In this retrospective study, we analyzed the presence of any association of three CD4+ CD25high regulatory T-cell subpopulations at 3 weeks after lung transplantation with the later incidence of chronic lung allograft dysfunction and graft survival. Among lung-transplanted patients between January 2009 and April 2018, only patients with sufficient T-cell measurements at 3 weeks after transplantation were included into the study. Putative regulatory T cells were defined as CD4+ CD25high T cells, detected in peripheral blood and further analyzed for CD127low , FoxP3+ , and CD152+ using fluorescence-activated cell sorting (FACS) analysis. Associations of regulatory T cells with chronic lung allograft dysfunction (CLAD) and graft survival were evaluated using Cox analysis. During the study period, 724 (71%) patients were included into the study. Freedom from chronic lung allograft dysfunction (CLAD) and graft survival amounted to 66% and 68% at 5 years. At the multivariable analysis, increasing frequencies of CD127low were associated with better freedom from CLAD (hazard ratio for each 1% increase of %CD127low , HR = 0.989, 95% CI = 0.981-0.996, P = 0.003) and better graft survival (HR = 0.991, 95% CI = 0.984-0.999, P = 0.026). A higher frequency of CD127low regulatory T cells in peripheral blood early after lung transplantation estimated a protective effect against chronic lung allograft dysfunction, mortality, and re-transplantation.

Background Whether Borna disease virus (BDV-1) is a human pathogen remained controversial until recent encephalitis cases showed BDV-1 infection could even be deadly. This called to mind previous evidence for an infectious contribution of BDV-1 to mental disorders. Pilot open trials suggested that BDV-1 infected depressed patients benefitted from antiviral therapy with a licensed drug (amantadine) which also tested sensitive in vitro. Here, we designed a double-blind placebo-controlled randomized clinical trial (RCT) which cross-linked depression and BDV-1 infection, addressing both the antidepressant and antiviral efficacy of amantadine. Methods The interventional phase II RCT (two 7-weeks-treatment periods and a 12-months follow-up) at the Hannover Medical School (MHH), Germany, assigned currently depressed BDV-1 infected patients with either major depression (MD; N = 23) or bipolar disorder (BD; N = 13) to amantadine sulphate (PK-Merz®; twice 100 mg orally daily) or placebo treatment, and contrariwise, respectively. Clinical changes were assessed every 2–3 weeks by the 21-item Hamilton rating scale for depression (HAMD) (total, single, and combined scores). BDV-1 activity was determined accordingly in blood plasma by enzyme immune assays for antigens (PAG), antibodies (AB) and circulating immune complexes (CIC). Results Primary outcomes (≥25% HAMD reduction, week 7) were 81.3% amantadine vs. 35.3% placebo responder ( p = 0.003), a large clinical effect size (ES; Cohen’s d) of 1.046, and excellent drug tolerance. Amantadine was safe reducing suicidal behaviour in the first 2 weeks. Pre-treatment maximum infection levels were predictive of clinical improvement (AB, p = 0.001; PAG, p = 0.026; HAMD week 7). Respective PAG and CIC levels correlated with AB reduction ( p = 0,001 and p = 0.034, respectively). Follow-up benefits (12 months) correlated with dropped cumulative infection measures over time ( p < 0.001). In vitro, amantadine concentrations as low as 2.4–10 ng/mL (50% infection-inhibitory dose) prevented infection with human BDV Hu-H1, while closely related memantine failed up to 100,000-fold higher concentration (200 μg/mL). Conclusions Our findings indicate profound antidepressant efficacy of safe oral amantadine treatment, paralleling antiviral effects at various infection levels. This not only supports the paradigm of a link of BDV-1 infection and depression. It provides a novel possibly practice-changing low cost mental health care perspective for depressed BDV-1-infected patients addressing global needs. Trial registration The trial was retrospectively registered in the German Clinical Trials Registry on 04th of March 2015. The trial ID is DRKS00007649; https://www.drks.de/drks_web/setLocale_EN.do

