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Background Peritonitis is responsible for thousands of deaths annually in Germany alone. Even source control (SC) and antibiotic treatment often fail to prevent severe sepsis or septic shock, and this situation has hardly improved in the past two decades. Most experimental immunomodulatory therapeutics for sepsis have been aimed at blocking or dampening a specific pro-inflammatory immunological mediator. However, the patient collective is large and heterogeneous. There are therefore grounds for investigating the possibility of developing personalized therapies by classifying patients into groups according to biomarkers. This study aims to combine an assessment of the efficacy of treatment with a preparation of human immunoglobulins G, A, and M (IgGAM) with individual status of various biomarkers (immunoglobulin level, procalcitonin, interleukin 6, antigen D-related human leucocyte antigen (HLA-DR), transcription factor NF-κB1, adrenomedullin, and pathogen spectrum). Methods/design A total of 200 patients with sepsis or septic shock will receive standard-of-care treatment (SoC). Of these, 133 patients (selected by 1:2 randomization) will in addition receive infusions of IgGAM for 5 days. All patients will be followed for approximately 90 days and assessed by the multiple-organ failure (MOF) score, by the EQ QLQ 5D quality-of-life scale, and by measurement of vital signs, biomarkers (as above), and survival. Discussion This study is intended to provide further information on the efficacy and safety of treatment with IgGAM and to offer the possibility of correlating these with the biomarkers to be studied. Specifically, it will test (at a descriptive level) the hypothesis that patients receiving IgGAM who have higher inflammation status (IL-6) and poorer immune status (low HLA-DR, low immunoglobulin levels) have a better outcome than patients who do not receive IgGAM. It is expected to provide information that will help to close the knowledge gap concerning the association between the effect of IgGAM and the presence of various biomarkers, thus possibly opening the way to a personalized medicine. Trial registration EudraCT, 2016–001788-34; ClinicalTrials.gov, NCT03334006. Registered on 17 Nov 2017. Trial sponsor: RWTH Aachen University, represented by the Center for Translational & Clinical Research Aachen (contact Dr. S. Isfort). Electronic supplementary material The online version of this article (10.1186/s13063-019-3244-4) contains supplementary material, which is available to authorized users.

Background and objectives The painDETECT questionnaire (PD-Q), a simple and reliable screening questionnaire of neuropathic pain, was developed in 2004 in cooperation with the German Research Network on Neuropathic Pain. The initial aim was to implement quality management and to improve the situation of neuropathic pain (NeP) patients in Germany. The PD-Q proved immediately successful and was translated into and validated in multiple languages. Subsequently a comprehensive electronic system (PD) comprising various validated questionnaires with regard to pain typical comorbidities, such as function, sleep, mood or anxiety, was implemented Germany wide. We aimed to provide a comprehensive overview about the development and validation as well as the application of the PD-Q in various clinical conditions. Methods This overview is based on a literature search on English full-text papers using the term 'painDETECT' in Medline and PubMed covering the time period from 2006 to September 2015, amended with further publications cited in the retrieved publications or provided by the questionnaire developers. Results PD-Q as screening tool for NeP described in patients with lower back pain (8 studies), rheumatoid arthritis and osteoarthritis (10), thoracotomy (2 studies), tumor diseases (4 studies), fibromyalgia (4 studies), diverse musculoskeletal conditions (12 studies) and diverse other conditions (10 studies). In addition, the PD-Q was used in 9 studies that investigated the effect of drugs for the treatment of patients with a NeP component. Conclusion To date more than 300,000 patients were assessed, providing the basis for one of the world's largest datasets for chronic pain. Among others the extensive pool of PD-Q data triggered the idea of subgrouping patients on the basis of their individual sensory profiles which might in the future lead to a stratified treatment approach and ultimately to personalized therapy. Started as a healthcare utilization project in Germany, the PD-Q is nowadays used for clinical and research purposes around the world.

