØ gezeigt. Des weiteren konnte in Analogie zur Sepsis demonstriert werden, daß die Synthese-Kapazität von Immunzellen offensichtlich mit der Schwere der Erkrankung, i.e. der Schwere der Sepsis bzw. der Schwere der Verletzung korreliert ist. Ziel von Folgestudien muß es nun sein, die den vorgestellten Ergebnissen zugrunde liegenden intrazellulären Steuerungsmechanismen aufzuklären

Precise Proximal Femur Fracture Classification for Interactive Training and Surgical Planning

We demonstrate the feasibility of a fully automatic computer-aided diagnosis (CAD) tool, based on deep learning, that localizes and classifies proximal femur fractures on X-ray images according to the AO classification. The proposed framework aims to improve patient treatment planning and provide support for the training of trauma surgeon residents. A database of 1347 clinical radiographic studies was collected. Radiologists and trauma surgeons annotated all fractures with bounding boxes, and provided a classification according to the AO standard. The proposed CAD tool for the classification of radiographs into types "A", "B" and "not-fractured", reaches a F1-score of 87% and AUC of 0.95, when classifying fractures versus not-fractured cases it improves up to 94% and 0.98. Prior localization of the fracture results in an improvement with respect to full image classification. 100% of the predicted centers of the region of interest are contained in the manually provided bounding boxes. The system retrieves on average 9 relevant images (from the same class) out of 10 cases. Our CAD scheme localizes, detects and further classifies proximal femur fractures achieving results comparable to expert-level and state-of-the-art performance. Our auxiliary localization model was highly accurate predicting the region of interest in the radiograph. We further investigated several strategies of verification for its adoption into the daily clinical routine. A sensitivity analysis of the size of the ROI and image retrieval as a clinical use case were presented.Comment: Accepted at IPCAI 2020 and IJCAR

Analysis of N-terminal pro-B-type natriuretic peptide and cardiac index in multiple injured patients: a prospective cohort study

Introduction Increased serum B-type natriuretic peptide (BNP) has been identified for diagnosis and prognosis of impaired cardiac function in patients suffering from congestive heart failure, ischemic heart disease, and sepsis. However, the prognostic value of BNP in multiple injured patients developing multiple organ dysfunction syndrome (MODS) remains undetermined. Therefore, the aims of this study were to assess N-terminal pro-BNP (NT-proBNP) in multiple injured patients and to correlate the results with invasively assessed cardiac output and clinical signs of MODS. Methods Twenty-six multiple injured patients presenting a New Injury Severity Score of greater than 16 points were included. The MODS score was calculated on admission as well as 24, 48, and 72 hours after injury. Patients were subdivided into groups: group A showed minor signs of organ dysfunction ( MODS score less than or equal to 4 points) and group B suffered from major organ dysfunction ( MODS score of greater than 4 points). Venous blood (5 mL) was collected after admission and 6, 12, 24, 48, and 72 hours after injury. NT-proBNP was determined using the Elecsys proBNP (R) assay. The hemodynamic monitoring of cardiac index (CI) was performed using transpulmonary thermodilution. Results Serum NT-proBNP levels were elevated in all 26 patients. At admission, the serum NT- proBNP values were 116 +/- 21 pg/mL in group A versus 209 +/- 93 pg/mL in group B. NT-proBNP was significantly lower at all subsequent time points in group A in comparison with group B (P < 0.001). In contrast, the CI in group A was significantly higher than in group B at all time points (P < 0.001). Concerning MODS score and CI at 24, 48, and 72 hours after injury, an inverse correlation was found (r = 0.664, P < 0.001). Furthermore, a correlation was found comparing MODS score and serum NT- proBNP levels (r = 0.75, P < 0.0001). Conclusions Serum NT-proBNP levels significantly correlate with clinical signs of MODS 24 hours after multiple injury. Furthermore, a distinct correlation of serum NT-proBNP and decreased CI was found. The data of this pilot study may indicate a potential value of NT-proBNP in the diagnosis of post-traumatic cardiac impairment. However, further studies are needed to elucidate this issue

Analysis of death in major trauma: value of prompt post mortem computed tomography (pmCT) in comparison to office hour autopsy