During bracket bonding, patients often report about thermosensitivity. The reason could be that modern light emitting diode (LED) light curing units run with intensities up to 3200 mW/cm2. In this in vitro pilot study with nonpulpal circulation approaches, the temperatures in the pulpal cavity were measured. The study included 60 extracted teeth divided into four equal groups: lower and upper incisors, premolars and molars. Starting at 37 °C (body temperature) as the reference, the temperature increase was measured for the first series on each tooth without a bracket, without and with a recommended hygienic barrier case for the LED light curing unit, and exposition to light once versus twice. The distance between the tooth and light curing unit was 3 mm. In the second test series, a metal bracket was also bonded to each tooth. In the third series, the light exposition distance was increased to 4 mm. In all three test series, significant intrapulpal temperature increase was found: The highest temperatures were recorded after exposure to light once without the hygienic barrier case. In the first test series, this approach showed temperatures even higher than 42.5 °C in the lower incisors (average 42.99 ± 2.23 °C) and premolars (average 42.94 ± 2.15 °C). Significant increases in the temperature of the pulpal cavity (up to 42.5 °C) may occur during bonding brackets according to the manufacturer’s recommendation with an LED light curing unit with in vitro nonpulpal circulation approaches. Therefore it could be reasonable to critically question the recommendation of the manufacturer.

Post-transplant hypertension (PTH) is a common complication in cyclosporine immunosuppressed patients; however choosing the right antihypertensive medication is challenging. In a long-term observational study (≤13y) we examined different antihypertensive medications on graft/patient survival of kidney recipients with pre-existing and PTH. Altogether thirty-three co-variables were analyzed including dose and type of immunosuppressive and antihypertensive medication, co-medications, serum biochemistries and the glomerular filtration rate (GFR). A Cox proportional-hazard multivariable survival model was developed to detect a Hazard Ratio (HR) of 3.0 at the Bonferroni corrected level α = 0.0015. Importantly, a significant relationship between immunosuppressive cyclosporine dose/serum concentration, systolic blood pressure (SBP) and GFR (p < 0.001) was observed with post-transplant hypertension being a major risk factor (HR6.1) for graft/patient survival. Although all medications lowered effectively elevated SBP the risk of graft failure/death was significantly increased when hypertension was treated with ACE inhibitors or β-blockers (HR3.3 and 3.1) but not with angiotensin receptor- and/or Ca-channel blockers. Antihypertensive medication was associated with a decline in GFR but β-blockers alone or in combination with ARB and/or CCB improved GFR. Neither BMI nor any of the drug combinations used in immunosuppression, i.e. prednisolone, mycophenolic acid, azathioprine and/or sirolimus influenced patient and/or graft survival while decision tree analyses informed on complex dependencies between immunosuppressive medications, dose of anti-hypertensive drug and diuretics in the management of hypertension. In conclusion, our study is suggestive for graft/patient survival to be influenced by the class of antihypertensive medication. A prospective randomized clinical trial is needed to confirm the results.

Prospective randomized controlled trials are difficult to obtain if a promising new therapy has to be tested against seemingly obsolete alternatives. One method to address this problem is to compare the results of (multicentre) trials to literature results. However, previous treatment-era changes and population-dependent results complicate objective comparisons. The presented approach describes a method to objectify such comparisons in cases in which individual raw data regarding a new therapy have to be compared to summary results regarding a conventional alternative published in the literature. The chosen example is the introduction of bovine neck veins as a substitute for dysfunctional human pulmonary valves, and the conventional therapeutic alternative is pulmonary-artery homografts. Literature research, subgroup identification, filtering, endpoint remodelling, weighting and, if necessary, confidence-limit calculation yield adjusted comparisons. These individual comparisons are then aggregated, first by article and then over several articles (similar to meta-analyses), resulting in a differentiated panel of answers (Multiply Adjusted Comparisons). In situations in which extensive raw data regarding a new therapeutic alternative but no randomized controlled trials and no raw data from previous studies using the conventional therapeutic alternative are available, the proposed method identifies the best evidence and is by far superior to unadjusted direct comparisons or gut feelings.