PainDETECT (PD-Q) is a patient reported screening questionnaire to identify patients with neuropathic pain based on questions regarding typically sensory symptoms of neuropathic pain. The aim of the present investigation was to assess the test-retest stability of pain descriptors of the PD-Q within a time window of 1-3 weeks.Data sets of 74 chronic pain patients sampled in an open pain register at two visits were analyzed and compared. Patients with change of pain localization between visits were excluded from analysis. Beside conventional measures (Pearson correlation coefficient r, intraclass correlation coefficient ICC, kappa), also calculated measures known from method comparison were used.The mean duration between visits was 15 days. The measures were in the range of r = 0.72-0.86, ICC = 0.71-0.86, and kappa = 0.62-0.72 for PD-Q pain descriptors (burning, prickling, mechanical allodynia, pain attacks, thermal hyperalgesia, numbness, pressure induced pain).The individual PD-Q pain descriptors showed accurate test-retest stability as a prerequisite for use in repeated measurements (e. g. post baseline or follow up data) in clinical trials.

Patients with neuropathic pain syndromes are heterogeneous. They present with a variety of sensory symptoms and pain qualities. The knowledge of these data and etiology-specific differences is important to optimize clinical trial design and to develop more effective drugs. This investigation uses epidemiological and clinical data on the symptomatology of 2100 patients with painful diabetic neuropathy (DPN) and postherpetic neuralgia (PHN) from a cross-sectional survey (painDETECT) to (1) describe characteristic epidemiological differences, (2) analyse typical patterns of sensory symptoms in both cohorts and (3) determine whether questionnaires can capture these characteristics. PHN patients suffer more often from clinically relevant sensory disturbances although the average pain intensity is only marginally higher. This difference is particularly obvious with dynamic mechanical allodynia which is present in half of the PHN patients and in 18% of the DPN patients. Thermal hyperalgesia occurs twice as often in PHN. Numbness is described more often in DPN. Age has no influence on sensory symptoms in both entities. A hierarchical cluster analysis revealed five distinct subgroups of patients showing a characteristic sensory profile, a typical constellation and combination of neuropathic symptoms. All subgroups occur in relevant numbers in both entities but the frequencies differ between PHN and DPN. Since sensory symptoms likely translate into pain-generating mechanisms enrichment for potential treatment responders might be possible in clinical trials by assessing the sensory profiles. Patient-Reported Outcomes can be used to obtain a precise sensory characterization of each patient.

Nociceptive and neuropathic components both contribute to pain. Since these components require different pain management strategies, correct pain diagnosis before and during treatment is highly desirable. As low back pain (LBP) patients constitute an important subgroup of chronic pain patients, we addressed the following issues: (i) to establish a simple, validated screening tool to detect neuropathic pain (NeP) components in chronic LBP patients, (ii) to determine the prevalence of neuropathic pain components in LBP in a large-scale survey, and (iii) to determine whether LBP patients with an NeP component suffer from worse, or different, co-morbidities.In co-operation with the German Research Network on Neuropathic Pain we developed and validated the painDETECT questionnaire (PD-Q) in a prospective, multicentre study and subsequently applied it to approximately 8000 LBP patients.The PD-Q is a reliable screening tool with high sensitivity, specificity and positive predictive accuracy; these were 84% in a palm-top computerised version and 85%, 80% and 83%, respectively, in a corresponding pencil-and-paper questionnaire. In an unselected cohort of chronic LBP patients, 37% were found to have predominantly neuropathic pain. Patients with NeP showed higher ratings of pain intensity, with more (and more severe) co-morbidities such as depression, panic/anxiety and sleep disorders. This also affected functionality and use of health-care resources. On the basis of given prevalence of LBP in the general population, we calculated that 14.5% of all female and 11.4% of all male Germans suffer from LBP with a predominant neuropathic pain component.Simple, patient-based, easy-to-use screening questionnaires can determine the prevalence of neuropathic pain components both in individual LBP patients and in heterogeneous cohorts of such patients. Since NeP correlates with more intense pain, more severe co-morbidity and poorer quality of life, accurate diagnosis is a milestone in choosing appropriate therapy.

