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Abstract Background Poor-grade aneurysmal subarachnoid hemorrhage (SAH) is associated with poor neurological outcome and high mortality. A major factor influencing morbidity and mortality is brain swelling in the acute phase. Decompressive craniectomy (DC) is currently used as an option in order to reduce intractably elevated intracranial pressure (ICP). However, execution and optimal timing of DC remain unclear. Methods PICASSO resembles a multicentric, prospective, 1:1 randomized standard treatment-controlled trial which analyzes whether primary DC (pDC) performed within 24 h combined with the best medical treatment in patients with poor-grade SAH reduces mortality and severe disability in comparison to best medical treatment alone and secondary craniectomy as ultima ratio therapy for elevated ICP. Consecutive patients presenting with poor-grade SAH, defined as grade 4–5 according to the World Federation of Neurosurgical Societies (WFNS), will be screened for eligibility. Two hundred sixteen patients will be randomized to receive either pDC additional to best medical treatment or best medical treatment alone. The primary outcome is the clinical outcome according to the modified Rankin Scale (mRS) at 12 months, which is dichotomized to favorable (mRS 0–4) and unfavorable (mRS 5–6). Secondary outcomes include morbidity and mortality, time to death, length of intensive care unit (ICU) stay and hospital stay, quality of life, rate of secondary DC due to intractably elevated ICP, effect of size of DC on outcome, use of duraplasty, and complications of DC. Discussion This multicenter trial aims to generate the first confirmatory data in a controlled randomized fashion that pDC improves the outcome in a clinically relevant endpoint in poor-grade SAH patients. Trial registration DRKS DRKS00017650. Registered on 09 June 2019.

Abstract Background The placebo effect as the symptom improvement following inert treatments is a fixed component of RCTs to differentiate between specific effects of the tested pharmacological substance from other unspecific effects. The PINgPOng study was set up to analyze the influence of a study team trained to either minimize the placebo response and optimize drug-placebo differences or to maximize the placebo response to increase drug efficacy by unspecific factors on the study results of a RCT in a classical early clinical trial setting. Methods/design PINgPOng is a single-center, prospective, randomized, double-blind, placebo-controlled study in a 3-group, 2-sequence, 2-period cross-over design. The study is conducted according to the principles of ICH-GCP and the Declaration of Helsinki on the Phase I-Unit of the University Hospital Bonn. The primary endpoint is the pain intensity in the cold pressor test before and after the administration of 15 mg oxycodone or placebo. The pain intensity is compared between three study conditions: 32 healthy volunteers in each study arm will be treated either by an untrained study team (arm A), by a study team trained to maximize (arm B), or to minimize placebo responses (arm C). Neuroendocrine factors (alpha-amylase activity, salivary cortisol), characteristic traits (anxiety, depression, stress), and somatic reactions are analyzed as covariates of the pain perception. Discussion The PINgPOng study will allow to answer the question whether and to what extent the behavior of a trained study team (neutral vs. maximize vs. minimize placebo responses) will differentially affect placebo responses in a setting of a highly standardized early clinical trial. The results will help to control the placebo effects by education of the clinical study team and to avoid unnecessary high placebo effects in clinical development. Trial registration German Clinical Trials Register DRKS00013586 . Registered on December 22, 2017.

Abstract Background To prospectively analyze factors associated with detecting epileptogenic lesions on MRI within the work-sharing process of neurologists, epileptologists, radiologists and neuroradiologists. Methods We assembled four sets of six MRI scans, each set representing five typical epileptogenic lesions (hippocampal sclerosis or limbic encephalitis; focal cortical dysplasias; periventricular nodular or other heterotopias; long-term epilepsy associated tumors; gliotic scar, hemosiderin or cavernoma), and non - lesional epilepsy. At professional conferences, we invited neurologists, epileptologists, radiologists, and neuroradiologists to read two out of four MRI sets, one of which was presented with a clinical focus hypothesis. Participants were randomly assigned to MRI sets. Effects of examiners’ specialty, duration of training and professional experience on detection rate of epileptogenic lesions were investigated. Results Fourty-eight neurologists, 22 epileptologists, 20 radiologists and 21 neuroradiologists read 1323 MRI scans. Overall, 613 of 1101 (55.7%) epileptogenic lesions were detected. Long-term epilepsy associated tumors (182/221, 82.4%) were found more frequently than gliotic scar, hemosiderin or cavernoma (157/220, 71.4%), hippocampal sclerosis or limbic encephalitis (141/220, 64.1%), nodular heterotopia (68/220, 30.9%) and focal cortical dysplasias (65/220, 29.5%, p

In stage IV periodontitis patients with pathologic tooth migration (PTM), interdisciplinary treatment includes regenerative periodontal surgery (RPS) with an application of biomaterials and orthodontic therapy (OT) to restore function, esthetics and thereby quality of life (QoL). In a 24-month randomized trial we explored the synergy between regenerative medicine and biomechanical force application. The following methods were used: Forty-three patients had been randomized to a combined treatment comprising RPS and subsequent OT starting either 4 weeks (early OT) or 6 months (late OT) post-operatively. Clinical periodontal parameters and oral health-related QoL (GOHAI) were recorded up to 24 months. We obtained the following results: Mean clinical attachment gain (∆CAL ± SD) was significantly higher with early OT (5.96 ± 2.1 mm) versus late OT (4.65 ± 1.76 mm) (p = 0.034). Pocket closure (PPD ≤ 4 mm) was obtained in 91% of defects with early OT compared to 90% with late OT. GOHAI-scores decreased significantly from 26.1 ± 7.5 to 9.6 ± 4.7 (early OT) and 25.1 ± 7.1 to 12.7 ± 5.6 (late OT). Inconclusion, teeth severely compromised by intrabony defects and PTM can be treated successfully by RPS followed by early OT with the advantage of an overall reduced treatment time. As a result of the combined periodontal-orthodontic therapy, the oral health-related QoL of patients was significantly improved. Early stimulation of wound healing with orthodontic forces had a favorable impact on the outcomes of regenerative periodontal surgery.

