Genetic Diversity And Sexual-Dimorphisms Are Important Contributors To The Inflammatory Response Induced By Endotoxin

Das biologische Geschlecht wird als ein Risikofaktor für die Entstehung und den Verlauf von septischen Zustandsbildern kontrovers diskutiert. In der hier vorgelegten Arbeit werden die Einflüsse genetischer Faktoren unter Berücksichtigung des biologischen Geschlechts und der Wirkung von Sexualsteroiden auf die entzündliche Antwort in einem Tiermodel untersucht. Hierzu wurde genotypisch verschieden Mausstämmen (A/J, C57BL6/J, DBA/2J, BALB/cJ und AKR/J) bakterielles Endotoxin (Lipopolysaccharid, LPS) intraperitoneal injiziert. Als Ausdruck der entzündlichen Antwort wurden Plasmaspiegel der Zytokine Tumor Nekrose Faktor alpha (TNF-a) und Interleukin 10 (IL-10) mittels ELSIA gemessen. Es zeigten sich deutliche geschlechtsspezifische Unterschiede in der LPS-induzierten entzündlichen Antwort von C57BL6/J-Mäusen (=B6), die hormonell bedingt zu sein scheinen. Der Vergleich mit A/J-Mäusen weist hier jedoch eine unterschiedliche Ausprägung und somit eine Abhängigkeit von genetischen Faktoren auf. Außerdem lässt sich die entzündliche Antwort durch Gabe von Sexual-Steroiden modulieren. Hierzu wurden Mäuse kastriert bzw. ovariektomiert und vor der Injektion von LPS mit 17-ß-Estrogen oder 5-a-Dihydrotestosteron behandelt. Männliche Tiere reagierten dabei allerdings deutlich besser auf diese Beeinflussung von außen. Darüber hinaus sind diese Effekte abhängig von genetischen Faktoren. Nach Änderung der hormonellen Bedingungen fanden sich bei den Männchen der einzelnen Stämme deutliche Unterschiede: Während sich einige Stämme z.T. unbeeinflusst, wie z.B. die IL-10 Plasmaspiegel von DBA/2J und BALB/c Mäusen nach Östrogen-Behandlung zeigten, fanden sich bei andere Stämme gar gegensätzliche Antworten, so z.B: die TNF-a Plasmaspiegel von A/J und B6 Mäusen nach Östrogen-Behandlung. Untersuchungen an der F1-Generation von A/J und B6 Mäusen zeigten, dass die beobachteten Effekte unabhängig von den Geschlechtschromosomen oder genetischem Imprinting zu sein scheinen. Die beobachteten Veränderungen durch hormonelle Manipulation wurden auch in ihrer Auswirkung auf den Verlauf nach einer letalen LPS-Injektion untersucht. Da Androgene allgemein als hauptsächlich verantwortlich für geschlechtsspezifische Unterschiede der entzündlichen Antwort eingeschätzt werden, wurde von der Verringerung der systemischen Androgenspiegel ein Überlebensvorteil erwartet. Um so interessanter war die Beobachtung, dass diesbezüglich lediglich A/J Mäuse nach chirurgischer Kastration vor den Auswirkungen von LPS geschützt waren. Dieser protektive Effekt könnte die Folge von sexual-steroid-abhängigen Änderungen in der Relation von pro- zu anti-inflammatorischer Komponente der entzündlichen Antwort sein. Es ist anzunehmen, dass dieser Schutz nur bei entsprechender genetischer Konstellation und wahrscheinlich in Abhängigkeit vom Verletzungsmechanismus zustande kommt. Östrogen-Behandlung von männlichen A/J and B6 Mäusen brachte kein verbessertes Überleben nach Endotoxinschock. Die vorgelegten Daten erlauben die Schlussfolgerung, dass biologisches Geschlecht und individuelle genetische Ausstattung gemeinsam einen messbaren Einfluss auf die LPS-induzierte entzündliche Antwort haben. Könnte man diese Ergebnisse auf Menschen übertragen, so ließe sich hieraus eine Erklärung für gegensätzliche Beobachtungen bei geschlechtsspezifischen Unterschieden in klinischen Studien ableiten. Genetische Marker könnten helfen, die Einflüsse des biologischen Geschlechts auf die entzündliche Antwort klinisch besser untersuchen zu können. Die Suche nach solchen Markern sollte in Zukunft intensiviert werden, da ihnen auch eine große Bedeutung für das Design von Laborexperimenten und klinischen Studien zukommt, aus denen sich dann eventuell sogar therapeutische Ansätzen zur Milderung der sekundären Effekte von Verletzungen ableiten lassen