Axial low back pain can be considered as a syndrome with both nociceptive and neuropathic pain components (mixed-pain). Especially neuropathic pain comprises a therapeutic challenge in practical experience and may explain why pharmacotherapy in back pain is often disappointing for both the patient and the therapist. This survey uses epidemiological and clinical data on the symptomatology of 1083 patients with axial low back pain from a cross sectional survey (painDETECT). Objectives were (1) to estimate whether neuropathic pain contributes to axial low back pain and if so to what extent. (2) To detect subgroups of patients with typical sensory symptom profiles and to analyse their demographic data and co-morbidities. (3) To compare patients with and without prior intervertebral disc surgery (IVD). Neuropathic pain components could be detected in 12% of the entire cohort. Cluster analyses of these patients revealed five distinct subgroups of patients showing a characteristic sensory profile, i.e. a typical constellation and combination of symptoms. All subgroups occurred in relevant numbers and some showed distinct neuropathic characteristics while others showed nociceptive features. Post-IVD-surgery patients showed a tendency to score more "neuropathic" than patients without surgery (not statistically significant). Axial low back pain has a high prevalence of co-morbidities with implication on therapeutic aspects. From these data it can be concluded that sensory profiles based on descriptor severity may serve as a better predictor for therapy assessment than pain intensity or sole diagnosis alone. Standardized phenotyping of pain symptoms with easy tools may help to develop an individualized therapy leading to a higher success rate in pharmacotherapy of axial low back pain.

The mechanism of thermally mediated CO insertion into vinylcyclopropanes by Fe(CO) 5 has been studied using deuterium labelled starting materials. The broad distribution of deuterium in the enone products suggests formation of an intermediate iron π-allyl hydride complex that is capable of internal deuterium delivery to several positions. The mechanistic differences between thermal and photoinduced CO insertion into vinylcyclopropanes are discussed.

Background Patients with diabetic neuropathy (DPN) and fibromyalgia differ substantially in pathogenetic factors and the spatial distribution of the perceived pain. We questioned whether, despite these obvious differences, similar abnormal sensory complaints and pain qualities exist in both entities. We hypothesized that similar sensory symptoms might be associated with similar mechanisms of pain generation. The aims were (1) to compare epidemiological features and co-morbidities and (2) to identify similarities and differences of sensory symptoms in both entities. Methods The present multi-center study compares epidemiological data and sensory symptoms of a large cohort of 1434 fibromyalgia patients and 1623 patients with painful diabetic neuropathy. Data acquisition included standard demographic questions and self-report questionnaires (MOS sleep scale, PHQ-9, PainDETECT). To identify subgroups of patients with characteristic combinations of symptoms (sensory profiles) a cluster analysis was performed using all patients in both cohorts. Results Significant differences in co-morbidities (depression, sleep disturbance) were found between both disorders. Patients of both aetiologies chose very similar descriptors to characterize their sensory perceptions. Burning pain, prickling and touch-evoked allodynia were present in the same frequency. Five subgroups with distinct symptom profiles could be detected. Two of the subgroups were characteristic for fibromyalgia whereas one profile occurred predominantly in DPN patients. Two profiles were found frequently in patients of both entities (20-35%). Conclusions DPN and fibromyalgia patients experience very similar sensory phenomena. The combination of sensory symptoms - the sensory profile - is in most cases distinct and almost unique for each one of the two entities indicating aetiology-specific mechanisms of symptom generation. Beside the unique aetiology-specific sensory profiles an overlap of sensory profiles can be found in 20-35% of patients of both aetiologies.

The cyclic vinylcyclopropane 6a reacts at elevated temperatures with iron pentacarbonyl to selectively give the enone 7a in 52% yield. Reducing the reaction time provided the isomeric ketones 7a–b. Partial chromatographic separation of this mixture allowed the complete spectroscopic identification of 7b by 1H NMR. The structure of 7c was determined from selected spectral data of the mixture of 7a and 7c. For comparison, the methyl substituted derivate 6b was subjected to a carbonylation under the above conditions exclusively providing 8 ini 42% yield. A mechanistic rationale for the two different modes of ring opening is presented.