Abstract Impaired skeletal muscle quality is a major risk factor for adverse outcomes in acute respiratory failure. However, conventional methods for skeletal muscle assessment are inapplicable in the critical care setting. This study aimed to determine the prognostic value of computed tomography (CT) fatty muscle fraction (FMF) as a biomarker of muscle quality in patients undergoing extracorporeal membrane oxygenation (ECMO). To calculate FMF, paraspinal skeletal muscle area was obtained from clinical CT and separated into areas of fatty and lean muscle based on densitometric thresholds. The cohort was binarized according to median FMF. Patients with high FMF displayed significantly increased 1-year mortality (72.7% versus 55.8%, P = 0.036) on Kaplan–Meier analysis. A multivariable logistic regression model was built to test the impact of FMF on outcome. FMF was identified as a significant predictor of 1-year mortality (hazard ratio per percent FMF, 1.017 [95% confidence interval, 1.002–1.033]; P = 0.031), independent of anthropometric characteristics, Charlson Comorbidity Index, Simplified Acute Physiology Score, Respiratory Extracorporeal Membrane Oxygenation Survival Prediction Score, and duration of ECMO support. To conclude, FMF predicted 1-year mortality independently of established clinical prognosticators in ECMO patients and may have the potential to become a new muscle quality imaging biomarker, which is available from clinical CT.

Abstract Background Prader-Willi-Syndrome (PWS) is characterized by hypothalamic-pituitary dysfunction. Recent research suggests starting growth hormone-treatment (GHT) as soon as possible. The aim of this study is to analyze possible differences in auxological parameters, carbohydrate and lipid metabolism between two groups of children with PWS that started GHT either during or after their first year of life. Study design Retrospective longitudinal study of 62 children (31 males) with genetically confirmed PWS. Upon diagnosis all children were offered GHT, some started immediately, others commenced later. Cohort A (n = 21; 11 males) started GHT at 0.3–0.99 yrs. (mean 0.72 yrs) and Cohort B (n = 41; 20 males) commenced GHT at 1.02–2.54 yrs. (mean 1.42 yrs) of age. Fasting morning blood samples and auxological parameters were obtained before the start of therapy and semi-annually thereafter. Differences between the two cohorts were estimated with a linear mixed-effect model. Results Mean length/height-SDSPWS differed significantly between the groups [1 yr: A: 0.37 (±0.83) vs B: 0.05 (±0.56); 5 yrs.: A: 0.81 (±0.67) vs B: 0.54 (±0.64); p = 0.012]. No significant differences were found in BMI, lean body mass or body fat. Low-density cholesterol was significantly lower in A than in B [LDL: 1 yr: A: 79 (±20) mg/dl vs B: 90 (±19) mg/dl; 5 yrs.: A: 91(±18) mg/dl vs 104 (±26) mg/dl; p = 0.024]. We found significant differences in the glucose homeostasis between the groups [fasting insulin: p = 0.012; HOMA-IR: p = 0.006; HbA1c: p

Abstract Background Myocardial T1 and T2 mapping are reliable diagnostic markers for the detection and follow up of acute myocarditis. The aim of this study was to compare the diagnostic performance of current mapping measurement approaches to differentiate between myocarditis patients and healthy individuals. Methods Fifty patients with clinically defined acute myocarditis and 30 healthy controls underwent cardiovascular magnetic resonance (CMR). Myocardial T1 relaxation times, T2 relaxation times, left ventricular (LV) function, T2 ratio, early gadolinium enhancement ratio, and presence of late gadolinium enhancement (LGE) were analysed. Native T1 and T2 relaxation times, as well as extracellular volume fraction (ECV) were measured for the entire LV myocardium (global), within the midventricular short axis slice (mSAX), within the midventricular septal wall (ConSept), and within the remote myocardium (remote). Receiver operating characteristics analysis was performed to compare diagnostic performance. Results All measurement approaches revealed significantly higher native T1 and T2 relaxation times as well as ECV values in patients compared to healthy controls (p 0.050 for all parameters). Conclusions Native T1 and T2 mapping allow for accurate detection of acute myocarditis irrespective of the measurement approach used. Even measurements performed exclusively within remote myocardium allow for reliable detection of acute myocarditis, demonstrating diffuse involvement of disease despite a mostly regional or patchy distribution pattern of visible pathologies. The global measurement approach provides the overall best diagnostic performance in acute myocarditis for both T1 and T2 mapping.

Abstract Background and aims Drug‐eluting devices (DEDs) are usually used as a standard therapy for revascularization in femoropopliteal artery disease. Randomized controlled trails have found that DEDs with paclitaxel result in superior patency rates and decreased target lesion revascularization. A meta‐analysis by Katsanos et al indicated an increased long‐term mortality in patients treated with paclitaxel‐coated devices. The aim of this observational clinical study was to assess the long‐term clinical outcomes and mortality risk after paclitaxel‐coated balloon angioplasty in patients with symptomatic peripheral artery disease. Methods We retrospectively evaluated 287 patients with peripheral interventions, including 173 drug‐coated balloon (DCB) angioplasties and 114 plain old balloon angioplasties (POBA), performed at our center between 2015 and 2018. Results There were no significant differences in mortality rates between patients who received DCB angioplasty and those who received POBA. In the first year, the hazard ratio (HR) for DCB angioplasty was 0.59 (95% confidence interval [CI] 0.31 to 1.12, P = .104). After 2 years, this HR was 0.64 (95% CI 0.36‐1.17, P = .145), while the 3‐year and 4‐year HR increased to 0.71 and 1.30 (3‐year: 95% CI 0.37‐1.33, P = ,283; 4‐year: 95% CI 0.55‐3.08, P = .546). No paclitaxel dose‐response relationship with mortality rate was identified when adjusted for key predictors of mortality. Conclusions Analyses of patient level data identified no significant mortality differences between DCB angioplasty and POBA after 4 years of follow‐up. Furthermore, there was no dose‐response relationship between paclitaxel and mortality. These findings demonstrate that paclitaxel DCB is safe. Further long‐term multicenter studies are needed to determine the risk of late mortality.

