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Hundreds of thousands of individuals who experience lasting sequelae after sepsis and infections in Germany do not receive optimal care. In this White Paper we present measures for improvement, which were developed by a multidisciplinary expect panel as part of the SEPFROK project. Improved care rests on four pillars: 1. cross-sectoral assessment of sequelae and a structured discharge and transition management, 2. interdisciplinary rehabilitation and aftercare with structural support, 3. strengthening the specific health literacy of patients and families, and 4. increased research into causes, prevention and treatment of sequelae. To achieve this, appropriate cross-sectoral care structures and legal frameworks must be created., Competing Interests: Die Autorinnen/Autoren geben an, dass kein Interessenkonflikt besteht., (Thieme. All rights reserved.)

Sepsis is characterized by a disproportionate host response to infection that often culminates in multiple organ failure. Current concepts invoke a deregulated immune reaction involving features of hyperinflammation, as well as protracted immune suppression. However, owing to the scarcity of human data, the precise origin of a long-term suppression of adaptive immunity remains doubtful. We report on an explorative clinical study of chronic critical illness (CCI) patients aimed at assessing the long-term consequences of sepsis on T cell function. Blood was drawn from 12 male CCI patients (median age 67 y, range 48-79 y) receiving continuous mechanical ventilation and renal replacement therapy in a long-term care hospital who had been treated in an external acute care hospital for severe sepsis. T cells were purified and subjected to flow cytometric immune-phenotyping and functional assays. We found that T cells from CCI patients featured higher basal levels of activation and stronger expression of the inhibitory surface receptor programmed cell death 1 compared with controls. However, T cells from CCI patients exhibited no suppressed TCR response at the level of proximal TCR signaling (activation/phosphorylation of PLCγ, Erk, Akt, LAT), activation marker upregulation (CD69, CD25, CD154, NUR77), IL-2 production, or clonal expansion. Rather, our data illustrate an augmented response in T cells from CCI patients in response to TCR/coreceptor (CD3/CD28) challenge. Thus, the present findings reveal that CCI sepsis patients feature signs of immune suppression but that their T cells exhibit a primed, rather than a suppressed, phenotype in their TCR response, arguing against a generalized T cell paralysis as a major cause of protracted immune suppression from sepsis., (Copyright © 2017 by The American Association of Immunologists, Inc.)

Oleanolic (OA) and ursolic acid (UA) are plant secondary metabolites with diverse pharmacological properties. To reach reasonable productivities with plant cell suspension cultures, elicitation is a widely used strategy. Within the presented work, the effects of different elicitors on growth and production of OA and UA in a Salvia fruticosa cell suspension culture were examined. Beside commonly used elicitors like jasmonic acid (JA) and yeast extract, the influence of medium filtrates of the endophytic fungi Aspergillus niger and Trichoderma virens was investigated. The best eliciting effects were achieved with JA and fungal medium filtrates. Both increased the triterpene content by approximately 70 %. Since JA showed significant growth inhibition, the volumetric triterpene yield did not increase. But, adding fungal filtrates increased the volumetric triterpene yield by approximately 70 % to 32.6 mgOA l(-1) and 65.9 mgUA l(-1) for T. virens compared to the control with 19.4 mgOA l(-1) and 33.3 mgUA l(-1). An elicitation strategy combining fungal medium filtrate of T. virens with sucrose feeding significantly enhanced cell dry weight concentration to 22.2 g l(-1) as well as triterpene content by approximately 140 %. In total, this led to an approximately 500 % increase of volumetric triterpene yield referring to the control with final values of 112.9 mgOA l(-1) and 210.4 mgUA l(-1). Despite the doubled cultivation duration, productivities of 6.7 mgOA l(-1) day(-1) and 12.4 mgUA l(-1) day(-1) were reached. These results demonstrate methods by which increased productivities of triterpenes can be achieved to attain yields competing with intact plants.

Background: The worldwide debate over the use of artificial nutrition and hydration remains controversial although the scientific and medical facts are unequivocal. Artificial nutrition and hydration are a medical intervention, requiring an indication, a therapeutic goal and the will (consent) of the competent patient., Methods: The guideline was developed by an international multidisciplinary working group based on the main aspects of the Guideline on "Ethical and Legal Aspects of Artificial Nutrition" published 2013 by the German Society for Nutritional Medicine (DGEM) after conducting a review of specific current literature. The text was extended and introduced a broader view in particular on the impact of culture and religion. The results were discussed at the ESPEN Congress in Lisbon 2015 and accepted in an online survey among ESPEN members., Results: The ESPEN Guideline on Ethical Aspects of Artificial Nutrition and Hydration is focused on the adult patient and provides a critical summary for physicians and caregivers. Special consideration is given to end of life issues and palliative medicine; to dementia and to specific situations like nursing care or the intensive care unit. The respect for autonomy is an important focus of the guideline as well as the careful wording to be used in the communication with patients and families. The other principles of Bioethics like beneficence, non-maleficence and justice are presented in the context of artificial nutrition and hydration. In this respect the withholding and withdrawing of artificial nutrition and/or hydration is discussed. Due to increasingly multicultural societies and the need for awareness of different values and beliefs an elaborated chapter is dedicated to cultural and religious issues and nutrition. Last but not least topics like voluntary refusal of nutrition and fluids, and forced feeding of competent persons (persons on hunger strike) is included in the guideline., (Copyright © 2016 Elsevier Ltd and European Society for Clinical Nutrition and Metabolism. All rights reserved.)