Objectives. Patients with FM are heterogeneous. They present with a variety of pain qualities, sensory abnormalities and additional comorbidities. The aim was to identify clinically distinguishable subgroups of patients. Methods. This investigation uses epidemiological and clinical data of 3035 FM patients from a cross-sectional survey (painDETECT) to (i) describe characteristic epidemiological data and comorbidities and (ii) detect subgroups of patients with typical patterns of sensory symptoms and comorbidities. Results. Clinically relevant sensory abnormalities (strongly, very strongly present) included pressure pain (58%), prickling (33%), burning (30%) and thermal hypersensitivity (24%). Pain attacks were complained by 40% of patients. Moderate to severe comorbid depression occurred in 66% of patients. Only 30% of the patients had optimal sleep. A hierarchical cluster analysis using descriptors of sensory abnormalities as well as the extent of comorbidities revealed five distinct subgroups of patients showing a characteristic clinical profile. Four subgroups of patients suffer from severe sensory disturbances in various combinations but lack pronounced comorbidities. In one subgroup, however, severe comorbidities dominate the clinical picture. Differences in pathophysiological mechanisms of pain generation can be attributed to each subgroup. Conclusions. The results of this study indicate that FM patients can be classified on the basis of their sensory symptoms and comorbidities by the use of a patient-reported questionnaire. Subgrouping of patients with FM may be used for future research and to tailor optimal treatment strategies for the appropriate patient.

Background: Although there is increasing knowledge of the prevalence of neuropathic pain, little has been done to isolate the cost of neuropathic pain, especially with reference to the frequent complaint of back pain.Aims: To estimate the prevalence of neuropathic components in back pain and associated costs. Methods: We used available epidemiological data to model the prevalence of neuropathic back pain in the general adult population, combining three studies: painDETECT 1, painDETECT 2, and the German back pain research network (GBPRN) study, representing a total of 21,047 subjects. The painDETECT screening questionnaire was used in the former two surveys to assess neuropathic pain components. Costing data were obtained from 1718 participants in the GBPRN survey. Results: According to our model, approximately 4% of the general adult population experienced back pain with a neuropathic component. Owing to the greater severity of neuropathic pain, its costs were found to be disproportionately high: among patients with persistent back pain, typical costs associated with a person suffering neuropathic back pain were higher than those of an average back pain patient, and as much as 67% higher than those of a patient with nociceptive back pain only. Approximately, 16% of the total costs associated with back pain were attributable to pain with a neuropathic component. Conclusions: Back pain with neuropathic components is likely to affect a relevant proportion of the general adult population and cause a disproportionately high share of back pain-related costs. (C) 2009 Published by Elsevier Ltd. on behalf of European Federation of International Association for the Study of Pain Chapters.

Following the recent introduction of hand-held computers to be used by patients instead of conventional pencil-and-paper questionnaires, a validation study under 'real-life' conditions was conducted, in order to compare these two clinical instruments when used by chronic pain patients to describe their pain using visual and numerical rating scales.Each of 200 chronic pain patients attending a single physician's practice was given two pain questionnaires to complete, one on paper and one on a hand-held computer; completion of these took place directly before and after consultation, in randomised order. The questions asked in the two questionnaires were identical: present pain, average pain, worst pain and those of the painDETECT questionnaire (the latter distinguishes characteristic symptoms of nociceptive pain). In accordance with standard practice, the paper questionnaire used numerical rating scales and the electronic one employed visual analogue scales, with or without a numerical indicator.Nearly all patients (99%) of the study population (58% female; aged 57+/-14 years) completed both questionnaires. In spite of the expected substantial intra-individual scatter, overall results from the two questionnaire types were highly consistent. Only a few differences of potential statistical significance (p5%) were observed, and none were found that would have led to different interpretations. No difference was seen between results from the electronic visual analogue scales with and without a numerical indicator.Under conditions of routine clinical practice, the hand-held computer questionnaire can give results equivalent to those obtained with the conventional paper questionnaire.