Introduction: The handover process in the emergency department (ED) is relevant for patient outcomes and lays the foundation for adequate patient care. The aim of this study was to examine the current prehospital to ED handover practice with regard to content, structure, and scope. Methods: We carried out a prospective, multicenter observational study using a specifically developed checklist. The steps of the handover process in the ED were documented in relation to qualification of the emergency medical services (EMS) staff, disease severity, injury patterns, and treatment priority. Results: We documented and evaluated 721 handovers based on the checklist. According to ISBAR (Identification, Situation, Background, Assessment, Recommendation), MIST (Mechanism, Injuries, Signs/Symptoms, Treatment), and BAUM (Situation [German: Bestand], Anamnesis, Examination [German: Untersuchung], Measures), almost all handovers showed a deficit in structure and scope (99.4%). The age of the patient was reported 339 times (47.0%) at the time of handover. The time of the emergency onset was reported in 272 cases (37.7%). The following vital signs were transferred more frequently for resuscitation room patients than for treatment room patients: blood pressure (BP)/(all comparisons p < 0.05), heart rate (HR), oxygen saturation (SpO 2) and Glasgow Coma Scale (GCS). Physicians transmitted these vital signs more frequently than paramedics BP, HR, SpO 2, and GCS. A handover with a complete ABCDE algorithm (Airway, Breathing, Circulation, Disability, Environment/Exposure) took place only 31 times (4.3%). There was a significant difference between the occupational groups (p < 0.05). Conclusion: Despite many studies on handover standardization, there is a remarkable inconsistency in the transfer of information. A “hand-off bundle” must be created to standardize the handover process, consisting of a uniform mnemonic accompanied by education of staff, training, and an audit process.

Background: Postoperative Delirium (POD) is the most common complication of elderly patients after surgery associated with increased postoperative morbidity, persistent care dependency and even mortality. Prevention of POD requires detection of patients at high risk prior to surgery. PROPDESC intends to provide an instrument for preoperative routine screening of patients' risk for POD. Methods: PROPDESC is a monocentric prospective observatory trial including 1000 patients older than 60 years from various disciplines of a university hospital planned for surgery of at least 60 min. To develop a score predicting the risk for POD, anesthesiological stratifications, laboratory values, medication and known risk factors as well as quality of life and cognitive performance are taken into account. POD assessment is performed daily on the first five days after the operation respectively the end of sedation in the intensive care units and normal wards. The score is evaluated from 600 data sets and subsequently validated internally. The most appropriate predictors are determined by a component-wise gradient boosting approach. Discussion: Based on retrospective investigations, etiology of POD is considered multifactorial. By a prospective analysis of various factors, PROPDESC intends to provide an applicable tool to predict the risk for POD from preoperative routine data and assessment of cognitive function. Objective is to establish an automatically generating score in preoperative routine to screen patients for increased risk of POD as starting point for POD reduction and management. Model compilation requires a high significance and enhancement within compound as well as regular availability of the selected predictors. Trial registration: DRKS, DRKS00015715. Registered 13 December 2018 - Retrospectively registered, https://www.drks.de/drks_web/navigate.do?navigationId=trial.HTML&TRIAL_ID=DRKS00015715. Keywords: Postoperative delirium, Risk prediction, Risk score

BACKGROUND:Major vascular complications (VCs) of ilio-femoral arterial access after percutaneous coronary interventions are infrequent, but are associated with increased mortality and morbidity. Routine endovascular repair of VCs is becoming the treatment of choice, especially for patients who cannot tolerate vascular surgery due to advanced cardiovascular disease or are in a bailout situation. Here, we review the different types of vascular access site complications associated with percutaneous coronary interventions (PCIs) and assess the safety and efficacy of endovascular treatment. METHODS:Data were retrospectively analysed from patients who experienced VCs after transfemoral PCIs, from December 2014 to May 2018. During this period, out of 2833 patients who underwent femoral coronary interventions, 53 (1.9%) experienced major VCs. RESULTS:In total, 40/53 (75.5%) cases with major VCs led to unplanned endovascular repair and 13/53 (24.5%) cases required surgical repair. VCs included 17 (32.1%) retroperitoneal bleeding events (BARC-2, 3a,b), 20 (37.7%) intimal dissections, and 16 (30.2%) femoral pseudoaneurysms. Overall, 32 (60.4%) patients received a covered stent, two (3.8%) received a nitinol stent, five (9.4%) patients with dissections were treated with prolonged balloon angioplasty alone, and one patient with femoral pseudoaneurysm underwent thrombin injection with simultaneous balloon occlusion. The mean hospital stay for patients after endovascular treatment was 11.06 ± 5.2 days, while for patients after surgical repair it was 17 ± 8.2 days. Endovascularly treated patients were transfused with red blood cells (13/40 32.5% vs. 2/13 15.4%) significantly more often than patients treated surgically, although surgically treated patients received more red blood cell concentrates per unit than endovascularly treated patients (1 ± 0.47 vs. 2 ± 0.93). During the one-year follow-up, no intermittent claudication was reported, and no patient required secondary endovascular or surgical repair. CONCLUSIONS:For patients who cannot tolerate vascular surgery due to advanced cardiovascular disease or are in a bailout situation, endovascular management of VCs following PCIs seems to be a feasible and safe treatment option, and represents an alternative to surgical repair in life-threatening situations. Endovascular treatment was associated with significantly fewer red blood cell concentrates per patient and fewer days in hospital than surgical treatment.