Differences between cases admitted to hospital and discharged from the emergency department after emergency medical services transport

Objective. Rising emergency medical services (EMS) utilisation increases transport to hospital emergency departments (ED). However, some patients receive outpatient treatment (discharged) while others are hospitalised (admitted). The aims of this analysis were to compare admitted and discharged cases, to assess whether cases that were discharged from the ED could be identified using dispatch data and to compare dispatch keyword categories and hospital diagnoses. Design. Retrospective observational study using linked secondary data. Setting and participants. 78 303 cases brought to 1 of 14 ED in the city of Munich, Germany, by EMS between 1 July 2013 and 30 June 2014. Main outcome measures. Characteristics of admitted and discharged cases were assessed. Logistic regression was used to estimate the association between discharge and age, sex, time of day, ambulance type and dispatch keyword category. Keyword categories were compared to hospital diagnoses. Results. 39.4% of cases were discharged. They were especially likely to be young (OR 10.53 (CI 9.31 to 11.92), comparing 70-year-olds) and to fall under the categories ‘accidents/trauma’ (OR 2.87 (CI 2.74 to 3.01)) or ‘other emergencies (unspecified)’ (OR 1.23 (CI 1.12 to 1.34) (compared with ‘cardiovascular’). Most frequent diagnoses came from chapter ‘injury and poisoning’ (30.1%) of the 10th revision of the international statistical classification of disease and related health problems (ICD-10), yet these diagnoses were more frequent at discharge (42.7 vs 22.0%) whereas circulatory system disease was less frequent (2.6 vs 21.8%). Except for accidents/trauma and intoxication/poisoning many underlying diagnoses were observed for the same dispatch keyword. Conclusion. Young age and dispatch for accidents or trauma were the strongest predictors of discharge. Even within the same dispatch keyword category the distribution of diagnoses differed between admitted and discharged cases. Discharge from the ED does not indicate that urgent response was unnecessary. However, these cases could be suitable for allocation to hospitals with low inpatient bed capacities and are of particular interest for future studies regarding the urgency of their condition

Rupture du contrat psychologique, stress et souffrance au travail : une recherche réalisée au sein du dispositif souffrance au travail du CHU Toulouse-Purpan

