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Background Postextrasystolic blood pressure potentiation (PESP), the pulse wave augmentation after an extrasystolic beat, is typically enhanced in heart failure (HF) patients. This study prospectively tested the association of PESP and mortality in cardiac patients. Methods and Results Consecutive patients (n=941; mean age, 61 years; 19% female) presenting with acute myocardial infarction were enrolled between May 2000 and March 2005 and followed up until August 2010. The main study outcome was 5‐year all‐cause mortality. Patients underwent noninvasive 30‐minute recordings of ECG and continuous blood pressure. PESP presence was based on the ratio between the first postectopic pulse wave amplitude and the mean of the subsequent 9 pulse wave amplitudes. A ratio above 1 was prospectively defined as PESP present. Ventricular premature complexes (VPCs) suitable for PESP quantification were present in recordings of 220 patients. PESP was present in 62 of these patients. Patients without suitable VPCs were classified as PESP absent. During the follow‐up, 72 patients died. Among the 220 patients in whom PESP was measurable, 27 died. Under univariable analysis, PESP was a significant predictor of death ( P P P P P P P =0.001) were independently associated with outcome. The combination of PESP presence and LVEF ≤35% identified a subgroup of patients with a particularly high mortality of 46.7%. Separate validation reproduced the finding in an unrelated population of 146 HF patients. Conclusions PESP, which likely reflects abnormalities of myocardial calcium cycling, predicts the mortality risk in postinfarction patients. Clinical Trial Registration URL: ClinicalTrials.gov . Unique identifier: NCT00196274.

Amyotrophic lateral sclerosis (ALS) is predominantly characterized by a progressive loss of motor function. While autonomic dysfunction has been described in ALS, little is known about the prevalence of lower urinary tract symptoms (LUTS) and intestinal dysfunction. We investigated disease severity, LUTS and intestinal dysfunction in 43 patients with ALS attending our outpatient department applying the ALS functional rating scale, the International Consultation on Incontinence Modular Questionnaire, the Urinary Distress Inventory and the Cleveland Clinic Incontinence Score. Results were compared to the German population of a cross-sectional study assessing LUTS in the healthy population, the EPIC study. Results showed that urinary incontinence was increased in patients with ALS aged ≥ 60 years compared to the EPIC cohort (female: 50%/19% (ALS/EPIC), p = 0.026; male: 36%/11% (ALS/EPIC), p = 0.002). No difference was seen at 40-59 years of age. Urge incontinence was the predominant presentation (73% of symptoms). A high symptom burden was stated (ICIQ-SF quality of life subscore 5.5/10). Intake of muscle relaxants and anticholinergics was associated with both urinary incontinence and severity of symptoms. Furthermore, a high prevalence of constipation (46%), but not stool incontinence (9%), was noted. In conclusion, the increased prevalence of urge incontinence and high symptom burden imply that in patients with ALS, LUTS should be increasingly investigated for.

Objective: Platelets play an important role in liver regeneration. One major problem after liver surgery represents the impaired postoperative liver function and delayed recovery. The aim of this study was to evaluate the association of platelet counts to liver regeneration and postoperative outcome after liver surgery for colorectal metastases. Methods: This study included 84 patients without chronic liver disease (such as viral hepatitis or liver cirrhosis) who received partial liver resection between July 2007 and July 2012 for colorectal liver metastases in our hospital. 65% received preoperative chemotherapy. All patients presented with normal liver function before surgery. Platelet counts were obtained between day -1 and day 12 to surgery and correlated with postoperative morbidity and mortality. Comparative analysis between patients with platelet counts ≤ 100/nl and >100/nl one day after liver surgery was performed in regard to postoperative outcome and liver regeneration. Results: Postoperative low platelet counts are associated with significant higher morbidity (p=0.003) and need of re-operation (p=0.004). Furthermore, thrombocytopenic patients showed impaired liver function with significantly higher bilirubin levels (p=0.001; p=0.005) and lower prothrombin time (p=0.015; 0.006) between day 1 and day 7. Conclusion: Postoperative low platelet counts are associated with higher morbidity after liver surgery. Low platelet counts lead to impaired liver function with delayed recovery after liver surgery.

In the last few decades, new developments in liver surgery have led to an expanded applicability and an improved safety. However, liver surgery is still associated with postoperative morbidity and mortality, especially in extended resections. We analyzed a large liver surgery database to investigate whether laboratory parameters like haemoglobin, leucocytes, bilirubin, haematocrit and lactate might be relevant preoperative predictors. It is not uncommon to observe missing values in such data. This also holds for many other data sources and research fields. For analysis, one can make use of imputation methods or approaches that are able to deal with missing values in the predictor variables. A representative of the latter are Random Forests which also provide variable importance measures to assess a variable's relevance for prediction. Applied to the liver surgery data, we observed divergent results for the laboratory parameters, depending on the method used to cope with missing values. We therefore performed an extensive simulation study to investigate the properties of each approach. Findings and recommendations: Complete case analysis should not be used as it distorts the relevance of completely observed variables in an undesirable way. The estimation of a variable's importance by a self-contained measure that can deal with missing values appropriately reflects the decreased relevance of variables with missing values. It can therefore be used to obtain insight into Random Forests which are commonly fit without preprocessing of missing values in the data. By contrast, multiple imputation allows for the assessment of a variable's relevance one would potentially observe in complete-data situations, if imputation performs well. For the laboratory data, lactate and bilirubin seem to be associated with the risk of liver failure and postoperative complications. These relations should be investigated by future studies in more detail. However, it is important to carefully consider the method used for analysis when there are missing values in the predictor variables.