PurposeThis study investigated the acute changes in full spectrum differential blood cell count including reticulocytes and immature reticulocytes after a voluntary maximal dry apnea in non-elite divers. Aim of the present study is to obtain information on important regulatory compensation mechanisms and to provide insights into apneic regulatory processes.MethodsTen apnea divers performed a voluntary dry mean apnea time of 317 sec [SD ±111 sec]. Differential blood cell count including reticulocytes was measured before and immediately after a single maximal breath-hold. To evaluate kinetics, blood samples were also taken after 30 min and 4 h. Value distributions are presented with dot plots. P-values were calculated using a mixed linear model for time dependency. Four difference values were compared to baseline values with Dunnett's procedure.ResultsSignificant changes were found in red blood cell parameters for erythrocytes, red cell distribution width, hematocrit, hemoglobin, MCV, reticulocytes and immature reticulocytes, and in white blood cell parameters for leucocytes, lymphocytes, immature granulocytes, monocytes, basophile granulocytes, neutrophil granulocytes and eosinophil granulocytes and for thrombocytes.ConclusionAdaptive mechanisms regarding cell counts in elite apnea divers are not readily transferable to non-elite recreational sportspersons. Divers and physicians should be aware of the limited adaptive performance of humans in the case of extended apnea.

The periodontal microbiota is ecologically diverse and may facilitate colonization by bacteria of enteric origin (Enterobacteriaceae, Enterococci) and co-infections with Candida albicans, possibly producing subgingival biofilms with high antimicrobial tolerance. This retrospective surveillance study followed periodontitis-associated superinfection profiles in a large patient sample. From 2008 to 2015, biofilm samples from deep periodontal pockets were collected from a total of 16,612 German adults diagnosed with periodontitis. The presence of selected Enterobacteriaceae, Enterococci, and Candida albicans was confirmed in overnight cultures. Antimicrobial susceptibility of these clinical isolates was tested by disk diffusion with antibiotics routinely used for treatment of oral infections, e.g., amoxicillin (AML), amoxicillin/clavulanic acid (AMC), doxycycline (DO), and ciprofloxacin (CIP). The mean annual prevalence of patients harboring Enterobacteriaceae in periodontal plaques was 11.5% in total and ranged from 2.5% for Enterobacter cloacae to 3.6% for Klebsiella oxytoca, 1.1% for Klebsiella pneumoniae, 2.8% for Serratia marcescens, and 1.5% for Serratia liquefaciens. In comparison, the mean detection rates for microbiota typically found in the oral cavity were higher, e.g., 5.6% for Enterococcus spp. and 21.8% for Candida albicans. Among the Enterobacteriaceae, species harboring intrinsic resistance to AML (Enterobacter spp., Klebsiella spp., Serratia spp.) were predominant. Non-susceptibility to AMC was observed for Serratia spp. and Enterobacter cloacae. By contrast, Enterococcus spp. only showed non-susceptibility to DO and CIP. Trends for increasing resistance were found to AML in Serratia liquefaciens and to DO in Enterococcus spp. Trend analysis showed decreasing resistance to AMC in Serratia liquefaciens and Klebsiella oxytoca; and to DO in Serratia marcescens, liquefaciens, and Enterobacter cloacae. This study confirms the low but consistent presence of Enterobacteriaceae and Enterococci among the subgingival microbiota recovered from periodontitis specimen. Although their pathogenetic role in periodontal lesions remains unclear, their presence in the oral cavity should be recognized as a potential reservoir for development and spread of antibiotic resistance in light of antibiotic usage in oral infections.

Aim of this study was to investigate the long-term results of botulinum toxin A (BoNT-A) injections for the treatment of benign essential blepharospasm (BEB) and to report our experience with (ultra-)long-term treatment with onabotulinumtoxin-A. We conducted a retrospective cross-sectional analysis at a university hospital. Patients with BEB and BoNT-A treatment were assigned to the Total Blepharospasm Group, patients with ≥21 onabotulinumtoxin-A injections to the Ona Long-Term Group. The Total Blepharospasm Group (n = 1940) included 33,933 BoNT-A injections. The age of patients at symptom onset was (mean ± SD) 58.0 ± 13.1 years, and 70.4% were female. The Ona long-term group (n = 234) included 10,632 onabotulinumtoxin-A injections. In this group, patients received 45.4 ± 22.9 injections with a mean dose of 22.2 IU ± 0.5. The duration of treatment was 12.6 ± 5.4 years, ranging from 2.9 to 30.0 years. The effect–duration–dose quotient did not change during long-term treatment. The observed side effects were comparable in type and frequency to other studies, even with the (ultra-)long treatment with onabotulinumtoxin-A. Our results, based on one of the largest patient populations and a treatment duration of up to 30 years, impressively demonstrate that onabotulinumtoxin-A is a safe and effective therapy for essential blepharospasm, even in the ultra-long term.

BackgroundThe measurement of the ankle-brachial pressure index is a straightforward method for the detection of peripheral disease in the lower limbs. Only a few old studies with small numbers of patients have been conducted comparing the gold standard, ankle-brachial pressure index measurement, with strain gauge plethysmography and reactive hyperaemia for detecting peripheral arterial disease. The purpose of this study was to evaluate the feasibility and accuracy of strain gauge plethysmography values compared with the Doppler ultrasound method, ankle-brachial pressure index, in the assessment of peripheral arterial disease, especially in patients with severe aortic stenosis.Methods221 ankle-brachial pressure index measurements and strain gauge plethysmography measurements of patients with suspected peripheral arterial disease, diagnosed peripheral arterial disease with or without aortic stenosis were compared.ResultsIrrespective of aortic stenosis in patients with and without peripheral arterial disease, the resting arterial blood flow was within the normal range. In patients with aortic stenosis, the time-to-peak flow couldn't detect peripheral arterial disease and was found to be a false negative. In patients without aortic stenosis, time-to-peak flow correlated well with the ankle-brachial pressure index for detecting peripheral arterial disease. Peak flow at 5 seconds was the one of the flow values that correlated with ankle-brachial pressure index and detected peripheral arterial disease in patients with and without aortic stenosis.ConclusionPeak flow at 5 seconds is one of flow value that correlated well with ankle-brachial pressure index in detecting peripheral arterial disease in patients with and without aortic stenosis. Detection of peripheral arterial disease in patients with severe aortic stenosis seems to be less sensitive with flow measurements than with ankle-brachial pressure index.

