Human biomonitoring of deoxynivalenol (DON) - Assessment of the exposure of young German adults from 1996 - 2021.

The mycotoxin deoxynivalenol (DON) is a frequently found contaminant in cereals and cereal-based products. As a German contribution to the European Joint Programme HBM4EU, we analysed the total DON concentration (tDON) in 24-h urine samples from the German Environmental Specimen Bank (ESB). In total, 360 samples collected in 1996, 2001, 2006, 2011, 2016, and 2021 from young adults in Muenster (Germany), were measured by high performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) after enzymatic deconjugation of the glucuronide metabolites. tDON was found in concentrations above the lower limit of quantification (0.3 µg/L) in 99% of the samples. Medians of the measured concentrations and the daily excretion were 4.3 µg/L and 7.9 µg/24 h, respectively. For only nine participants, urinary tDON concentrations exceeded the provisional Human biomonitoring guidance value (HBM GV) of 23 µg/L. Urinary tDON concentrations were significantly higher for male participants. However, 24-h excretion values normalized to the participant's body weight did not exhibit any significant difference between males and females and the magnitude remained unchanged over the sampling years with exception of the sampling year 2001. Daily intakes were estimated from excretion values. Exceedance of the tolerable daily intake (TDI) of 1 µg/kg bw per day was observed for less than 1% of all participants. TDI exceedances were only present in the sampling year 2001 and not in more recent sampling years while exceedance of the HBM guidance value was also observed in 2011 and 2021.

Determination of trace elements in urine by inductively coupled plasma-tandem mass spectrometry - Biomonitoring of adults in the German capital region.

A method was developed and validated for multi-element analyses of human urine samples using inductively coupled plasma-tandem mass spectrometry. The combination of a simple sample preparation and the state-of-the-art technique allows high-throughput and lowest limits of quantification up to 1 ng/L. Thereby coefficients of variation ranges from 0.4% (V) to 3.7% (Be), and 0.9% (Cd) to 4.8% (Ni) for intraday and interday precision, respectively. The method's performance is demonstrated by successful participation in international interlaboratory comparison programs as external quality assurance. Moreover, the method was applied for the analysis of first-morning void urine samples of adults (N = 77) living in the German capital region. 15 metals and metalloids (Astotal, Be, Bi, Cd, Co, Cr, In, Mn, Mo, Ni, Pb, Sn, Tl, V, and Zn) were determined. With exception of indium, all elements were found in urine samples above the limit of quantification, demonstrating the suitability to measure the general population's exposure to these metals and metalloids. The method presented here shall be used for analysis of urine samples collected in the upcoming German Environmental Survey, GerES VI, a cross-sectional, population-representative study.

Biomonitoring as an Underused Exposure Assessment Tool in Occupational Safety and Health Context-Challenges and Way Forward.

Recent advances in analytical chemistry have allowed a greater possibility of using quantitative approaches for measuring human exposure to chemicals. One of these approaches is biomonitoring (BM), which provides unequivocal evidence that both exposure and uptake of a chemical have taken place. BM has been a longstanding practice in occupational health for several reasons. BM integrates exposure from all routes. It can help identify unintentional and unexpected exposures and assess the effectiveness of existing risk-management measures. BM also provides relevant information to support policy development by delivering better evidence of workers' exposure to chemical substances, even within the framework of the present regulations. Thus, BM can allow for both the evaluation of the impact of regulation and identification of further needs for new or improved regulation. However, despite all these well-recognized advantages, BM is currently an underused exposure assessment tool. This paper provides an overview of the key aspects to be considered when using BM in the context of occupational health interventions. Additionally, this paper describes the potential of BM as an exposure assessment tool, distinguishing the role of BM in exposure assessment and health surveillance and clarifies ethical and communication aspects to guarantee that general data protection regulations are followed. In addition, actions and research needs are identified (particularly with reference to the European situation), which aim to encourage the increased use of BM as an exposure assessment tool.

Calculated initial parenteral treatment of bacterial infections: Skin and soft tissue infections.

This is the ninth chapter of the guideline "Calculated Parenteral Initial Therapy of Adult Bacterial Disorders - Update 2018" in the 2nd updated version. The German guideline by the Paul-Ehrlich-Gesellschaft für Chemotherapie e.V. (PEG) has been translated to address an international audience. The chapter contains the first German S2k guidelines for bacterial skin and soft tissue infections. They encompass recommendations on diagnosis and treatment of the defined entities erysipelas (caused by beta-hämolytic streptococci), limited superficial cellulitis (S. aureus), severe cellulitis, abscess, complicated skin and soft tissue infections, infections of feet in diabetic patients ("diabetic foot"), necrotizing soft tissue infection and bite injuries.