OBJECTIVES To assess the risk factors for increased antimicrobial resistance among Enterobacteriaceae representing the most common biliary pathogens. METHODS A retrospective analysis was conducted of 276 patients with acute cholangitis treated at a German tertiary centre between April 1996 and May 2009. The resistance patterns among Enterobacteriaceae isolated from blood/bile cultures were compared and related to age, sex, the genesis of the cholangitis and the type and number of previous interventional procedures [percutaneous transhepatic cholangiography (PTC)/endoscopic retrograde cholangiography (ERC)]. Univariate and multivariate generalized estimation equation models were used to compute ORs with corresponding 95% CIs for the binomial outcomes. RESULTS According to the univariate analysis, patients undergoing stent therapy had a smaller proportion of Enterobacteriaceae with susceptibility to quinolones (ofloxacin/ciprofloxacin) (184/239 versus 205/221; P

Background Repetitive navigated transcranial magnetic stimulation (rTMS) has been used for studying language organization in healthy volunteers and patients, and to detect cortical areas involved in language processing. However, little is known about the reliability of this method. To determine the reliability of rTMS language mapping, we conducted both an interobserver and an intraobserver investigation. Methods Ten right-handed healthy subjects underwent language mapping by rTMS and the same object-naming task three times. Intraobserver and interobserver reliability of seven different error types were tested by two investigators. Analysis was performed blinded to the previous results and stimulated cortical sites. Results Overall, the results of both the interobserver and the intraobserver investigations show variable accordance. This is demonstrated by comparing the error rates of all different error types of the three examinations. Considering the most important error type, “no response”, there is only small variability in inter- and intraobserver mapping. Conclusions With our current protocol, interobserver and intraobserver comparisons only corresponded partially. Thus, although rTMS seems a promising method for preoperative planning as well as neuropsychological research, the current protocol needs further improvement.

We aimed to describe and evaluate an autocalibrating algorithm for determination of cardiac output (CO) based on the analysis of an arterial pressure (AP) waveform recorded using radial artery applanation tonometry (AT) in a continuous non-invasive manner. To exemplarily describe and evaluate the CO algorithm, we deliberately selected 22 intensive care unit patients with impeccable AP waveforms from a database including AP data obtained with AT (T-Line system; Tensys Medical Inc.). When recording AP data for this prospectively maintained database, we had simultaneously noted CO measurements obtained from just calibrated pulse contour analysis (PiCCO system; Pulsion Medical Systems) every minute. We applied the autocalibrating CO algorithm to the AT-derived AP waveforms and noted the computed CO values every minute during a total of 15 min of data recording per patient (3 × 5-min intervals). These 330 AT-derived CO (AT-CO) values were then statistically compared to the corresponding pulse contour CO (PC-CO) values. Mean ± standard deviation for PC-CO and AT-CO was 7.0 ± 2.0 and 6.9 ± 2.1 L/min, respectively. The coefficient of variation for PC-CO and AT-CO was 0.280 and 0.299, respectively. Bland-Altman analysis demonstrated a bias of +0.1 L/min (standard deviation 0.8 L/min; 95% limits of agreement -1.5 to 1.7 L/min, percentage error 23%). CO can be computed based on the analysis of the AP waveform recorded with AT. In the selected patients included in this pilot analysis, a percentage error of 23% indicates clinically acceptable agreement between AT-CO and PC-CO.