(1) Purpose: As it is known, patients with liver cirrhosis (LC) undergoing colon surgery or hernia surgery have high perioperative morbidity and mortality. However, data about patients with LC undergoing small bowel surgery is lacking. This study aimed to analyze the morbidity and mortality of patients with LC after small bowel surgery in order to determine predictive risk factors for a poor outcome. (2) Methods: A retrospective analysis was performed of all patients undergoing small bowel surgery between January 2002 and July 2018 and identified 76 patients with LC. Postoperative complications were analyzed using the classification of Dindo/Clavien (D/C) and further subdivided (hemorrhage, pulmonary complication, wound healing disturbances, renal failure). A total of 38 possible predictive factors underwent univariate and multivariate analyses for different postoperative complications and in-hospital mortality. (3) Results: Postoperative complications [D/C grade ≥ II] occurred in 90.8% of patients and severe complications (D/C grade ≥ IIIB) in 53.9% of patients. Nine patients (11.8%) died during the postoperative course. Predictive factors for overall complications were “additional surgery” (OR 5.3) and “bowel anastomosis” (OR 5.6). For postoperative mortality, we identified the model of end-stage liver disease (MELD) score (OR 1.3) and portal hypertension (OR 5.8) as predictors. The most common complication was hemorrhage, followed by pulmonary complications, hydropic decompensation, renal failure, and wound healing disturbances. The most common risk factors for those complications were portal hypertension (PH), poor liver function, emergency or additional surgery, ascites, and high ASA score. (4) Conclusions: LC has a devastating influence on patients’ outcomes after small bowel resection. PH, poor liver function, high ASA score, and additional or emergency surgery as well as ascites were significant risk factors for worse outcomes. Therefore, PH should be treated before surgery whenever possible. Expansion of the operation should be avoided whenever possible and in case of at least moderate preoperative ascites, the creation of an anastomotic ostomy should be evaluated to prevent leakages.

Abstract Background 37 million individuals are currently infected with Onchocerca volvulus (O. volvulus), a parasitic nematode that elicits various dermal manifestations and eye damage in man. Disease control is primarily based on distributing ivermectin in mass drug administration (MDA) programmes which aim at breaking transmission by eliminating microfilariae (MF), the worm's offspring. The majority of infected individuals present generalized onchocerciasis, which is characterized by hyporesponsive immune responses and high parasite burden including MF. Recently, in areas that have been part of MDA programmes, individuals have been identified that present nodules but are amicrofilaridermic (a-MF) and our previous study showed that this group has a distinct immune profile. Expanding on those findings we determined the immune responses of O. volvulus-infected individuals to a Plasmodium-derived antigen MSP-1 (merozoite surface protein-1), which is required by the parasite to enter erythrocytes. Methods Isolated PBMCs from O. volvulus-infected individuals (164 MF+ and 46 a-MF) and non-infected volunteers from the same region (NEN), were stimulated with MSP-1 and the resulting supernatant screened for the presence of IL-5, IL-13, IFN-γ, TNF-α, IL-6, IL-17A and IL-10. These findings were then further analyzed following regression analysis using the covariates MF, ivermectin (IVM) and region. The latter referred to the Central or Ashanti regions of Ghana, which, at the time sampling, had received 8 or 1 round of MDA respectively. Results IL-5, IL-13 and IFN-γ responses to MSP-1 were not altered between NEN and O. volvulus-infected individuals nor were any associations revealed in the regression analysis. IL-10, IL-6 and TNF-α MSP-1 responses were, however, significantly elevated in cultures from infected individuals. Interestingly, when compared to a-MF individuals, MSP-induced IL-17A responses were significantly higher in MF+ patients. Following multivariable regression analysis these IL-10, IL-6, TNF-α and IL-17A responses were all dominantly associated with the regional covariate. Conclusions Consequently, areas with a lowered infection pressure due to IVM MDA appear to influence bystander responses to Plasmodium-derived antigens in community members even if they have not regularly participated in the therapy.

The search for new macrofilaricidal drugs against onchocerciasis that can be administered in shorter regimens than required for doxycycline (DOX, 200mg/d given for 4-6 weeks), identified minocycline (MIN) with superior efficacy to DOX. Further reduction in the treatment regimen may be achieved with co-administration with standard anti-filarial drugs. Therefore a randomized, open-label, pilot trial was carried out in an area in Ghana endemic for onchocerciasis, comprising 5 different regimens: the standard regimen DOX 200mg/d for 4 weeks (DOX 4w, N = 33), the experimental regimens MIN 200mg/d for 3 weeks (MIN 3w; N = 30), DOX 200mg/d for 3 weeks plus albendazole (ALB) 800mg/d for 3 days (DOX 3w + ALB 3d, N = 32), DOX 200mg/d for 3 weeks (DOX 3w, N = 31) and ALB 800mg for 3 days (ALB 3d, N = 30). Out of 158 randomized participants, 116 (74.4%) were present for the follow-up at 6 months of whom 99 participants (63.5%) followed the treatment per protocol and underwent surgery. Histological analysis of the adult worms in the extirpated nodules revealed absence of Wolbachia in 98.8% (DOX 4w), 81.4% (DOX 3w + ALB 3d), 72.7% (MIN 3w), 64.1% (DOX 3w) and 35.2% (ALB 3d) of the female worms. All 4 treatment regimens showed superiority to ALB 3d (p < 0.001, p < 0.001, p = 0.002, p = 0.008, respectively), which was confirmed by real-time PCR. Additionally, DOX 4w showed superiority to all other treatment arms. Furthermore DOX 4w and DOX 3w + ALB 3d showed a higher amount of female worms with degenerated embryogenesis compared to ALB 3d (p = 0.028, p = 0.042, respectively). These results confirm earlier studies that DOX 4w is sufficient for Wolbachia depletion and the desired parasitological effects. The data further suggest that there is an additive effect of ALB (3 days) on top of that of DOX alone, and that MIN shows a trend for stronger potency than DOX. These latter two results are preliminary and need confirmation in a fully randomized controlled phase 2 trial. TRIAL REGISTRATION:ClinicalTrials.gov #06010453.