Calculated parenteral initial treatment of bacterial infections: Intra-abdominal infections.

This is the seventh chapter of the guideline "Calculated initial parenteral treatment of bacterial infections in adults - update 2018" in the 2nd updated version. The German guideline by the Paul-Ehrlich-Gesellschaft für Chemotherapie e.V. (PEG) has been translated to address an international audience. The chapter deals with the empirical and targeted antimicrobial therapy of complicated intra-abdominal infections. It includes recommendations for antibacterial and antifungal treatment.

Personalized medicine with IgGAM compared with standard of care for treatment of peritonitis after infectious source control (the PEPPER trial): study protocol for a randomized controlled trial.

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).

S2k guidelines for skin and soft tissue infections Excerpts from the S2k guidelines for "calculated initial parenteral treatment of bacterial infections in adults - update 2018".

These first German S2k guidelines for bacterial skin and soft tissue infections were developed as one chapter of the recommendations for "calculated initial parenteral treatment of bacterial infections" issued under the auspices of the Paul-Ehrlich Society, of which the main part is presented here. Well-calculated antibiotic therapies require precise diagnostic criteria. Erysipelas is defined as non-purulent infection considered to be caused by beta-hemolytic strepto-cocci. It is diagnosed clinically by its bright-red erythema and early fever or chills at disease onset. Penicillin is the treatment of choice. Limited soft tissue infection (cellulitis) is usually caused by Staphylococcus (S.) aureus, frequently originates from chronic wounds and presents with a more violaceous-red hue and only rarely with initial fever or chills. Treatment consists of first- or second--generation cephalosporins or flucloxacillin (IV). Severe cellulitis is a purulent, partially necrotic infection which extends through tissue boundaries to fascias and requires surgical management in addition to antibiotics. Moreover, it frequently fulfills the criteria for "complicated soft tissue infections", as previously defined by the Food and Drug Administration for use in clinical trials (they include comorbidities such as uncontrolled diabetes, peripheral artery disease, neutropenia). It requires antibiotics which besides S. aureus target anaerobic and/or gramnegative bacteria. The rare so-called necrotizing skin and soft tissue infections represent a distinct entity. They are characterized by rapid, life-threatening progression due to special bacterial toxins that cause ischemic necrosis and shock and need rapid and thorough debridement in addition to appropriate antibiotics. For cutaneous abscesses the first-line treatment is adequate drainage. Additional antibiotic therapy is required only under certain circumstances (e.g., involvement of the face, hands, or anogenital region, or if drainage is somehow complicated). The present guidelines also contain consensus-based recommendations for higher doses of antibiotics than those approved or usually given in clinical trials. The goal is to deliver rational antibiotic treatment that is both effective and well-tolerated and that exerts no unnecessary selection pressure in terms of multidrug resistance.

[Antiembolic Stockings - Great Effects in Edoxaban Approval Studies]. / Medizinische Thromboseprophylaxestrümpfe ­ große Wirkung in Zulassungsstudien von Edoxaban.

In this age of evidence-based medicine, the use of medical thrombosis prophylaxis stockings (AES) as a physical strategy for the prevention of lower limb venous thrombosis has been questioned. The current German S3 guidelines even state that their non-application is, in the vast majority of cases, explicitly covered by the recommendations of this guideline. Low molecular weight heparins (NMH) and direct oral anticoagulants (DOAK) have received approval for thrombosis prophylaxis in elective knee and hip joint replacement, but the use of AES is absent from these approval studies. The results of the additional effects of the AES in the approval studies of Edoxaban were published for the first time. According to these results, the incidence of venous thromboembolism was 6.0% when AES were worn and 13.0% when AES were not worn. Since the approval studies of NMH and the DOAKs did not control for the use of AES, the impact of AES on the overall results remains unclear. Therefore the study results are only valid in the context of the general application of AES. Guidelines commissions should take this into account in their recommendations.

Survival of diabetes patients with major amputation is comparable to malignant disease.

INTRODUCTION: Almost all studies on diabetic foot syndrome focused on prevention of amputation and did not investigate long-term prognosis and survival of patients as a primary outcome parameter. METHODS: We did a retrospective cohort study including 314 patients who had diabetic foot syndrome and underwent amputation between December 1995 and January 2001. RESULTS: A total of 48% of patients received minor amputation (group I), 15% only major amputation (group II) and 36% initially underwent a minor amputation that was followed by a major amputation (group III). Statistically significant differences were observed in comparison of the median survival of group I to group II (51 vs. 40 months; p = 0.016) and of group II to group III (40 vs. 55 months; p = 0.003). DISCUSSION: The prognosis of patients with major amputation due to diabetic foot syndrome is comparable to patients with malignant diseases. Vascular interventions did not improve the individual prognosis of patients.