Nonoperative treatment of stable juvenile osteochondritis dissecans (JOCD) lesions of the knee fails in up to 50% of cases. Healing predictors are needed to identify potential failures and thus determine treatment options.A predictive model for healing potential after 6 and 12 months of nonoperative treatment of stable JOCD lesions based on sensitive magnetic resonance imagining (MRI) follow-up measurements was developed.Cohort study (diagnosis); Level of evidence, 2.A retrospective cross-sectional study was conducted to analyze 62 white patients (76 stable JOCD lesions) who were initially treated by restriction of activity until they were free of pain. The primary end point was healing investigated on MRI with follow-up measurements after 6 and 12 months of nonoperative treatment. Multivariate logistic regression was used to determine the influence of age, sex, JOCD lesion size, clinical symptoms, and the occurrence of cystlike lesions (CLLs) on healing potential. Additionally, optimal prognostic cutoffs were defined to differentiate failures from nonfailures.After 6 months of nonoperative treatment, 51 (67%) of 76 stable JOCD lesions showed no progression toward healing or showed signs of instability. Normalized lesion width and area and CLL occurrence differed significantly between failures and nonfailures (P.05). A multivariate logistic regression best-predictors model that included age, CLL size, and normalized lesion width best predicted healing after 6 months and resulted in an area under the curve (AUC) of 0.779 (P.001). A cutoff at 48% healing probability, as predicted by a nomogram based on age, normalized lesion width, and CLL size, differentiated failures from nonfailures (sensitivity, 60.0%; specificity, 83.7%). After 12 months, 37 lesions (49%) had progressed toward healing, and the sole observation of CLL size had the highest predictive validity (AUC, 0.766). The optimal cutoff was a healing probability of 61% (lesion size, 1.3 mm; sensitivity, 70.3%; specificity, 74.1%).A 6-month period of nonoperative treatment with or without casting might be appropriate if the healing potential is48%. A 12-month period of nonoperative treatment may be successful if the CLL is1.3 mm in length as assessed on MRI.

Ocular vestibular evoked myogenic potentials (oVEMP) are strongly influenced by recording conditions and stimulus parameters. Throughout the published literature, a large variety of stimuli is used for eliciting oVEMP. Our objective was to determine the effects of different rise/fall times and plateau times on oVEMP amplitudes and latencies. 32 healthy subjects were enrolled in the study. 500 Hz air-conducted tone bursts with the parameters rise-plateau-fall time 0-4-0, 4-0-4, 2-2-2 and 2-4-2 ms were used for eliciting oVEMP. For all stimuli, response prevalences were 100 %. The 4-0-4 ms stimulus generated the smallest amplitudes, whereas the 2-2-2 and 0-4-0 ms stimuli achieved the largest amplitudes. n1 and p1 latencies were significantly shorter for the 0-4-0 ms than for the other stimuli, whereas latencies in response to the 4-0-4 ms stimulus were prolonged. Hence, a variety of stimuli is suitable for evoking oVEMP in healthy subjects. We recommend a 2-2-2 ms stimulus for clinical testing of oVEMP elicited by air conducted sound, because it reproducibly generates oVEMP without exposing the ear to unnecessary amounts of acoustic energy.

Background For accuracy in navigated transcranial magnetic stimulation (nTMS), determination of the hotspot location of small hand muscles is crucial because it is the basis for the resting motor threshold (RMT) and, therefore, its spatial resolution. We investigated intra- and interobserver differences of hotspot mapping to provide evidence for the reproducibility of this method. Ten subjects underwent nTMS motor mapping of the hotspot for the abductor pollicis brevis muscle (APB) three times. The first two sessions were performed by the same examiner; the third mapping was performed by a different examiner. Distances between the first and second mappings (intraobserver variability) and between the second and third mappings (interobserver variability) were measured. Results Intraobserver variability had a mean of 8.1 ± 3.3 mm (limits of agreement (LOA) 1.7 to 14.6 mm), whereas mean interobserver variability was 10.3 ± 3.3 mm (LOA 3.8 to 16.7 mm). Concerning RMT, CCC was 0.725 (95% CI: 0.276; 0.914). The mean variability in the same cortical depth was measured as 5.7 ± 3.3 mm (LOA −0.7 to 12.2 mm) for intraobserver and 9.2 ± 3.3 mm (LOA 2.7 to 15.8 mm) for interobserver examinations. When evaluating the RMT, CCC was 0.709 (95% CI: 0.244; 0.909). Conclusions Overall, intraobserver variability showed higher reliability than interobserver variability. Our findings show that we can achieve good reliability in hotspot determination, ranging within the calculated precision of the system.

Background: Differentiation between septic and aseptic loosening of joint replacements is essential for successful revision surgery, but reliable markers for the diagnosis of low-grade infection are lacking. The present study was performed to assess intra-articular and systemic levels of antimicrobial peptides and proinflammatory cytokines as diagnostic markers for periprosthetic joint infection. Methods: Fifteen consecutive patients with staphylococcal periprosthetic joint infections and twenty control patients with aseptic loosening of total hip and knee replacements were included in this prospective, single-center, controlled clinical trial. Expression of the antimicrobial peptides human β-defensin-2 (HBD-2), human β-defensin-3 (HBD-3), and cathelicidin LL-37 (LL-37) was determined by ELISA (enzyme-linked immunosorbent assay) in serum and joint aspirates. Proinflammatory cytokines were assessed in serum and joint aspirates with use of cytometric bead arrays. C-reactive protein in serum, microbiology, and histopathology of periprosthetic tissue served as the “gold standard” for the diagnosis of infection. Results: The antimicrobial peptides HBD-3 and LL-37 were significantly elevated in joint aspirates from patients with periprosthetic joint infection compared with patients with aseptic loosening, and the area under the curve (AUC) in a receiver operating characteristic curve analysis was equal to 0.745 and 0.875, respectively. Additionally, significant local increases in the proinflammatory cytokines interleukin (IL)-1β, IL-4, IL-6, IL-17A, interferon (IFN)-γ, and tumor necrosis factor (TNF)-α were observed to be associated with infection. Logistic regression analysis indicated that the combination of an antimicrobial peptide with another synovial fluid biomarker improved diagnostic accuracy; the AUC value was 0.916 for LL-37 and IL-4, 0.895 for LL-37 and IL-6, 0.972 for HBD-3 and IL-4, and 0.849 for HBD-3 and IL-6. In contrast, the only antimicrobial peptides and cytokines in serum that showed a significant systemic increase in association with infection were HBD-2, IL-4, and IL-6 (all of which had an AUC value of