BACKGROUND:Myocardial dysfunction occurs in a variety of fetal disorders. Findings from adult cardiology, where n-terminal pro-B-type natriuretic peptide (nt-proBNP) is an established biomarker of left ventricular dysfunction have been extended to fetal life. Since fetal blood sampling is technically challenging we investigated amniotic fluid nt-proBNP for its suitability to diagnose fetal myocardial dysfunction. METHODS:Ultrasound, Doppler examination and echocardiography was applied to classify cases and controls. Amniotic fluid nt-proBNP to amniotic fluid total protein ratio was calculated and compared to the gestational age-dependent reference intervals. In a subset of cases, fetal and maternal plasma nt-proBNP levels were determined. RESULTS:Specimen from 391 fetuses could be analyzed (171 cases, 220 controls). There was a high correlation between amniotic fluid and fetal blood nt-proBNP levels (r = 0.441 for cases; r = 0.515 for controls), whereas no correlation could be detected between maternal and fetal (blood and amniotic fluid) nt-proBNP concentrations. Specificity and positive likelihood ratio of amniotic fluid nt-proBNP to amniotic fluid total protein ratio were high (0.97 and 4.3, respectively). CONCLUSION:Amniotic fluid nt-proBNP measurement allows diagnostic confirmation of fetal myocardial dysfunction. It may serve as a useful adjunct in addition and correlation to existing tests of myocardial function, particularly in the context of invasive fetal therapy, where access to the amniotic cavity is part of the procedure.

In view of their common chronic inflammatory process, we sought to determine the linkage between peripheral artery disease and chronic obstructive pulmonary disease (COPD). 107 COPD patients (mean±sd age 64.6±10.4 years, 52.2% male) and 22 control smokers without previously diagnosed peripheral artery disease underwent standardised angiological examination for lower extremity artery disease (LEAD) and carotid artery disease. LEAD was significantly more prevalent in COPD patients than in controls (80.4% versus 54.5%, p=0.002). Among COPD patients, 57.0%, 12.2%, 10.3% and 0.9% were found to be in Fontaine stages I, IIA, IIB and III, respectively. As with carotid artery disease, its frequency increased from 36.4% in controls to 58.9% in COPD patients (p=0.003). Carotid plaque burden, LEAD Fontaine degrees as well as pulse wave index and ankle–brachial index manifested significant impairment over percentage predicted forced expiratory volume in 1 s (FEV1 % pred) (p=0.02, p

BackgroundCardiac magnetic resonance (CMR) can detect inflammatory myocardial alterations in patients suspected of having acute myocarditis. There is limited information regarding the degree of normalization of CMR parameters during the course of the disease and the time window during which quantitative CMR should be most reasonably implemented for diagnostic work‐up. Methods and ResultsTwenty‐four patients with suspected acute myocarditis and 45 control subjects underwent CMR. Initial CMR was performed 2.6±1.9 days after admission. Myocarditis patients underwent CMR follow‐up after 2.4±0.6, 5.5±1.3, and 16.2±9.9 weeks. The CMR protocol included assessment of standard Lake Louise criteria, T1 relaxation times, extracellular volume fraction, and T2 relaxation times. Group differences between myocarditis patients and control subjects were highest in the acute stage of the disease (P

BACKGROUND:In the Sudan, Schistosoma mansoni infections are a major cause of morbidity in school-aged children and infection rates are associated with available clean water sources. During infection, immune responses pass through a Th1 followed by Th2 and Treg phases and patterns can relate to different stages of infection or immunity. METHODOLOGY:This retrospective study evaluated immunoepidemiological aspects in 234 individuals (range 4-85 years old) from Kassala and Khartoum states in 2011. Systemic immune profiles (cytokines and immunoglobulins) and epidemiological parameters were surveyed in n = 110 persons presenting patent S. mansoni infections (egg+), n = 63 individuals positive for S. mansoni via PCR in sera but egg negative (SmPCR+) and n = 61 people who were infection-free (Sm uninf). Immunoepidemiological findings were further investigated using two binary multivariable regression analysis. PRINCIPAL FINDINGS:Nearly all egg+ individuals had no access to latrines and over 90% obtained water via the canal stemming from the Atbara River. With regards to age, infection and an egg+ status was linked to young and adolescent groups. In terms of immunology, S. mansoni infection per se was strongly associated with increased SEA-specific IgG4 but not IgE levels. IL-6, IL-13 and IL-10 were significantly elevated in patently-infected individuals and positively correlated with egg load. In contrast, IL-2 and IL-1β were significantly lower in SmPCR+ individuals when compared to Sm uninf and egg+ groups which was further confirmed during multivariate regression analysis. CONCLUSIONS/SIGNIFICANCE:Schistosomiasis remains an important public health problem in the Sudan with a high number of patent individuals. In addition, SmPCR diagnostics revealed another cohort of infected individuals with a unique immunological profile and provides an avenue for future studies on non-patent infection states. Future studies should investigate the downstream signalling pathways/mechanisms of IL-2 and IL-1β as potential diagnostic markers in order to distinguish patent from non-patent individuals.