The purpose of this research is to study the origins and psychosocial consequences of the working situations leading to stress and mental suffering. It is looking primarily at how the psychological contract has been impacted by the changes that have evolved in the working environment in the past years. It is more particularly centered on the mental processes through which a breach of the psychological contract is being perceived and on the processes that are applied to cope with this altered employment relationship.From a theoretical standpoint, this research departs from the traditional approach to occupational stress insofar as it integrates subjective dynamics into the study of stress and suffering at work. Our theory suggests that the heterogeneous experiences and temporalities of employees have an influence on the organizational socialization as well as on the development of the employment relationship and the subjective regulation of conflicts. A local public hospital service offering psychological care for people suffering from their working situation provide the frame of the research. The information collected via this clinical work done with 103 persons is used for the qualitative and quantitative data analyses. The clinical observations are systematically compared to the results of the statistical analysis. We establish a link between the perception of a violation of the psychological contract and the deterioration of the mental health of the persons received in this psychological care center. We underline the impact of the contract’s breach, often a consequence of changes occurring in the working environment, on the individual as well as on the employment relationship. The empirical and the statistical results emphasize the need for the development and the implementation of psychosocial risks prevention measures by multidisciplinary working groups.Cette recherche a pour objet l’étude des déterminants et des effets psychosociaux des situations de travail en termes de stress et de souffrance. C’est sous l’angle du contrat psychologique qu’elle s’intéresse à l’impact des transformations du travail de ces dernières années sur les conditions de son exercice et les relations d’emploi. Elle porte plus particulièrement sur les processus d’interprétation des ruptures du contrat psychologique et les processus d’ajustement et de restructuration des sujets consécutifs aux évolutions de ces relations d’emploi. Au plan théorique la recherche se démarque sensiblement des modèles traditionnels en intégrant, dans l’étude du stress et de la souffrance au travail, les dynamiques subjectives. Notre position théorique considère que, le sujet est actif et pluriel dans sa socialisation et dans le développement de ses relations avec son contexte de travail, autant que dans la recherche de réponses aux exigences de l’organisation et aux siennes que dans les régulations subjectives des conflits qui en naissent. Une consultation hospitalière de souffrance au travail constitue le cadre de cette recherche. Les données recueillies auprès de 103 personnes reçues en accompagnement psychologique dans ce dispositif ont fait l’objet d’une analyse qualitative et d’une analyse quantitative. Des observations cliniques ont été systématiquement confrontées aux résultats d’analyses statistiques.Nous mettons en évidence un lien entre la perception d’une violation du contrat psychologique et la dégradation de l’état de santé psychologique des personnes reçues en consultation. Nous soulignons l’impact de la rupture du contrat, souvent déclenchée par une transformation dans le milieu du travail, autant sur l’individu que sur sa relation de travail. De ces observations et résultats ressort la nécessité de développer des démarches de prévention pluridisciplinaire

Autologous bone graft versus demineralized bone matrix in internal fixation of ununited long bones

Background Non-unions are severe complications in orthopaedic trauma care and occur in 10% of all fractures. The golden standard for the treatment of ununited fractures includes open reduction and internal fixation (ORIF) as well as augmentation with autologous-bone-grafting. However, there is morbidity associated with the bone-graft donor site and some patients offer limited quantity or quality of autologous-bone graft material. Since allogene bone-grafts are introduced on the market, this comparative study aims to evaluate healing characteristics of ununited bones treated with ORIF combined with either iliac-crest-autologous-bone-grafting (ICABG) or demineralized-bone-matrix (DBM). Methods and results From 2000 to 2006 out of sixty-two consecutive patients with non-unions presenting at our Level I Trauma Center, twenty patients had ununited diaphyseal fractures of long bones and were treated by ORIF combined either by ICABG- (n = 10) or DBM-augmentation (n = 10). At the time of index-operation, patients of the DBM-group had a higher level of comorbidity (ASA-value: p = 0.014). Mean duration of follow-up was 56.6 months (ICABG-group) and 41.2 months (DBM-group). All patients were clinically and radiographically assessed and adverse effects related to bone grafting were documented. The results showed that two non-unions augmented with ICABG failed osseous healing (20%) whereas all non-unions grafted by DBM showed successful consolidation during the first year after the index operation (p = 0.146). No early complications were documented in both groups but two patients of the ICABG-group suffered long-term problems at the donor site (20%) (p = 0.146). Pain intensity were comparable in both groups (p = 0.326). However, patients treated with DBM were more satisfied with the surgical procedure (p = 0.031). Conclusion With the use of DBM, the costs for augmentation of the non-union-site are more expensive compared to ICABG (calculated difference: 160 €/case). Nevertheless, this study demonstrated that the application of DBM compared to ICABG led to an advanced outcome in the treatment of non-unions and simultaneously to a decreased quantity of adverse effects. Therefore we conclude that DBM should be offered as an alternative to ICABG, in particular to patients with elevated comorbidity and those with limited availability or reduced quality of autologous-bone graft material. Introductio

Nonparametric change point estimation for survival distributions with a partially constant hazard rate