One of the most disabling symptoms of hepatitis C virus (HCV) infection is chronic fatigue. While this is accepted for HCV polymerase chain reaction (PCR)-positive patients, a relationship between HCV infection and chronic fatigue is questioned after successful virus eradication. As fatigue is a subjective criterion, we aimed to evaluate in addition mood alterations and cognitive function in HCV-exposed patients with only mild liver disease and to assess a) possible interrelationships between these factors and health-related quality of life and b) the impact of viremia and former interferon treatment. One hundred and fifty-nine anti-HCV-positive individuals without advanced liver disease answered health-related quality of life (HRQoL), fatigue and depression questionnaires and underwent a battery of attention and memory tests. Accompanying diseases which could distort the results of the study such as HIV co-infection or drug addiction were exclusion criteria. The patients were subdivided into four groups according to their viremia status and interferon treatment history. Patients' data were evaluated with respect to norms given in the respective test manuals and in addition compared to those of 33 age-matched healthy controls. Eighty-five per cent of the patients had chronic fatigue, 50-60% mild depression or anxiety, 45% memory deficits and 30% attention deficits, irrespective of their HCV viremia status or treatment history. HRQoL correlated negatively with chronic fatigue (P<.001), while cognitive deficits-especially memory function-were independent from fatigue and depression. HCV infection may cause long-standing cerebral dysfunction that significantly impairs HRQoL and may even persist after clearance of the virus.

Background. There is little information about the anesthesiologic management of lung transplantation. Therefore, we characterized intraoperative variables and their impact on survival in dependence to preoperative characteristics of recipients and donors. Methods. We analyzed 808 lung transplantations performed at our institution between 1987 and 2006, described patients in relation to the use of cardiopulmonary bypass (CPB), and used both recursive-partitioning and multivariate analyses to examine patients, donors, anesthesiologic management (e.g. gas exchange, hemo-dynamics, transfusions), extracorporeal life support (e.g. unplanned/planned CPB), and other variables. Results. Compared with off-pump transplantations (n = 389), unplanned CPB (n = 216) resulted in more transfusions and both doubled duration of postoperative ventilation (7.2 +/- 16.5 vs. 16.5 +/- 23.7 days, p<0.001) and hospital mortality (10 vs. 19%, p = 0.006) ; after planned CPB (n = 88), mortality doubled again (42%, p<0.001). Pulmonary diseases, their severity and comorbidities differed between groups, but pulmonary diseases were similar between patients with unplanned and planned CPB. According to recursive-partitioning analyses postoperative ventilation of < 4 days 10h discriminated best between survivors and non-survivors, and the duration of postoperative ventilation was also predictive for survival (odds ratio (OR), 1.02 ; 1-day increments). Intraoperative independent risk factors were transfusions of packed red blood cells (OR, 1.10 ; 10-unit increments), planned CPB (OR 2.4) and donors at least 20 cm taller than the recipient (OR 6.0). Conclusions. Apart from avoiding CPB, further efforts towards shorter postoperative ventilation and avoiding the intraoperative need for excessive transfusions may have the potential to improve outcomes as these were identified as important risk factors and were associated with CPB use.

This study investigates differences in treatment and outcome of ventilated patients with acute respiratory distress syndrome (ARDS) between university and non-university hospitals in Germany.

Die Vielfältigkeit der Prinzipien in der Behandlung des parapneumonischen Pleuraempyems zeugt von der bis heute bestehenden Unklarheit über den korrekten Verfahrensweg zum jeweiligen Zeitpunkt – Identisches gilt für die Behandlung des Pleuraempyems im Rahmen von operativen Eingriffen. Das parapneumonische Pleuraempyem wurde von verschiedenen amerikanischen Fachgesellschaften unter unterschiedlichen Aspekten klassifiziert: Einteilung nach der natürlichen Verlaufsform bzw. nach der Zusammensetzung des Ergusses (American Thoracic Society – ATS), Einteilung nach der Risikowahrscheinlichkeit für ein schlechtes Behandlungsergebnis (American College of Chest Physicians – ACCP), oder es wurden Behandlungsalgorithmen empfohlen, basierend auf einer systematischen Analyse ausgewählter Literatur (British Thoracic Society – BTS). Die Behandlungsstrategie des parapneumonischen Pleuraempyems, aber auch des Empyems im Rahmen von Operationen sollte adaptiert an das jeweilige Stadium erfolgen. Das Behandlungsspektrum umfasst die alleinige Drainagenbehandlung, die Drainagentherapie mit Fibrinolytika, das thorakoskopische Débridement, die geschlossene Empyemektomie per VATS oder offenchirurgisch, die Dekortikation in offener bzw. minimalinvasiver Technik sowie die Behandlung mittels Thoraxfensteranlage, Thorakomyoplastik bzw. die Vakuumversiegelung mit Unterdrucktherapie. Die Vielfältigkeit der Behandlungsoptionen aus konservativen und operativen Methoden bedingt den zentralen Stellenwert der Thoraxchirurgie.