Laparoscopic Pylorus- and Spleen-Preserving Duodenopancreatectomy for a Multifocal Neuroendocrine Tumor.

BACKGROUND: In contrast to laparoscopic left pancreatic resection, laparoscopic total duodenopancreatectomy is a procedure that has not been standardized until now. It is not only the complexity that limits such a procedure but also its rare indication. The following article demonstrates the technical aspects of laparoscopic pylorus- and spleen-preserving duodenopancreatectomy. CASE REPORT: The indication for intervention in the underlying case was a patient diagnosed with a multiple endocrine neoplasia (MEN) I syndrome and a multifocal neuroendocrine tumor (NET) infiltrating the duodenum and the pancreas. The patient was post median laparotomy which was necessary after jejunal perforation due to a peptic ulcer. The resection was carried out entirely laparoscopically, and the reconstruction, which included a biliodigestive anastomosis and a gastroenterostomy, was carried out by means of a median upper abdomen laparotomy of 7 cm in length through which the resected specimen was also removed. The total operative time was 391 min. The blood loss accounted for 250 ml. The postoperative course was uneventful, and the patient was discharged on the eighth postoperative day. CONCLUSION: Laparoscopic pancreatectomy is a treatment option in carefully selected indications. The complexity of the operation demands a high level of expertise in the surgical team.

Spontaneous and non-spontaneous bleeding complications in patients with oral vitamin K antagonist therapy.

PURPOSE: The aim of the study was to evaluate potential differences between patients with spontaneous and non-spontaneous bleeding episodes during treatment with vitamin K antagonists which mainly resulted in compartment syndromes. METHODS: The population in this study comprised 116 patients who suffered at least one bleeding complication which required surgical treatment during therapy with an oral vitamin K antagonist. The patients were treated between September 2001 and July 2008. RESULTS: Significant differences were observed between the two patient groups with regard to the presence of renal failure, arterial hypertension, and diabetes mellitus, which occurred more frequently in patients with spontaneous bleeding. Also, significantly more patients with spontaneous bleedings developed compartment syndrome that needed emergency operation. Overall mortality was 9.6 %, was associated with multiorgan failure in all patients, and was not different between the two patient groups. CONCLUSIONS: The identification of high-risk patients before treatment with an oral vitamin K antagonist is of major importance. The existence of over-anticoagulation syndrome and compartment syndrome is associated with significant mortality and morbidity and should not be underestimated.

Nontypeable Haemophilus Influenzae Infection Upregulates the NLRP3 Inflammasome and Leads to Caspase-1-Dependent Secretion of Interleukin-1ß - A Possible Pathway of Exacerbations in COPD.

RATIONALE: Nontypeable Haemophilus influenzae (NTHi) is the most common cause for bacterial exacerbations in chronic obstructive pulmonary disease (COPD). Recent investigations suggest the participation of the inflammasome in the pathomechanism of airway inflammation. The inflammasome is a cytosolic protein complex important for early inflammatory responses, by processing Interleukin-1ß (IL-1ß) to its active form. OBJECTIVES: Since inflammasome activation has been described for a variety of inflammatory diseases, we investigated whether this pathway plays a role in NTHi infection of the airways. METHODS: A murine macrophage cell line (RAW 264.7), human alveolar macrophages and human lung tissue (HLT) were stimulated with viable or non-viable NTHi and/or nigericin, a potassium ionophore. Secreted cytokines were measured with ELISA and participating proteins detected via Western Blot or immunohistochemistry. MEASUREMENTS AND MAIN RESULTS: Western Blot analysis of cells and immunohistochemistry of lung tissue detected the inflammasome key components NLRP3 and caspase-1 after stimulation, leading to a significant induction of IL-1ß expression (RAW: control at the lower detection limit vs. NTHi 505±111pg/ml, p<0.01). Inhibition of caspase-1 in human lung tissue led to a significant reduction of IL-1ß and IL-18 levels (IL-1ß: NTHi 24 h 17423±3198pg/ml vs. NTHi+Z-YVAD-FMK 6961±1751pg/ml, p<0.01). CONCLUSION: Our data demonstrate the upregulation of the NRLP3-inflammasome during NTHi-induced inflammation in respiratory cells and tissues. Our findings concerning caspase-1 dependent IL-1ß release suggest a role for the inflammasome in respiratory tract infections with NTHi which may be relevant for the pathogenesis of bacterial exacerbations in COPD.