We present a new method for estimating a change point in the hazard function of a survival distribution assuming a constant hazard rate after the change point and a decreasing hazard rate before the change point. Our method is based on fitting a stump regression to p-values for testing hazard rates in small time intervals. We present three real data examples describing survival patterns of severely ill patients, whose excess mortality rates are known to persist far beyond hospital discharge. For designing survival studies in these patients and for the definition of hospital performance metrics (e.g. mortality), it is essential to define adequate and objective end points. The reliable estimation of a change point will help researchers to identify such end points. By precisely knowing this change point, clinicians can distinguish between the acute phase with high hazard (time elapsed after admission and before the change point was reached), and the chronic phase (time elapsed after the change point) in which hazard is fairly constant. We show in an extensive simulation study that maximum likelihood estimation is not robust in this setting, and we evaluate our new estimation strategy including bootstrap confidence intervals and finite sample bias correction

Testing mechanical chest compression devices of different design for their suitability for prehospital patient transport - a simulator-based study

BACKGROUND Mechanical chest compression (mCPR) offers advantages during transport under cardiopulmonary resuscitation. Little is known how devices of different design perform en-route. Aim of the study was to measure performance of mCPR devices of different construction-design during ground-based pre-hospital transport. METHODS We tested animax mono (AM), autopulse (AP), corpuls cpr (CC) and LUCAS2 (L2). The route had 6 stages (transport on soft stretcher or gurney involving a stairwell, trips with turntable ladder, rescue basket and ambulance including loading/unloading). Stationary mCPR with the respective device served as control. A four-person team carried an intubated and bag-ventilated mannequin under mCPR to assess device-stability (displacement, pressure point correctness), compliance with 2015 ERC guideline criteria for high-quality chest compressions (frequency, proportion of recommended pressure depth and compression-ventilation ratio) and user satisfaction (by standardized questionnaire). RESULTS All devices performed comparable to stationary use. Displacement rates ranged from 83% (AM) to 11% (L2). Two incorrect pressure points occurred over 15,962 compressions (0.013%). Guideline-compliant pressure depth was > 90% in all devices. Electrically powered devices showed constant frequencies while muscle-powered AM showed more variability (median 100/min, interquartile range 9). Although physical effort of AM use was comparable (median 4.0 vs. 4.5 on visual scale up to 10), participants preferred electrical devices. CONCLUSION All devices showed good to very good performance although device-stability, guideline compliance and user satisfaction varied by design. Our results underline the importance to check stability and connection to patient under transport

Predictors of poor outcomes after significant chest trauma in multiply injured patients: a retrospective analysis from the German Trauma Registry (Trauma Register DGU (R))

Background: Blunt thoracic trauma is one of the critical injury mechanisms in multiply injured trauma victims. Although these patients present a plethora of potential structural damages to vital organs, it remains debated which injuries actually influence outcome and thereby should be addressed initially. Hence, the aim of this study was to identify the influence of critical structural damages on mortality. Methods: All patients in the database of the TraumaRegister DGU (R) (TR-DGU) from 2002-2011 with AIS Chest >= 2, blunt trauma, age of 16 or older and an ISS >= 16 were analyzed. Outcome parameters were in-hospital mortality as well as ventilation time in patients surviving the initial 14 days after trauma. Results: 22613 Patients were included (mean ISS 30.5 +/- 12.6; 74.7% male; Mean Age 46.1 +/- 197 years; mortality 17.5%; mean duration of ventilation 7.3 +/- 11.5; mean ICU stay 11.7 +/- 14.1 days). Only a limited number of specific injuries had a significant impact on survival. Major thoracic vessel injuries (AIS >= 5), bilateral lung contusion, bilateral flail chest, structural heart injury (AIS >= 3) significantly influence mortality in study patients. Several extrathoracic factors (age, blood transfusion, systolic blood pressure and extrathoracic severe injuries) were also predictive of increased mortality. Most injuries of the thoracic wall had no or only a moderate effect on the duration of ventilation. Injuries to the lung (laceration, contusion or pneumothoraces) had a moderate prolonging effect. Cardiac injuries and severe injuries to the thoracic vessels induced a substantially prolonged ventilation interval. Conclusions: We demonstrate quantitatively the influence of specific structural damages of the chest on critical outcome parameters. While most injuries of the chest wall have no or only limited impact in the study collective, injuries to the lung overall show adverse outcome. Injuries to the heart or thoracic vessels have a devastating prognosis following blunt chest trauma