Background: To analyze diagnostic accuracy of prompt post mortem Computed Tomography (pmCT) in determining causes of death in patients who died during trauma room management and to compare the results to gold standard autopsy during office hours. Methods: Multiple injured patients who died during trauma room care were enrolled. PmCT was performed immediately followed by autopsy during office hours. PmCT and autopsy were analyzed primarily regarding pmCT ability to find causes of death and secondarily to define exact causes of death including accurate anatomic localizations. For the secondary analysis data was divided in group-I with equal results of pmCT and autopsy, group-II with autopsy providing superior results and group-III with pmCT providing superior information contributing to but not majorly causing death. Results: Seventeen multiple trauma patients were enrolled. Since multiple trauma patients were enrolled more injuries than patients are provided. Eight patients sustained deadly head injuries (47.1 %), 11 chest (64.7 %), 4 skeletal system (23.5 %) injuries and one patient drowned (5.8 %). Primary analysis revealed in 16/17 patients (94.1 %) causes of death in accordance with autopsy. Secondary analysis revealed in 9/17 cases (group-I) good agreement of autopsy and pmCT. In seven cases autopsy provided superior results (group-II) whereas in 1 case pmCT found more information (group-III). Discussion: The presented work studied the diagnostic value of pmCT in defining causes of death in comparison to standard autopsy. Primary analysis revealed that in 94.1% of cases pmCT was able to define causes of death even if only indirect signs were present. Secondary analysis showed that pmCT and autopsy showed equal results regarding causes of death in 52.9%. Conclusions: PmCT is useful in traumatic death allowing for an immediate identification of causes of death and providing detailed information on bony lesions, brain injuries and gas formations. It is advisable to conduct pmCT especially in cases without consent to autopsy to gain information about possible causes of death and to rule out possible clinical errors

Septic arthritis as a severe complication of elective arthroscopy:clinical management strategies

Infection of a peripheral joint following arthroscopic surgery presents with an incidence of approximately 0.42% an extremely rare entity. However, septic arthritis is a serious situation possibly leading to an irreparable joint damage. Especially at delayed diagnosis patients' safety can be endangered severely. Only few precise statements regarding diagnosis and therapy have been published so far. Besides an accurate analysis of the patient's anamnesis and the assessment of the C-reactive protein especially arthrocentesis is required for diagnostic workup. For early stage infections arthroscopic therapy is proven to be of value. In addition a calculated and consecutive germ-adjusted antibiotic therapy is essential. In case of persisting signs of infection the indication for re-arthroscopy or conversion to open revision has to be stated in time. The number of necessary revisions is dependent on the initial stage of infection. For pain therapy postoperative immobilization of the affected joint is occasionally essential, if otherwise possibly early mobilization of the joint should be performed

A rare differential diagnosis to occupational neck pain: bilateral stylohyoid syndrome

Chronic neck pain is widely prevalent and a common source of disability in the working-age population. Etiology of chronic neck pain includes neck sprain, mechanical or muscular neck pain, myofascial pain syndrome, postural neck pain as well as pain due to degenerative changes. We report the case of a 42 year old secretary, complaining about a longer history of neck pain and limited movement of the cervical spine. Surprisingly, the adequate radiologic examination revealed a bilateral ossification of the stylohyoid ligament complex. Her symptoms remained intractable from conservative treatment consisting of anti-inflammatory medication as well as physical therapy. Hence the patient was admitted to surgical resection of the ossified stylohyoid ligament complex. Afterwards she was free of any complaints and went back to work. Therefore, ossification of the stylohyoid ligament complex causing severe neck pain and movement disorder should be regarded as a rare differential diagnosis of occupational related neck pain

Mid-term outcome comparing temporary K-wire fixation versus PDS augmentation of Rockwood grade III acromioclavicular joint separations

Backround The treatment of acute acromioclavicular (AC) joint injuries depends mainly on the type of the dislocation and patient demands. This study compares the mid term outcome of two frequently performed surgical concepts of Rockwood grade III AC joint separations: The temporary articular fixation with K-wires (TKW) and the refixation with an absorbable polydioxansulfate (PDS) sling. Findings Retrospective observational study of 86 patients with a mean age of 37 years underwent either TKW (n = 70) or PDS treatment (n = 16) of Rockwood grade III AC joint injuries. Mid term outcome with a mean follow up of 3 years was measured using a standardized functional patient questionnaire including Constant score, ASES rating scale, SPADI, XSMFA-D and a pain score. K-wire therapy resulted in significantly better functional results expressed by Constant score (88 ± 10 vs. 73 ± 18), ASES rating scale (29 ± 3 vs. 25 ± 5), SPADI (3 ± 9 vs. 9 ± 13), XSMFA-D function (13 ± 2 vs. 14 ± 3), XSMFA-D impairment (4 ± 1 vs. 6 ± 2) and pain score (1 ± 1 vs. 2 ± 2). Conclusion Either temporary K-wire fixation and PDS sling enable good or satisfying functional results in the treatment of Rockwood grade III AC separations. However functional outcome parameters indicate a significant advantage for the K-wire technique

Age and gender as determinants of the bone quality of the greater tuberosity: A HR-pQCT cadaver study