Objectives: To describe the time course of recovery of walking function and other activities of daily living in patients with intensive care unit (ICU)-acquired muscle weakness., Design: This is a cohort study., Participants: We included critically ill patients with ICU-acquired muscle weakness., Setting: Post-acute ICU and rehabilitation units in Germany., Measures: We measured walking function, muscle strength, activities in daily living, motor and cognitive function., Results: We recruited 150 patients (30% female) who fulfilled our inclusion and exclusion criteria. The primary outcome recovery of walking function was achieved after a median of 28.5 days (IQR=45) after rehabilitation onset and after a median of 81.5 days (IQR=64) after onset of illness. Our final multivariate model for recovery of walking function included two clinical variables from baseline: the Functional Status Score ICU (adjusted HR=1.07 (95% CI 1.03 to 1.12) and the ability to reach forward in cm (adjusted HR=1.02 (95% CI 1.00 to 1.04). All secondary outcomes but not pain improved significantly in the first 8 weeks after study onset., Conclusions: We found good recovery of walking function for most patients and described the recovery of walking function of people with ICU-acquired muscle weakness., Trials Registrations Number: Sächsische Landesärztekammer EK-BR-32/13-1; DRKS00007181, German Register of Clinical Trials., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/)

Objectives: To examine the frequency of acute stress disorder and posttraumatic stress disorder in chronically critically ill patients with a specific focus on severe sepsis, to classify different courses of stress disorders from 4 weeks to 6 months after transfer from acute care hospital to postacute rehabilitation, and to identify patients at risk by examining the relationship between clinical, demographic, and psychological variables and stress disorder symptoms., Design: Prospective longitudinal cohort study, three assessment times within 4 weeks, 3 months, and 6 months after transfer to postacute rehabilitation., Setting: Patients were consecutively enrolled in a large rehabilitation hospital (Clinic Bavaria, Kreischa, Germany) admitted for ventilator weaning from acute care hospitals., Patients: We included 90 patients with admission diagnosis critical illness polyneuropathy or critical illness myopathy with or without severe sepsis, age between 18 and 70 years with a length of ICU stay greater than 5 days., Interventions: None., Measurements and Main Results: Acute stress disorder and posttraumatic stress disorder were diagnosed according to the Diagnostic and Statistical Manual of Mental Disorders, 4th Edition, criteria by a trained and experienced clinical psychologist using a semistructured clinical interview for Diagnostic and Statistical Manual of Mental Disorders. We further administered the Acute Stress Disorder Scale and the Posttraumatic Symptom Scale-10 to assess symptoms of acute stress disorder and posttraumatic stress disorder. Three percent of the patients had an acute stress disorder diagnosis 4 weeks after transfer to postacute rehabilitation. Posttraumatic stress disorder was found in 7% of the patients at 3-month follow-up and in 12% after 6 months, respectively. Eighteen percent of the patients showed a delayed onset of posttraumatic stress disorder. Sepsis turned out to be a significant predictor of posttraumatic stress disorder symptoms at 3-month follow-up., Conclusions: A regular screening of post-ICU patients after discharge from hospital should be an integral part of aftercare management. The underlying mechanisms of severe sepsis in the development of posttraumatic stress disorder need further examination.

Introduction: Critical illness myopathy (CIM) and polyneuropathy (CIP) are common complications of critical illness that frequently occur together. Both cause so called intensive care unit (ICU)-acquired muscle weakness. This weakness of limb muscles increases morbidity and delay rehabilitation and recovery of walking ability. Although full recovery has been reported people with severe weakness may take months to improve walking. Focused physical rehabilitation of people with ICU-acquired muscle weakness is therefore of great importance. However, although physical rehabilitation is common, detailed knowledge about the pattern and the time course of recovery of walking function are not well understood. Therefore, the aim of the General Weakness Syndrome Therapy (GymNAST) study is to describe the time course of recovery of walking function and other activities of daily living in these patients., Methods and Analysis: We conduct a prospective cohort study of people with ICU-acquired muscle weakness with defined diagnosis of CIM or CIP. Based on our sample size calculation, approximately 150 patients will be recruited from the ICU of our hospital in Germany. Amount and content of physical rehabilitation, clinical tests for example, muscle strength and motor function and neuropsychological assessments will be used as independent variables. The primary outcomes will include recovery of walking function and mobility. Secondary outcomes will include global motor function, activities in daily life and participation., Ethics and Dissemination: The study is being carried out in agreement with the Declaration of Helsinki and conducted with the approval of the local medical Ethics Committee (Landesärztekammer Sachsen, Germany, reference number EK-BR-32/13-1) and with the understanding and written consent of each patient's guardian. The results of this study will be published in peer-reviewed journals and disseminated to the medical society and general public., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.)