The identification of body fluids is an essential tool for clarifying the course of events at a criminal site. The analytical problem is the fact that the biological material has been very often exposed to detrimental exogenous influences. Thereby, the molecular substrates used for the identification of the traces may become degraded. So far, most protocols utilize cell specific proteins or RNAs. Instead of measuring these more sensitive compounds this paper describes the application of the differential DNA-methylation. As a result of two genome wide screenings with the Illumina HumanMethylation BeadChips 27 and 450k we identified 150 candidate loci revealing differential methylation with regard to the body fluids venous blood, menstrual blood, vaginal fluid, saliva and sperm. Among them we selected 9 loci as the most promising markers. For the final determination of the methylation degree we applied the SNuPE-method. Because the degree of methylation might be modified by various endogenous and exogenous factors, we tested each marker with approximately 100 samples of each target fluid in a validation study. The stability of the detection procedure is proved in various simulated forensic surroundings according to standardized conditions. We studied the potential influence of 12 relatively common tumors on the methylation of the 9 markers. For this purpose the target fluids of 34 patients have been analysed. Only the cervix carcinoma might have an remarkable effect because impairing the signal of both vaginal markers. Using the Illumina MiSeq device we tested the potential influence of cis acting sequence variants on the methylation degree of the 9 markers in the specific body fluid DNA of 50 individuals. For 4 marker loci we observed such an influence either by sole SNPs or haplotypes. The identification of each target fluid is possible in arbitrary mixtures with the remaining four body fluids. The sensitivity of the individual body fluid tests is in the same range as for the forensic STR-analysis. It is the first forensic body fluid protocol which considers the exogenic and endogenic parameters potentially interfering with the true results.

[This corrects the article DOI: 10.1371/journal.pone.0147973.].

Sakir Uen1, Rolf Fimmers2, Burkhard Weisser3, Osman Balta1, Georg Nickenig1, Thomas Mengden11Division of Hypertension and Vascular Medicine, Department of Internal Medicine II, University Clinic, Bonn, Germany; 2Department of Biometry and Medical Statistics, University of Bonn, Bonn, Germany; 3Department of Sports Medicine, University of Kiel, Kiel, GermanyIntroduction: This study compared ST segment depression (ST depression) during cycle ergometry (ergometry) versus simultaneous 24-hour ambulatory blood pressure measurement and electrocardiogram recording (24-h ABPM/ECG) during everyday life.Methods: In a German multicenter study, ergometry and 24-h ABPM/ECG records of 239 hypertensive patients were retrospectively analyzed. ST depression was defined as an ST segment depression (1 mm limb or chest recordings V1 to V6) in an incremental cycle ergometry, or 1 mm in the 24-h ABPM/ECG recording under everyday conditions. Blood pressure parameters at the onset of ST depression in the context of the respective method were compared.Results: 18 patients had ST depression only in ergometry (group B), 23 had ST depression only during 24-h ABPM/ECG monitoring (group C) and 28 patients had ST depression with both methods (group D). Group A had no ST depression with any method. In group D, at the onset of ST depression with 24-h ABPM/ECG investigation, all parameters except diastolic blood pressure were significantly lower compared with the corresponding parameters at the onset of ST depression with ergometry (systolic blood pressure: 148 ± 19 vers 188 ± 35 mmHg, p

Livestock-associated bacteria with resistance to two or more antibiotic drug classes have heightened our awareness for the consequences of antibiotic consumption and spread of resistant bacterial strains in the veterinary field. In this study we assessed the prevalence of concomitant colonization with livestock-associated methicillin-resistant Staphylococcus aureus (LA-MRSA) and enterobacteriaceae expressing extended-spectrum betalactamases (ESBL-E) in farms at the German-Dutch border region. Nasal colonization of pigs with MRSA (113/547 (20.7%)) was less frequent than rectal colonization with ESBL-E (163/540 (30.2%)). On the individual farm level MRSA correlated with ESBL-E recovery. The data further provide information on prevalence at different stages of pig production, including abattoirs, as well as in air samples and humans living and working on the farms. Notably, MRSA was detected in stable air samples of 34 out of 35 pig farms, highlighting air as an important MRSA transmission reservoir. The majority of MRSA isolates, including those from humans, displayed tetracycline resistance and spa types t011 and t034 characteristic for LA-MRSA, demonstrating transmission from pigs to humans. ESBL-E positive air samples were detected on 6 out of 35 farms but no pig-to-human transmission was found. Detection of ESBL-E, e.g. mostly Escherichia coli with CTX-M-type ESBL, was limited to these six farms. Molecular typing revealed transmission of ESBL-E within the pig compartments; however, related strains were also found on unrelated farms. Although our data suggest that acquisition of MRSA and ESBL-E might occur among pigs in the abattoirs, MRSA and ESBL-E were not detected on the carcasses. Altogether, our data define stable air (MRSA), pig compartments (ESBL-E) and abattoir waiting areas (MRSA and ESBL-E) as major hot spots for transmission of MRSA and/or ESBL-E along the pig production chain.

Endoscopic lung volume reduction (ELVR) is an emerging therapy for emphysematous COPD. However, any resulting changes in lung perfusion and ventilation remain undetermined. Here, we report ELVR-mediated adaptations in lung perfusion and ventilation, as investigated by means of pulmonary scintigraphy.In this observational study, we enrolled 26 patients (64.9 ± 9.4 yrs, 57.7% male) with COPD heterogeneous emphysema undergoing ELVR with endobronchial valves (Zephyr, Pulmonx, Inc.). Mean baseline FEV1 and RV were 32.9% and 253.8% predicted, respectively. Lung scintigraphy was conducted prior to ELVR and eight weeks thereafter. Analyses of perfusion and ventilation shifts were performed and complemented by correlation analyses between paired zones.After ELVR, target zone perfusion showed a mean relative reduction of 43.32% (p

BACKGROUND: In adult and pediatric cardiology, n-terminal pro-B-type natriuretic peptide (nt-proBNP) serves as biomarker in the diagnosis and management of cardiovascular dysfunction. Elevated levels of circulating nt-proBNP are present in fetal conditions associated with myocardial pressure or volume load. Compared to fetal blood sampling, amniocentesis is technically easier and can be performed from early pregnancy onwards. We aimed to investigate amniotic fluid (AF) nt-proBNP concentrations in normal pregnancies between 10 and 34 weeks of gestation. METHODS: Nt-proBNP and total protein (TP) was measured in AF by chemiluminescence assay (photometry, respectively). To adjust for a potential dilutional effect, the AF-nt-proBNP/AF-TP ratio was analyzed. Reference intervals were constructed by regression modeling across gestational age. RESULTS: 132 samples were analyzed. A negative correlation between AF-nt-proBNP/AF-TP ratio and gestational age was observed. Curves for the mean and the 5% and 95% reference interval between 10 and 34 weeks of gestation were established. CONCLUSION: In normal pregnancy, nt-proBNP is present in AF and decreases during gestation. Our data provide the basis for research on AF-nt-proBNP as biomarker in fetal medicine.