Background The aim of the study was to investigate the effect of red blood cell (RBC) transfusion on hemodynamic parameters including transpulmonary thermodilution (TPTD)-derived variables. Methods We compared hemodynamic parameters obtained before and after RBC transfusion (2 RBC units) in 34 intensive care unit (ICU) patients. Results Directly after RBC transfusion, we observed a significant increase in hematocrit (28 ± 3 vs. 22 ± 2%, p

The aim of this biomechanical in vitro study was to compare the novel technique of double intramedullary cortical button (DICB) fixation with the well-established method of suture anchor (SA) fixation for distal biceps tendon repair.A matched-pair analysis (24 human cadaveric radii) was performed with respect to cyclic loadings and failure strengths. Twelve specimens per group were cyclically loaded for 1,000 cycles at 1.5 Hz from 5 to 50 N and from 5 to 100 N, respectively. The tendon-bone displacement was optically analysed using the Image J Software (National Institute of Health). Afterwards, all specimens were pulled to failure. Maximum load to failure and mode of failure were recorded.All DICB constructs passed the cyclic loading test, whereas 4 of the 12 specimens within the SA group failed by anchor pull-out. Cyclic loading showed a mean tendon-bone displacement of 0.6 ± 1.4 mm for the DICB group and 1.4 ± 1.4 mm for the SA group (n.s.) after 1,000 cycles with 50 N, and a mean displacement of 2.1 ± 2.4 mm for the DICB group and 3.5 ± 3.7 mm for the SA group (n.s.) after 1,000 cycles with 100 N. Load to failure testing showed a mean failure load of 312 ± 76 N and a stiffness of 67.1 ± 11.7 N/mm for the DICB technique. The mean load to failure for the SA repair was 200 ± 120 N (n.s.) and the stiffness was 55.9 ± 21.3 N/mm (n.s.).The novel technique of DICB fixation showed small tendon-bone displacement during cyclic testing and reliable fixation strength to the bone in load to failure. Moreover, all DICB constructs passed cyclic loadings without failure. Based on the current findings, a more aggressive postoperative rehabilitation may be allowed for the DICB repair in clinical use.

Background Once aprotinin was no longer available for clinical use, ɛ-aminocaproic acid (EACA) and tranexamic acid became the only two options for antifibrinolytic therapy. We compared aprotinin and EACA with respect to their blood-sparing efficacy and other major clinical outcome criteria in infants undergoing cardiac surgery. Methods We retrospectively analysed data from a large consecutive cohort of infants ( n =227) aged 31–365 days undergoing primary cardiac surgery requiring cardiopulmonary bypass encompassing the transition from aprotinin to EACA (aprotinin n =88, EACA n =139); all other aspects including the medical team and departmental protocols remained unchanged. The primary outcome was postoperative blood loss measured as chest tube output (CTO). Secondary outcome parameters were transfusion requirements, reoperation due to bleeding, renal, vascular, and neurological complications, and in-hospital mortality. Results CTO was significantly higher in the EACA patients {aprotinin 18 (13–27) ml kg −1 24 h −1 , EACA 23 (15–37) ml kg −1 24 h −1 [mean (inter-quartile range)], P =0.001}, but transfusion requirements and donor exposures were not significantly different. A sensitivity analysis strengthened our finding that the increased blood loss in the EACA group was attributable to lower efficacy of EACA. There were no significant differences in the other clinical outcome measures. Conclusions CTO was lower in aprotinin-treated patients. Nonetheless, EACA remains a suitable substitute without measurable differences in other clinical outcome criteria.

Background The occurrence of severe carotid artery disease in more than 12% of patients requiring coronary artery bypass grafting (CABG) results in a discrepancy concerning best treatment for both diseases. We reviewed the early outcome of patients with CABG and/or valve replacement (VR) and simultaneous carotid endarterectomy (CEA). Methods We retrospectively evaluated 386 patients after simultaneous operation between 7/1994 and 9/2010. Total 326 patients received isolated CABG, 56 CABG and/ or VR, 4 aortic surgery. Mean age was 68.3 years (range: 45 to 87). Male patients were 229. Severity of stenosis at operated side was 70 to 80% in 167, 80 to 99% in 219 patients. Total 164 patients showed bilateral carotid stenosis, 32 had contralateral occlusion. We analyzed risk factors, morbidity, incidence of neurological events, and 30-day mortality. Results Perioperative stroke with hemiplegia occurred in 10 patients (2.6%). Three patients experienced PRIND, seven TIA. A 30-day mortality was 5.2%. Total 8 deaths were cardiac related, 10 due to extracardial reasons, and 2 patients developed a cerebral death. Conclusions Simultaneous CEA and cardiac surgery can be performed with a low risk for neurological complications and acceptable mortality. Occlusion of contralateral carotid artery could be identified as an evident predictor for increased neurological complications.