AIM:To evaluate whether contrast enhanced ultrasound (CEUS) might also be used for response prediction and early response evaluation in patients receiving bevacizumab based chemotherapy for metastasized colorectal cancer.METHODS:Thirty consecutive patients with non primary resectable liver metastases from colorectal cancer underwent CEUS before treatment (CEUS date 1) and before the second (CEUS date 2) and fourth (CEUS date 3) cycle of bevacizumab based chemotherapy. Three parameters [PEAK, Time to peak (TTP) and RISE RATE]were correlated with radiological response.RESULTS:For neoadjuvant purpose a reduction of tumour mass was required to assume clinical response. Based on these response criteria there was a significant (P < 0.001) correlation in TTP between metastases of responders (9.08 s) and non-responders (14.76 s) archived on CEUS date 1. By calculating a standardized quotient (metastases divided by normal liver tissue) we were able to define a cut off, predicting response with a sensitivity of 92.3 % and a specificity of 100 %. To reflect a palliative intention only those patients with progressive disease were classified as non-responders. In this stetting TTP was also significantly (P < 0.01) different between responders and non-responders. In contrast, Peak and Rise rate did not show any significant difference between responder and non-responder.CONCLUSION:CEUS might serve as a surrogate marker to predict treatment response in patients with metastasized colorectal cancer who receive antiangiogenic therapy.

BACKGROUND:Pollen grains with a diameter of more than 10 μm preferentially deposit in the upper airways. Their contribution to lower airway inflammation is unclear. One hypothesis is that lower airway inflammation is mainly caused by allergen containing pollen starch granules, which are released from the pollen grains and can easily enter the peripheral airways because of their smaller size.OBJECTIVE:To investigate the differential effect of pollen grains and pollen starch granules on nasal symptoms and lower airway inflammation.METHODS:In a 2-period crossover design, 30 patients with allergic rhinitis and mild intermittent asthma underwent 2 allergen challenges on consecutive days in an environmental challenge chamber with either a mixture of pollen grains plus starch granules or starch granules only. End points were the total nasal symptom score (TNSS), nasal secretion weight, nasal flow, spirometry, and exhaled nitric oxide (eNO).RESULTS:The presence of pollen grains had a significant and considerable effect on increase in TNSS and secretion weight and on decrease in nasal flow. Starch granules alone only had minimal effects on nasal symptoms. Challenges with starch granules significantly increased eNO. Pollen had no effect on eNO.CONCLUSION:Pollen grains cause nasal symptoms but do not augment lower airway inflammation, whereas starch granules trigger lower airway inflammation but hardly induce nasal symptoms.