Outcome and management of invasive candidiasis following oesophageal perforation.

The regular colonisation of the oesophagus with a Candida species can, after oesophageal perforation, result in a contamination of the mediastinum and the pleura with a Candida species. A patient cohort of 80 patients with oesophageal perforation between 1986 and 2010 was analysed retrospectively. The most common sources with positive results for Candida were mediastinal biopsies and broncho-alveolar secretions. Candida species were detected in 30% of the patients. The mortality rate was 41% in patients with positive microbiology results for Candida, whereas it was 23% in the remaining patient cohort. This difference did not reach statistical significance (P = 0.124). Mortality associated with oesophageal perforation was attributed mainly to septic complications, such as mediastinitis and severe pneumonia. During the study period we observed a shift towards non-albicans species that were less susceptible or resistant to fluconazole. In selected patients with risk factors as immunosuppression, granulocytopenia and long-term intensive-care treatment together with the finding of Candida, an antimycotic therapy should be started. A surgical approach offers the possibility to obtain deep tissue biopsies. The antimycotic therapy should start with an echinocandin, as the resistance to fluconazole is growing and to cover non-albicans Candida species, too.

Primary metastasized extraskeletal Ewing sarcoma of the vulva: report of a case and review of the literature.

PURPOSE: Ewing's sarcoma (ES) and primitive neuroectodermal tumor (PNET) are closely related malignant neoplasms, usually affecting the skeletal system. Extraosseous ES/PNETs are uncommon, with occasional reports of tumors affecting the genitourinary tract. Only few cases of primary vulvar Ewing's sarcoma/PNET have previously been reported. METHODS: We present a patient with primary vulvar Ewing's sarcoma with pulmonary metastasis who presented at the Department of Gynecology and Obstetrics, University of Schleswig-Holstein, Campus Luebeck. RESULTS: The present report is the third case of a primary vulvar Ewing's sarcoma and the first constellation with pulmonary metastasis at diagnosis in the current literature. We present the diagnostic and therapeutic management including surgery, chemotherapy and radiation. CONCLUSION: The treatment of the Ewing's sarcomas and PNETs requires a multidisciplinary systemic approach. Despite its rarity, the differential diagnosis of vulvar sarcoma must be considered in young women.

The application of cold-plasma coagulation on the visceral pleura results in a predictable depth of necrosis without fistula generation.

A technique for the safe transfer of electric energy to the pulmonary surface for the potential evaporation of malignant tumours is non-existent to date. By conducting the current study, we wanted to generate data on the potential beneficiary effects and complications of using cold-plasma coagulation on the pulmonary surface. Cold-plasma coagulation was applied to the pulmonary surface in eight female mini-pigs via a thoracoscopic access. After 12 days, we performed a re-thoracoscopy on the contralateral side. After a further 12 days, we performed a median sternotomy and did cold-plasma coagulation on previously untreated areas of either lung. No pulmonary fistulas were detected. In two of the eight pigs, we found a localized chronic pneumonia. None of the pigs died during the course of the study. Morbidity was also low with two pigs refusing food intake, one pig with dyspnoea after difficult intubation and one pig coughing. All events were self-limited and occurred only on post-operative Day 1. The treatment effect was almost linear and correlated to the generator energy applied. The differences between the effects reached statistical significance (P < 0.05). The application of cold-plasma coagulation to the pulmonary surface is safe in pigs. A potential clinical application of this technique is treatment of malignant pleural mesothelioma.

Multivisceral and standard resections in colorectal cancer.

PURPOSE: The current study was designed to identify prognostic factors for long-term survival in patients with advanced colorectal cancer in a consecutive cohort. METHODS: A total of 123 patients were operated because of T4 colorectal cancer between 1 January 2002 and 31 December 2008 in the Clinic of Surgery, UK-SH Campus Luebeck. RESULTS: A total of 78 patients underwent a multivisceral resection. The postoperative morbidity was elevated in the patient group with multivisceral resections (34.6% vs. 26.7%). Nevertheless, we detected no significant differences concerning 30 days mortality (7.7% vs. 8.9%; p = 0.815). The main prognostic factor that reached significance in the multivariate analysis was the possibility to obtain a R0 resection (p < 0.0001) resulting in a 5-year survival rate of 55% for patients with curative resection. There were no statistically significant differences in 5-year survival between multivisceral and non-multivisceral resections (p = 0.608). Also we were not able to detect any significant differences for cancer of colonic or rectal origin (p = 0.839), for laparoscopic vs. open procedures (p = 0.610), and for emergency vs. planned operations (p = 0.674). Moreover, the existence of lymph node metastases was not a predictive factor concerning survival as there was no difference between patients with and without lymph node metastases (p = 0.658). CONCLUSIONS: Multivisceral resections are associated with the same 5-year survival as standard resections. Therefore, the aim to perform a R0 resection should always be the main goal in surgery for colorectal cancer. In planned operations, a laparoscopic approach is justified in selected patients.