The therapeutic activity of the epidermal growth factor receptor (EGFR)-directed monoclonal antibody cetuximab in gastric cancer is currently being investigated. Reliable biomarkers for the identification of patients who are likely to benefit from the treatment are not available. The aim of the study was to examine the drug sensitivity of five gastric cancer cell lines towards cetuximab as a single agent and to establish predictive markers for chemosensitivity in this cell culture model. The effect of a combination of cetuximab with chemotherapy was compared between a sensitive and a nonsensitive cell line.EGFR expression, activation and localisation, the presence and subcellular localisation of the cell adhesion molecule E-cadherin as well as MET activation were examined by Western blot analysis, flow cytometry and immunofluorescence staining. Cells were treated with varying concentrations of cetuximab and cisplatin and 5-fluorouracil in tumour-relevant concentrations. The biological endpoint was cell viability, which was measured by XTT cell proliferation assay. Response to treatment was evaluated using statistical methods.We assessed the activity of cetuximab in five gastric cancer cell lines (AGS, KATOIII, MKN1, MKN28 and MKN45). The viability of two cell lines, MKN1 and MKN28, was significantly reduced by cetuximab treatment. High EGFR expression and low levels of receptor activation were associated with cetuximab responsiveness. MET activation as well as mutations of KRAS and CDH1 (gene encoding E-cadherin) was associated with cetuximab resistance.These data indicate that our examinations may be clinically relevant, and the candidate markers should therefore be tested in clinical studies.

The T-Line TL-200 (Tensys Medical Inc., San Diego, CA, USA) is a noninvasive arterial blood pressure (BP) monitoring system allowing continuous beat-to-beat monitoring of systolic arterial pressure (SAP), mean arterial pressure (MAP), and diastolic arterial pressure (DAP). It provides a real-time BP waveform like that obtained using an arterial catheter for BP monitoring. The aim of this study was to compare BP measurements obtained using the T-Line TL-200 system with simultaneous invasive BP measurements using a femoral arterial catheter in unselected critically ill medical patients.

The therapeutic activity of the epidermal growth factor receptor (EGFR)-directed monoclonal antibody cetuximab in gastric cancer is currently being investigated in clinical studies. Reliable biomarkers for the identification of patients who are likely to benefit from this treatment are not available. In this study, we assessed the activity of cetuximab in five gastric cancer cell lines (AGS, AZ521, Hs746T, LMSU and MKN1). The viability of two of these cell lines, AZ521 and MKN1, was significantly reduced by cetuximab treatment. High expression and secretion levels of the EGFR-binding ligand, amphiregulin (AREG), were associated with cetuximab responsiveness. MET activation and mutations in Kirsten-Ras gene (KRAS) were associated with cetuximab resistance. By introducing a hierarchy between these markers, we established a model that facilitated the correct classification of all five gastric cancer cell lines as cetuximab responsive or non-responsive. The highest priority was allocated to activating KRAS mutations, followed by MET activation and finally by the levels of secreted AREG. In order to validate these results, we used three additional human gastric cancer cell lines (KATOIII, MKN28 and MKN45). In conclusion, we propose that our model allows the response of gastric cancer cell lines to cetuximab treatment to be predicted.

The purpose of this study was to investigate characteristics of critically ill patients with Stenotrophomonas maltophilia (S. maltophilia) isolated from the respiratory tract, to identify risk factors for S. maltophilia-pneumonia and intensive care unit (ICU) mortality and to analyze antibiotic susceptibility of S. maltophilia. This was a retrospective analysis of 64 medical ICU patients with S. maltophilia in the respiratory tract. Thirty-six patients fulfilled the criteria for diagnosis of pneumonia. A significantly higher lung injury score (LIS) was observed in patients with pneumonia compared to patients with colonization (p = 0.010). Independent risk factors for S. maltophilia-pneumonia were higher Sequential Organ Failure Assessment (SOFA) score (p = 0.009) and immunosuppression (p = 0.014). Patients with S. maltophilia-pneumonia had higher ICU mortality within a 28-day follow-up (p = 0.040) and higher hospital mortality (p = 0.018) than patients with colonization. The highest antibiotic susceptibility rates were observed to trimethoprim-sulfamethoxazole, tigecycline, and moxifloxacin. Higher SOFA score when S. maltophilia was isolated (p = 0.001) and development of renal failure (p = 0.021) were independent risk factors for ICU mortality. Higher SOFA score and immunosuppression are independent risk factors for S. maltophilia-pneumonia. Patients with S. maltophilia-pneumonia have a significantly higher ICU mortality within a 28-day follow-up, hospital mortality and LIS compared to patients with S. maltophilia-colonization.