Background: A significant proportion of patients with long-term mechanical ventilation (MV) and difficult or prolonged weaning suffer from primary or secondary neurological conditions and concomitant functional disorders, in addition to respiratory problems. Therefore, these patients are treated in neurological weaning departments., Material and Methods: Using a questionnaire members of the German Working Group for early neurorehabilitation were interviewed with respect to the structure of weaning facilities, weaning strategies, patient characteristics and treatment outcome of patients admitted for weaning in 2009., Results: In the year 2009 a total of 1,486 patients were admitted to 7 participating neurological weaning units. The primary diagnosis was a neurological condition in 97.5% of the patients. In 62.9% of the patients the neurological condition was considered to be primarily responsible for the MV, 22.8% demonstrated pulmonary factors and for 3.0% a cardiac condition was determined to be decisive. In 5.0% of the patients it was not possible to ascertain a single cause or factor. Weaning was successful in 69.8% of all cases, 64.9% (965 patients) were released from the facility without MV, 274 patients (18.4%) were released with MV, 61.3% of these (168 patients) were referred to other rehabilitation facilities or into the care of the family physician and 38.7% (106 patients) were transferred to other hospitals due to special medical problems. The total mortality rate was 16.6% (247 patients deceased)., Conclusions: In this first comprehensive evaluation of German neurological weaning centers for patients with long-term MV, structures and treatment outcomes were compared with recent results from the literature.

Improvement in prolongation and quality of life has been made possible by medical progress, but life for the patient can become ever more dependent on artificial support and death may be prolonged in unwanted ways. The choice between prolongation of life, quality of life and the abatement of suffering is of great importance in decisions on the continuation or cessation of dialysis and is naturally a process of weighing different positions. This process requires not only medical decision-making but also a structure for the organization of communication between all involved parties. Only thus is it possible to reach a satisfactory resolution to such a situation, a resolution that shows medical responsibility on the part of the physician and one that can be borne by all those involved.

Even with highly developed ultrasound systems, diagnosis of deep leg vein thrombosis is difficult in lower leg veins and in the area of the adductor channel. In order to evaluate color duplex-sonography, contrast media duplex-sonography and phlebography in comparison, 79 patients (38 men and 40 women aged 54 to 89) with deep leg vein thrombosis were examined. As a result, patients suffering from thrombosis were characterized by a vein-artery quotient of > 2.0 (p < 0.01). In color Doppler duplex-sonography false negative findings occurred in 12 cases of lower leg vein thrombosis and in 3 cases of thrombosis within the adductor channel. By contrast media duplex-sonography the diagnostic reliability could be increased to a sensitivity of over 95 per cent.

Thirty patients (12 men and 4 women over 60, and 8 men and 6 women under 60 years) with angiographically intact brain vessels were examined by intracranial Duplex Sonography. The flow velocity within the Arteria cerebri media was found to show normal values. In order to examine the connection between the degree of seriousness of a one-sided internal carotid stenosis and the resulting flow velocity in both medial cerebral arteries, 74 patients (36 over and 38 under 60 years) with temporary neurologic deficits or transitory ischemic attacks were examined. One to three weeks after angiography, intracranial Duplex Sonography was carried out. The group of patients over 60 years with a one-sided 50 percent internal carotid stenosis showed significantly lower maximum low velocity values of the homolateral Arteria cerebri media in comparison with the control group. The group of patients under 60 years also presented with significantly lower flow velocity values of the homolateral A. cerebri media, but only in the cases with filiform stenoses or occlusions. The advantages and disadvantages of this ultrasound method are discusses.

72 patients at the age of 44 to 76 years with transitory ischaemic attacks which happened and for a short time reversible deficits, respectively, were diagnosed both conventionally duplex-sonographically and with the colour-coded duplex sonography under the question of vascular stenotic process in the region of the cervical vessels. After the ultrasound examination within two weeks an angiography was performed. As a result was shown that in 10 patients with an angiogram without pathological findings by means of the colour-coded duplex sonography in 3 cases plaque formations could be proved which could be clearly diagnosed only by colour marking.