Objective: In this observational study, we compared the outcomes of moxifloxacin monotherapy as compared to beta-lactam monotherapy as well as beta-lactam combination therapy in patients with community-acquired pneumonia (CAP).Methods: Patients recruited within the German Competence Network for CAP (CAPNETZ) were evaluated for treatment regimen. Primary outcome variables were six months overall mortality, pneumonia-related mortality according to clinical judgment and treatment failures (necessity for treatment change and death).Results: Overall, 4091 patients (mean age 64.4 +/- 17.8 (range 18-101) years, 2433 male (59.5%)) were included. 2068 patients received moxifloxacin (n = 365) or beta-lactam monotherapy (n = 1703). 330 patients died within six months. After controlling for confounders in multivariate analysis, moxifloxacin monotherapy had higher survival as compared to beta-lactam monotherapy (hazard ratio for moxifloxacin 0.57, 95% CI 0.35-0.92). Multivariate analysis including interaction terms showed that the protective effect of moxifloxacin was not present for CRB-65 class 0 but increased with higher CRB-65 scores (HR 0.69, 95% CI 0.50-0.96). Regarding pneumonia-related death, moxifloxacin monotherapy was also protective in multivariate analysis (HR 0.36, 95% CI 0.13-0.99). Moxifloxacin was also significantly associated with less treatment failures (p < 0.001). In addition, it was not inferior to combination beta-lactam treatment (p = 0.062).Conclusions: In CRB-65 class 0 moxifloxacin was equivalent to beta-lactams. Our observations are in support of a use of moxifloxacin monotherapy in hospitalized patients with moderate CAP (CRB-65 classes 1 and 2). (C) 2011 The British Infection Association. Published by Elsevier Ltd. All rights reserved.

Background: Recent studies have shown that narrow-band imaging (NBI) is a powerful diagnostic tool for the differentiation between neoplastic and non-neoplastic colorectal polyps.Objective: To develop a computer-based method for classification of colorectal polyps.Design: A prospective study.Setting: University hospital.Patients: A total of 214 patients with colorectal polyps who underwent a zoom NBI colonoscopy.Interventions: A total of 434 detected polyps 10 mm or smaller were imaged and subsequently removed for histological analysis.Main Outcome Measurements: Diagnostic performance in polyp classification by 2 experts, 2 nonexperts, and a computer-based algorithm.Results: The expert group and the computer-based algorithm achieved a comparable diagnostic performance (expert group: 93.4% sensitivity, 91.8% specificity, and 92.7% accuracy; computer-based algorithm: 95.0% sensitivity, 90.3% specificity, and 93.1% accuracy) and were both significantly superior to the nonexpert group (86.0% sensitivity, 87.8% specificity, and 86.8% accuracy) in terms of sensitivity, negative predictive value, and accuracy. Subgroup analysis of 255 polyps 5 mm or smaller revealed comparable results without significant differences in the overall analysis of all polyps.Limitations: No fully automatic classification system.Conclusions: The study demonstrates that computer-based classification of colon polyps can be achieved with high diagnostic performance. (Gastrointest Endosc 2011;74:1354-9.)

Background and study aims: Narrow-band imaging (NBI) has been developed as a new technique to differentiate tissue patterns in vivo. The aim of this study was to evaluate the diagnostic accuracy of NBI endoscopy with and without high magnification for the differentiation of neoplastic from non-neoplastic colorectal polyps.Patients and methods: Among 200 colorectal polyps from 131 patients, 100 lesions were classified according to vascular patterns by NBI endoscopy with high optical magnification and 100 lesions by high-definition endoscopy without high magnification. Additionally, the clarity of the vessel network was assessed. Histologic analysis was performed on all lesions.Results: NBI endoscopy with high magnification resulted in a sensitivity of 92.1% and a specificity of 89.2% for the differentiation of neoplastic versus non-neoplastic lesions. This performance was statistically comparable to high-definition NBI endoscopy without high magnification, which showed a sensitivity of 87.9% and specificity of 90.5%. However, vessel network was significantly better visualized by NBI endoscopy with optical magnification compared with high-definition NBI endoscopy without high magnification. In comparison with NBI endoscopy, white-light endoscopy, with or without magnification, resulted in inferior discrimination between neoplastic and non-neoplastic polyps.Conclusion: The results demonstrate that the superior visibility of capillary vessels by the NBI technique allows the evaluation of colorectal lesions - based on the vascular patterns - with high diagnostic accuracy. In clinical routine, high-definition NBI endoscopy without high magnification may be used to sufficiently predict colorectal polyp histology, and high magnification can additionally facilitate visualization of vascular networks.