Optimal surgical treatment of high-grade acromioclavicular joint dislocations is still controversially discussed. The purpose of the present controlled laboratory study was to evaluate whether a polydioxansulfate (PDS(®)) cord augmentation with separate reconstruction of the coracoclavicular (CC) ligaments and the acromioclavicular (AC) complex provides sufficient vertical stability in a biomechanical cadaver model.Twenty-four shoulders of fresh-frozen cadaveric specimen were tested. Cyclic loading and load to failure protocol was performed in vertical direction on 12 native AC joints and repeated after reconstruction. The reconstruction of the coracoclavicular ligament was performed using two CC PDS cerclages and an additional AC PDS cerclage.In static load testing for vertical force, the native AC joint complex measured 590.1 N (±95.8 N), elongation 13.4 mm (±2.1 mm) and stiffness 48.7 N/mm (±12.0 N/mm). The mean maximum load to failure in the reconstructed joints was 569.9 N (±97.9 N), elongation 18.8 mm (±4.7 mm) and stiffness 37.9 N/mm (±8.0 N/mm). During dynamic testing of the reconstructed AC joints, all specimens reached the critical elongation of 12.0 mm, defined as clinical failure between 200 and 300 N. The mean amount of repetitions at clinical failure was 305. A plastic deformation of the reconstructed specimens throughout cyclic loading could not be detected.The AC joint reconstruction with acromioclavicular and coracoclavicular PDS cord cerclages did not provide the aspired vertical stability in a cadaver model.Basic Science Study.

Purpose The purpose of this study was to evaluate prediction factors for extubation failure (need for reintubation within 48 hours) in medical intensive care unit patients. Materials and Methods Sixty-one patients extubated after mechanical ventilation for more than 48 hours were included in the study. A retrospective analysis of medical records and a prospectively maintained database on respiratory parameters was conducted. Results Low serum anion gap (P = .001), low serum anion gap corrected for serum albumin (P = .010), and low arterial partial pressure of oxygen (Pa o 2)/fraction of inspired oxygen (F io 2) ratio (P = .032) were significantly associated with extubation failure. Binary logistic regression analysis revealed low uncorrected and corrected serum anion gap (P = .006 and P = .025, respectively; odds ratio, 0.59 for both) and low Pa o 2/F io 2 ratio (P = .038; odds ratio, 0.99) as risk factors for extubation failure. Regarding extubation failure, receiver operating characteristic curve (ROC) analysis demonstrated good predictive capabilities of serum anion gap (ROC area under the curve, 0.835; P = .004; cutoff, 7.7 mEq/L; sensitivity, 70.4%; specificity, 85.7%) and corrected serum anion gap (ROC area under the curve, 0.808; P = .009; cutoff, 8.8 mEq/L; sensitivity, 87.5%; specificity, 71.4%). A significantly higher risk for extubation failure was observed in patients with serum anion gap 5.2 mEq/L or less (relative risk, 8.8; 95% confidence interval, 2.4-32.4; P = .004) and corrected serum anion gap 8.6 mEq/L or less (relative risk, 10.0; 95% confidence interval, 2.2-44.9; P = .004). Conclusions Low preextubation serum anion gap values and low preextubation Pa o 2/F io 2 ratio might help to predict extubation failure in medical intensive care unit patients.

Purpose The aim of this study was to evaluate continuous vancomycin infusion (contV) in intensive care unit patients. Materials and Methods A retrospective study in 164 patients treated with contV was conducted. They were compared with 75 patients treated with intermittent vancomycin infusion. Results The median duration of vancomycin therapy in the contV group was 6 (5%-95% percentile range, 2-21) days. The median daily vancomycin dose in the contV group was 960 (526-1723) mg, resulting in a median serum vancomycin plateau concentration of 19.8 (9.8-29.4) mg/L (target: 15-25 mg/L). The contV administration regime was sufficient regarding achievement of the target serum vancomycin concentration. However, in the contV group, serum vancomycin levels were frequently in a subtherapeutic range on treatment days 1 (44%), 2 (29%), and 3 (23%). In the contV group, serum vancomycin concentration determinations per treatment day were performed significantly less often compared with the intermittent vancomycin infusion group (0.38 [0.15-0.75] vs 0.43 [0.22-1.00], P = .041). Conclusions In medical intensive care unit patients, contV is sufficient to achieve target serum vancomycin concentrations. Because contV frequently resulted in subtherapeutic drug levels on the first days of therapy, a higher loading or starting dose might be necessary.