A randomized trial of the efficacy and safety of sequential intravenous/oral moxifloxacin monotherapy versus intravenous piperacillin/tazobactam followed by oral amoxicillin/clavulanate for complicated skin and skin structure infections.

OBJECTIVES: The primary aim of the RELIEF study was to evaluate the efficacy and safety of two sequential intravenous (iv)/oral regimens: moxifloxacin iv/oral versus piperacillin/tazobactam (TZP) iv followed by oral amoxicillin/clavulanate (AMC). PATIENTS AND METHODS: The study had a prospective, randomized, double-dummy, double-blind, multicentre design. Patients ≥18 years were prospectively stratified according to complicated skin and skin structure infection (cSSSI) subtype/diagnosis (major abscess, diabetic foot infection, wound infection or infected ischaemic ulcer), surgical intervention and severity of illness. Diagnoses and disease severity were based on predetermined criteria, documented by repeated photographs, and confirmed by an independent data review committee. Patients were randomized to receive either 400 mg of moxifloxacin iv once daily followed by 400 mg of moxifloxacin orally once daily or 4.0/0.5 g of TZP iv thrice daily followed by 875/125 mg of AMC orally twice daily for 7-21 days. The primary efficacy variable was clinical response at test of cure (TOC) for the per-protocol (PP) population. Clinical efficacy was assessed by the data review committee based on repeated photographs and case descriptions. Clinical trials registry number: NCT 00402727. RESULTS: A total of 813 patients were randomized. Clinical success rates at TOC were similar for moxifloxacin and TZP-AMC in the PP [320/361 (88.6%) versus 275/307 (89.6%), respectively; P = 0.758] and intent-to-treat (ITT) [350/426 (82.2%) versus 305/377 (80.9%), respectively; P = 0.632] populations. Thus, moxifloxacin was non-inferior to TZP-AMC. Bacteriological success rates were high in both treatment arms [moxifloxacin: 432/497 (86.9%) versus TZP-AMC: 370/429 (86.2%), microbiologically valid (MBV) population]. Moxifloxacin was non-inferior to TZP-AMC at TOC in both the MBV and the ITT populations. Both treatments were well tolerated. CONCLUSIONS: Once-daily iv/oral moxifloxacin monotherapy was clinically and bacteriologically non-inferior to iv TZP thrice daily followed by oral AMC twice daily in patients with cSSSIs.

Diagnosis and therapy of Candida infections: joint recommendations of the German Speaking Mycological Society and the Paul-Ehrlich-Society for Chemotherapy.

Invasive Candida infections are important causes of morbidity and mortality in immunocompromised and hospitalised patients. This article provides the joint recommendations of the German-speaking Mycological Society (Deutschsprachige Mykologische Gesellschaft, DMyKG) and the Paul-Ehrlich-Society for Chemotherapy (PEG) for diagnosis and treatment of invasive and superficial Candida infections. The recommendations are based on published results of clinical trials, case-series and expert opinion using the evidence criteria set forth by the Infectious Diseases Society of America (IDSA). Key recommendations are summarised here: The cornerstone of diagnosis remains the detection of the organism by culture with identification of the isolate at the species level; in vitro susceptibility testing is mandatory for invasive isolates. Options for initial therapy of candidaemia and other invasive Candida infections in non-granulocytopenic patients include fluconazole or one of the three approved echinocandin compounds; liposomal amphotericin B and voriconazole are secondary alternatives because of their less favourable pharmacological properties. In granulocytopenic patients, an echinocandin or liposomal amphotericin B is recommended as initial therapy based on the fungicidal mode of action. Indwelling central venous catheters serve as a main source of infection independent of the pathogenesis of candidaemia in the individual patients and should be removed whenever feasible. Pre-existing immunosuppressive treatment, particularly by glucocorticosteroids, ought to be discontinued, if feasible, or reduced. The duration of treatment for uncomplicated candidaemia is 14 days following the first negative blood culture and resolution of all associated symptoms and findings. Ophthalmoscopy is recommended prior to the discontinuation of antifungal chemotherapy to rule out endophthalmitis or chorioretinitis. Beyond these key recommendations, this article provides detailed recommendations for specific disease entities, for antifungal treatment in paediatric patients as well as a comprehensive discussion of epidemiology, clinical presentation and emerging diagnostic options of invasive and superficial Candida infections.