OBJECTIVE: Chronic back pain is characterized by a combination of neuropathic and nociceptive mechanisms of pain generation. The prevalence of the neuropathic pain component is unknown. Thus, in the context of an explorative study, we aimed to determine the prevalence of signs and symptoms indicating neuropathic pain in adult patients treated by orthopaedists. We also aimed to assess the usefulness of handheld computers (PDAs) in data collection. METHODS: Prospective epidemiological study in 18 orthopaedic practices or centres throughout Germany. Physician and patient questionnaires (paper/pencil or on handheld computers, PDAs) for patients with back pain of at least 3 months in duration were applied, as well as the von Korff score to assess pain intensity (visual analogue scale, VAS; 0 = no pain, 10 = worst possible pain) and pain characteristics, the Hannover Functional Ability Questionnaire (FFbH-R), and if patients agreed to provide information, the short-form Patient Health Questionnaire (PHQ-D) for depression. RESULTS: For 717 patients, both patient and physician questionnaires were available. Mean patient age was 56 years; pain was predominantly located in the low back (87%). Median current pain intensity on the VAS was 5.0. Confirmed key signs and symptoms indicated neuropathic pain was frequent, e.g. radicular pain radiating beyond the knee towards the foot (40.0%), positive Lasegue sign (18.4%), or absent patellar reflex (17.3%). A third of all patients (33.5%) had >or=3 characteristic signs for neuropathic pain. Patient functionality was severely reduced (median 43.3%). There were no relevant differences in outcomes between patients using the paper/pencil method (47%) versus those preferring PDAs (53%). CONCLUSION: Screening for neuropathic pain in this setting is feasible with simple questionnaires and scales on PDAs. Neuropathic pain is a major contributor to chronic back pain and a frequent component in patients seen by orthopaedists. At least one third of all patients should undergo additional diagnostic measures to confirm the cause of neuropathic pain

The cyclic vinylcyclopropane 6a reacts at elevated temperatures with iron pentacarbonyl to selectively give the enone 7a in 52% yield. Reducing the reaction time provided the isomeric ketones 7a–b. Partial chromatographic separation of this mixture allowed the complete spectroscopic identification of 7b by 1H NMR. The structure of 7c was determined from selected spectral data of the mixture of 7a and 7c. For comparison, the methyl substituted derivate 6b was subjected to a carbonylation under the above conditions exclusively providing 8 ini 42% yield. A mechanistic rationale for the two different modes of ring opening is presented.

Patients with neuropathic pain syndromes are heterogeneous. They present with a variety of sensory symptoms and pain qualities. The knowledge of these data and etiology-specific differences is important to optimize clinical trial design and to develop more effective drugs. This investigation uses epidemiological and clinical data on the symptomatology of 2100 patients with painful diabetic neuropathy (DPN) and postherpetic neuralgia (PHN) from a cross-sectional survey (painDETECT) to (1) describe characteristic epidemiological differences, (2) analyse typical patterns of sensory symptoms in both cohorts and (3) determine whether questionnaires can capture these characteristics. PHN patients suffer more often from clinically relevant sensory disturbances although the average pain intensity is only marginally higher. This difference is particularly obvious with dynamic mechanical allodynia which is present in half of the PHN patients and in 18% of the DPN patients. Thermal hyperalgesia occurs twice as often inPHN. Numbness is described more often in DPN. Age has no influence on sensory symptoms in both entities. A hierarchical cluster analysis revealed five distinct subgroups of patients showing a characteristic sensory profile, a typical constellation and combination of neuropathic symptoms. All subgroups occur in relevant numbers in both entities but the frequencies differ between PHN and DPN. Since sensory symptoms likely translate into pain-generating mechanisms enrichment for potential treatment responders might be possible in clinical trials by assessing the sensory profiles. Patient-Reported Outcomes can be used to obtain a precise sensory characterization of each patient.

The response of a variety of vinylcyclopropanes, bearing an ester group in the β-position, upon expose to pentacarbonyl iron at elevated temperatures is established. Dienic esters with a single configuration of the double bonds are obtained by this route in high yield. Steric and electronic factors, governing the course of the reactions, were investigated using nitrile and alkyl substituted vinylcyclopropanes.