To evaluate the accuracy of measurements of the optic nerve sheath diameter (ONSD) in children by comparing transbulbar sonography with magnetic resonance imaging (MRI). 65 children (age: 3 mo- 17y; mean age: 11.3y) underwent MR imaging of the brain including a heavily T 2-w sequence of the orbit and transbulbar sonography using a 17 MHz linear array transducer. Measurements of the ONSD were performed retrospectively by two experienced readers and all images were evaluated regarding the image quality. Bland-Altman Plots were produced to assess the accuracy of measurements. The correlation between readers and between MR imaging and transbulbar sonography was calculated by the concordance correlation coefficient (CCC). Overall the mean values of the ONSD for MRI (5.86 ± 0.66 mm) and transbulbar sonography (5.86 ± 0.71 mm) were identical. There was a high correlation between readers for measurements of the ONSD both for transbulbar sonography (CCC = 0.93) as well as for MRI (CCC = 0.9). Comparing the measurement values between transbulbar sonography and MRI, the correlation of ONSD values was good to moderate with a high dependency on image quality (CCC [0.31, 0.68]). We were able to demonstrate that the ONSD values of transbulbar sonography in children correlate well with MRI if the relevant anatomic structures are depicted and the measuring points are set correctly. Based on the findings of our study, it seems necessary to define normal and cut-off values for the ONSD in children again to finally assess the clinical relevance of the ONSD as a noninvasive parameter for the evaluation of intracranial pressure.ZIEL:: Evaluation der Genauigkeit von Messungen des Nervenscheidendurchmessers des Nervus opticus (ONSD) bei Kindern durch den Vergleich zwischen transbulbärer Sonografie und Magnetresonanztomografie (MRT). 65 Kinder (Altersspanne: 3 Monate – 17 Jahre; Mittelwert: 11,3 Jahre) erhielten eine MRT-Untersuchung des Kopfes inklusive einer stark T 2-gewichteten Sequenz der Orbita und eine transbulbäre Sonografie mit einem 17 MHz-Linearschallkopf. Die Messungen des ONSD erfolgten retrospektiv durch zwei erfahrene Untersucher und alle Bilder wurden hinsichtlich der Bildqualität beurteilt. Mittels Bland-Altman-Plots wurde die Messgenauigkeit ermittelt. Die Korrelation zwischen den Betrachtern und zwischen den Messergebnissen aus MRT und transbulbärer Sonografie wurde durch concordance correlation coefficients (CCC) bestimmt. Insgesamt fand sich eine exakte Übereinstimmung der Mittelwerte des ONSD zwischen MRT (5,86 ± 0,66 mm) und transbulbärer Sonografie (5,86 ± 0,71 mm). Es bestand eine hohe Korrelation der Messungen des ONSD zwischen den Betrachtern sowohl für die transbulbäre Sonografie (CCC = 0,93) als auch die MRT (CCC = 0,9). Vergleicht man die Werte der ONSD-Messungen zwischen transbulbärer Sonografie und MRT, ergab sich eine mittlere bis gute Korrelation mit deutlicher Abhängigkeit der Ergebnisse von der Bildqualität (CCC [0.31, 0.68]). Wir konnten zeigen, dass die ONSD-Messwerte der transbulbären Sonografie gut mit denen der MRT korrelieren, wenn die relevanten anatomischen Strukturen dargestellt sind und die Messpunkte korrekt gesetzt werden. Basierend auf den Ergebnissen der Studie erscheint es notwendig, nochmals Norm- und Grenzwerte für den ONSD bei Kindern zu bestimmen, um die klinische Bedeutung des ONSD bei der Hirndruckdiagnostik abschließend beurteilen zu können.

For the subjective assessment of workload, Borg's Rating of Perceived Exertion (RPE) scale is a global measure of perceived workload during anaesthesia induction, maintenance and emergence in the real workplace. In the present study, validity and reliability of the RPE scale were analysed for a full-scale simulator environment using scenarios of induction of general anaesthesia with and without critical incidents.Seventeen anaesthetists (professional experience 1-30 years) participated in this randomised cross-over trial. Each participant rated their workload using the RPE scale after three different simulator sessions. No critical incident was simulated in the 1st session. In a randomised order, workload was increased by simulation of a critical incident in the 2nd or 3rd session. For the analysis of validity and reliability, univariate and multivariate regression analysis and the concordance correlation coefficient were used.RPE scores were significantly increased after managing a simulated critical incident [13.0, 95% confidence interval (CI) 11.6-14.5] compared to normal anaesthesia induction (9.4, 95% CI 8.2-10.6; P0.001). Reliability was moderate (concordance correlation coefficient = 0.55; 95% CI 0.13-0.80) for uneventful sessions.RPE scores were significantly increased after critical incidents during simulated anaesthesia induction and indicate good construct validity. Reliability may be impaired by the fact that the first session was announced to be without a critical incident. The RPE scale is easy to administer and a valid tool for subjective workload assessment in simulator settings. Reliability is moderate.