Background: Age-dependent trabecular changes of the humeral head might weaken the fixation of suture anchors used for rotator cuff (RC) repair. This might lead to suture anchor loosening and thus compromise the integrity of the repair. The aim of this study was to analyze whether the trabecular microstructure within the RC footprint is influenced by age, gender or handedness. Methods: Axial HR-pQCT scans (Scanco Medical) of 64 freshly frozen cadaveric human humeral head specimens (age 72.3 +/- 17.4 years) were analyzed to determine the bone volume-to-total volume ratio (BV/TV), trabecular thickness (Trab Th), trabecular number (Trab N) and connectivity density (Conn Dens). Within the RC footprint, 2 volumes of interest (VOI), posteromedial (PM) and anterolateral (AL) and one control VOI in the subarticular bone (SC) were set. Results: The highest BV/TV was found in SC: 0.22 +/- 0.06% vs. PM: 0.04 +/- 0.05% vs. AL: 0.02 +/- 0.04%; p &lt; 0.05. Trab Th accounted for 0.26 +/- 0.05 mu m in SC, 0.23 +/- 0.09 mu m in AL and 0.21 +/- 0.05 mu m in PM. In parallel, Trab N and Conn Dens were found to be the highest in SC. Gender analysis yielded higher values for BV/TV, Trab Th, Trab N and Conn Dens for PM in males compared to females (p &lt; 0.05). There were no significant findings when comparing both sides. We furthermore found a strong inverse correlation between age and BV/TV, which was more pronounced in the female specimens (r = -0.72, p &lt; 0.00001). Conclusions: The presented microarchitectural data allow for future subtle biomechanical testing comprising knowledge on age-and sex-related changes of the tuberosities of the humeral head. Furthermore, the insights on the trabecular structure of the humeral head of the elderly may lead to the development of new fixation materials in bone with inferior bone quality

Early down-regulation of the pro-inflammatory potential of monocytes is correlated to organ dysfunction in patients after severe multiple injury: a cohort study

Introduction Severe tissue trauma results in a general inflammatory immune response (SIRS) representing an overall inflammatory reaction of the immune system. However, there is little known about the functional alterations of monocytes in the early posttraumatic phase, characterized by the battle of the individual with the initial trauma. Methods Thirteen patients with severe multiple injury; injury severity score (ISS) >16 points (17 to 57) were included. The cytokine synthesis profiles of monocytes were characterized on admission, and followed up 6, 12, 24, 48, and 72 hours after severe multiple injury using flow cytometry. Whole blood was challenged with lipopolysaccharide (LPS) and subsequently analyzed for intracellular monocyte-related TNF-alpha, IL-1 beta, IL-6, and IL-8. The degree of organ dysfunction was assessed using the multiple organ dysfunction syndrome (MODS)-score of Marshall on admission, 24 hours and 72 hours after injury. Results Our data clearly show that the capacity of circulating monocytes to produce these mediators de novo was significantly diminished very early reaching a nadir 24 hours after severe injury followed by a rapid and nearly complete recovery another 48 hours later compared with admission and controls, respectively. In contrast to the initial injury severity, there was a significant correlation detectable between the clinical signs of multiple organ dysfunction and the ex vivo cytokine response. Conclusions As our data derived from very narrow intervals of measurements, they might contribute to a more detailed understanding of the early immune alterations recognized after severe trauma. It can be concluded that indeed as previously postulated an immediate hyperactivation of circulating monocytes is rapidly followed by a substantial paralysis of cell function. Moreover, our findings clearly demonstrate that the restricted capacity of monocytes to produce proinflammatory cytokines after severe injury is not only an in vitro phenomenon but also undistinguishable associated with the onset of organ dysfunction in the clinical scenario

Medical-based Deep Curriculum Learning for Improved Fracture Classification

International audienceAbstract. Current deep-learning-based methods do not easily integrate into clinical protocols, neither take full advantage of medical knowledge.In this work, we propose and compare several strategies relying on curriculum learning, to support the classification of proximal femur fracturefrom X-ray images, a challenging problem as reflected by existing intra- and inter-expert disagreement. Our strategies are derived from knowledgesuch as medical decision trees and inconsistencies in the annotations of multiple experts, which allows us to assign a degree of diculty to eachtraining sample. We demonstrate that if we start learning \easy" examples and move towards \hard", the model can reach better performance,even with fewer data. The evaluation is performed on the classification of a clinical dataset of about 1000 X-ray images. Our results show that,compared to class-uniform and random strategies, the proposed medical knowledge-based curriculum, performs up to 15% better in terms ofaccuracy, achieving the performance of experienced trauma surgeons. Keywords: Curriculum learning, multi-label classification, bone fractures, computer-aided diagnosis, medical decision tre