Background and study aims: Recent studies have shown that narrow-band imaging (NBI) is a powerful diagnostic tool for differentiating between neoplastic and nonneoplastic colorectal polyps. The aim of the present study was to develop and evaluate a computer-based method for automated classification of colorectal polyps on the basis of vascularization features.Patients and methods: In a prospective pilot study with 128 patients who were undergoing zoom NBI colonoscopy, 209 detected polyps were visualized and subsequently removed for histological analysis. The proposed computer-based method consists of image preprocessing, vessel segmentation, feature extraction, and classification. The results of the automated classification were compared to those of human observers blinded to the histological gold standard.Results: Consensus decision between the human observers resulted in a sensitivity of 93.8% and a specificity of 85.7%. A "safe" decision, i.e., classifying polyps as neoplastic in cases when there was interobserver discrepancy, yielded a sensitivity of 96.9% and a specificity of 71.4%. The overall correct classification rates were 91.9% for the consensus decision and 90.9% for the safe decision. With ideal settings the computer-based approach achieved a sensitivity of approximately 90% and a specificity of approximately 70%, while the overall correct classification rate was 85.3%. The computer-based classification showed a specificity of 61.2% when a sensitivity of 93.8% was selected, and a 53.1% specificity with a sensitivity of 96.9%.Conclusions: Automated classification of colonic polyps on the basis of NBI vascularization features is feasible, but classification by observers is still superior. Further research is needed to clarify whether the performance of the automated classification system can be improved.

BACKGROUND AND OBJECTIVE:Sympathetic activity, measured as changes in electrical skin impedance, may be used to assess the adequacy of general anaesthesia. The aim of this prospective study was to evaluate electrical skin impedance in comparison with bispectral index values and the Observer's Assessment of Alertness and Sedation (OAAS) scale during propofol infusion.METHODS:Electrical skin impedance was measured with an electrosympathicograph. In 22 patients and eight healthy volunteers, anaesthesia was induced and maintained with propofol that was administered via a target-controlled infusion pump at increasing plasma concentrations. Bispectral index, electrosympathicograph and OAAS values were compared at six successive predicted target plasma concentrations (T 1-6: 0, 1.3, 1.7, 2.0, 2.4 and 2.8 microg ml(-1)).RESULTS:The changes in the electrical skin impedance measured with the assistance of the electrosympathicograph correlated with the changes in bispectral index values at each measurement time point and during the whole course (P < 0.0001), with the target plasma propofol concentrations (P < 0.0001), and with the OAAS scale (P < 0.0001).CONCLUSION:The observed correlations between electrical skin impedance, predicted plasma concentrations of propofol and OAAS scale appear to justify further investigation of skin impedance as a depth of anaesthesia monitor.

UNLABELLED:Antihistamines and nasal decongestants are well-established therapeutics in allergic rhinitis. However, no data are available which directly compare the effect size of the single substances with their combination in a single study including placebo (PLA) treatment.OBJECTIVE:The aim of this study was to evaluate the effect of a combination of cetirizine (CET) and pseudoephedrine (PSE) and to compare it to treatment with CET or PSE alone and to PLA during grass pollen allergen challenge in an environmental challenge chamber (ECC).MATERIAL AND METHODS:In a randomized, double-blind, placebo-controlled, four-way crossover study the effect of a combination of 10 mg CET with 120 mg PSE (CET + PSE) versus CET or PSE alone or PLA on symptoms, nasal flow, and nasal secretions was investigated in 49 patients with intermittent allergic rhinitis. Subjects underwent four 6-h pollen exposures in an ECC with administration of the drugs after 2 h.RESULTS:The induction of nasal symptoms, nasal secretion and nasal obstruction (measured as nasal flow) during the first 2 h of pollen exposure was highly reproducible at the 4 consecutive exposures. The symptom of nasal obstruction was significantly reduced after treatment with CET + PSE compared to the treatment with CET or PSE alone or PLA (p < 0.0001). Furthermore, the combination treatment significantly reduced the total nasal symptom score (TNSS) and visual analogue scale score (VAS) compared to the single treatments or PLA. Nasal flow was significantly increased after treatment with CET + PSE and PSE and nasal secretions were significantly reduced by CET + PSE and CET without significant additional improvement of the combination therapy.CONCLUSION:The combination treatment with CET and PSE is more effective than treatment with single substances in subjects with allergic rhinitis.