BACKGROUND: The German Version of the Manchester Triage System (MTS) has found widespread use in EDs across German-speaking Europe. Studies about the quality criteria validity and reliability of the MTS currently only exist for the English-language version. Most importantly, the content of the German version differs from the English version with respect to presentation diagrams and change indicators, which have a significant impact on the category assigned. This investigation offers a preliminary assessment in terms of validity and inter-rater reliability of the German MTS. METHODS: Construct validity of assigned MTS level was assessed based on comparisons to hospitalization (general / intensive care), mortality, ED and hospital length of stay, level of prehospital care and number of invasive diagnostics. A sample of 45,469 patients was used. Inter-rater agreement between an expert and triage nurses (reliability) was calculated separately for a subset group of 167 emergency patients. RESULTS: For general hospital admission the area under the curve (AUC) of the receiver operating characteristic was 0.749; for admission to ICU it was 0.871. An examination of MTS-level and number of deceased patients showed that the higher the priority derived from MTS, the higher the number of deaths (p

BackgroundTNFα levels are increased in liver cirrhosis even in the absence of infection, most likely owing to a continuous endotoxin influx into the portal blood. Soluble TNFα receptors (sTNFR type I and II) reflect release of the short-lived TNFα, because they are cleaved from the cells after binding of TNFα. The aims were to investigate the circulating levels of soluble TNFR-I and -II in cirrhotic patients receiving TIPS.MethodsForty-nine patients with liver cirrhosis and portal hypertension (12 viral, 37 alcoholic) received TIPS for prevention of re-bleeding (n = 14), therapy-refractory ascites (n = 20), or both (n = 15). Portal and hepatic venous blood was drawn in these patients during the TIPS procedure and during the control catheterization two weeks later. sTNFR-I and sTNFR-II were measured by ELISA, correlated to clinical and biochemical characteristics.ResultsBefore TIPS insertion, sTNFR-II levels were lower in portal venous blood than in the hepatic venous blood, as well as in portal venous blood after TIPS insertion. No significant differences were measured in sTNFR-I levels. Hepatic venous levels of sTNFR-I above 4.5 ng/mL (p = 0.036) and sTNFR-II above 7 ng/mL (p = 0.05) after TIPS insertion were associated with decreased survival. A multivariate Cox-regression survival analysis identified the hepatic venous levels of sTNFR-I (p = 0.004) two weeks after TIPS, and Child score (p = 0.002) as independent predictors of mortality, while MELD-score was not.ConclusionHepatic venous levels of sTNFR-I after TIPS insertion may predict mortality in patients with severe portal hypertension.

Systemic mast cell activation disease (MCAD) comprises disorders characterized by an enhanced release of mast cell mediators accompanied by accumulation of dysfunctional mast cells. Demonstration of familial clustering would be an important step towards defining the genetic contribution to the risk of systemic MCAD. The present study aimed to quantify familial aggregation for MCAD and to investigate the variability of clinical and molecular findings (e.g. somatic mutations in KIT) among affected family members in three selected pedigrees. Our data suggest that systemic MCAD pedigrees include more systemic MCAD cases than would be expected by chance, i.e., compared with the prevalence of MCAD in the general population. The prevalence of MCAD suspected by symptom self-report in first-degree relatives of patients with MCAD amounted to approximately 46%, compared to prevalence in the general German population of about 17% (p

OBJECTIVE: We analyzed the association between renal and cardiovascular parameters in fetuses with isolated severe urinary tract malformations. METHODS: 39 fetuses at a mean gestational age of 23.6 weeks with nephropathies or urinary tract malformations and markedly impaired or absent renal function were prospectively examined. Fetal echocardiography was performed, and thicknesses of the interventricular septum, and left and right ventricular wall were measured. Blood flow velocity waveforms of the umbilical artery, middle cerebral artery, and ductus venosus were obtained by color Doppler ultrasound. Concentrations of circulating n-terminal pro-B-type natriuretic peptide (nt-proBNP), cystatin C, ß2-microglobulin, and hemoglobin were determined from fetal blood samples. RESULTS: Malformations included 21 cases of obstructive uropathy, 10 fetuses with bilateral nephropathy, and 8 cases of bilateral renal agenesis. Marked biventricular myocardial hypertrophy was present in all cases. The ratio between measured and gestational age-adjusted normal values was 2.01 (interventricular septum), 1.85, and 1.78 (right and left ventricular wall, respectively). Compared to controls, levels of circulating nt-proBNP were significantly increased (median (IQR) 5035 ng/L (5936 ng/L) vs. 1874 ng/L (1092 ng/L); p

Dysregulation of the alternative pathway (AP) of complement cascade has been implicated in the pathogenesis of age-related macular degeneration (AMD), the leading cause of blindness in the elderly. To further test the hypothesis that defective control of complement activation underlies AMD, parameters of complement activation in blood plasma were determined together with disease-associated genetic markers in AMD patients. Plasma concentrations of activation products C3d, Ba, C3a, C5a, SC5b-9, substrate proteins C3, C4, factor B and regulators factor H and factor D were quantified in patients (n = 112) and controls (n = 67). Subjects were analyzed for single nucleotide polymorphisms in factor H (CFH), factor B-C2 (BF-C2) and complement C3 (C3) genes which were previously found to be associated with AMD. All activation products, especially markers of chronic complement activation Ba and C3d (p