PURPOSE: We performed a cadaver study to evaluate the accuracy of measurements of the optic nerve and the optic nerve sheath for high resolution US (HRUS) and magnetic resonance imaging (MRI). MATERIALS AND METHODS: Five Thiel-fixated cadaver specimens of the optic nerve were examined with HRUS and MRI. Measurements of the optic nerve and the ONSD were performed before and after the filling of the optic nerve sheath with saline solution. Statistical analysis included the calculation of the agreement of measurements and the evaluation of the intraobserver and interobserver variation. RESULTS: Overall a good correlation of measurement values between HRUS and MRI can be found (mean difference: 0.02 - 0.97 mm). The repeatability coefficient (RC) and concordance correlation coefficient (CCC) values were good to excellent for most acquisitions (RC 0.2 - 1.11 mm; CCC 0.684 - 0.949). The highest variation of measurement values was found for transbulbar sonography (RC 0.58 - 1.83 mm; CCC 0.615 / 0.608). CONCLUSION: If decisive anatomic structures are clearly depicted and the measuring points are set correctly, there is a good correlation between HRUS and MRI measurements of the optic nerve and the ONSD even on transbulbar sonography. As most of the standard and cut-off values that have been published for ultrasound are significantly lower than the results obtained with MRI, a reevaluation of sonographic ONSD measurement with correlation to MRI is necessary.

Breast cancer is globally a major threat for women's health. Screening and adequate follow-up can significantly reduce the mortality from breast cancer. Human second reading of screening mammograms can increase breast cancer detection rates, whereas this has not been proven for current computer-aided detection systems as "second reader". Critical factors include the detection accuracy of the systems and the screening experience and training of the radiologist with the system. When assessing the performance of systems and system components, the choice of evaluation methods is particularly critical. Core assets herein are reference image databases and statistical methods.We have analyzed characteristics and usage of the currently largest publicly available mammography database, the Digital Database for Screening Mammography (DDSM) from the University of South Florida, in literature indexed in Medline, IEEE Xplore, SpringerLink, and SPIE, with respect to type of computer-aided diagnosis (CAD) (detection, CADe, or diagnostics, CADx), selection of database subsets, choice of evaluation method, and quality of descriptions.59 publications presenting 106 evaluation studies met our selection criteria. In 54 studies (50.9%), the selection of test items (cases, images, regions of interest) extracted from the DDSM was not reproducible. Only 2 CADx studies, not any CADe studies, used the entire DDSM. The number of test items varies from 100 to 6000. Different statistical evaluation methods are chosen. Most common are train/test (34.9% of the studies), leave-one-out (23.6%), and N-fold cross-validation (18.9%). Database-related terminology tends to be imprecise or ambiguous, especially regarding the term "case".Overall, both the use of the DDSM as data source for evaluation of mammography CAD systems, and the application of statistical evaluation methods were found highly diverse. Results reported from different studies are therefore hardly comparable. Drawbacks of the DDSM (e.g. varying quality of lesion annotations) may contribute to the reasons. But larger bias seems to be caused by authors' own decisions upon study design. RECOMMENDATIONS/CONCLUSION: For future evaluation studies, we derive a set of 13 recommendations concerning the construction and usage of a test database, as well as the application of statistical evaluation methods.

Workload assessment is an important tool for improving patient safety in anaesthesia. We tested the hypothesis that heart rate, pupil size, and duration of fixation increase, whereas saccade amplitude decreases with increased workload during simulated critical incidents.Fifteen trainee anaesthetists participated in this randomized cross-over trial. Each participant used a head-mounted eye-tracking device (EyeSeeCam) during induction of general anaesthesia in a full-scale simulation during three different sessions. No critical incident was simulated in the first session. In a randomized order, workload was increased by simulation of a critical incident in the second or third session. Pupil size, duration of fixations, saccadic amplitude, and heart rate of each participant and the simulator conditions were recorded continuously and synchronized. The data were analysed by paired sample t-tests and mixed-effects regression analysis.The findings of the second and third sessions of 11 participants were analysed. Pupil diameter and heart rate increased simultaneously as the severity of the simulated critical incident increased. Allowing for individual effects, the simulator conditions explained 92.6% of the variance in pupil diameter and 93.6% of the variance in heart rate (both P0.001). The duration of fixation decreased with increased workload. The saccadic amplitude remained unaffected by workload changes.Pupil size and heart rate reflect workload increase within simulator sessions, but they do not permit overall workload comparisons between individuals or sessions. Contrary to our assumption, the duration of fixation decreased with increased workload. Saccade amplitude did not reflect workload fluctuations.

To prevent postpneumonectomy bronchopleural fistula, coverage of the bronchial stump is recommended, especially for patients treated with neoadjuvant and adjuvant chemotherapy or radiochemotherapy. We compared outcomes after proximal pericardial fat pad coverage and coverage with pleura and surrounding tissues, by retrospective analysis of the records of 243 patients. Postpneumonectomy bronchopleural fistula occurred in 7/143 (4.9%) patients who had pericardial fat pad coverage, and in 6/100 (6.0%) treated by pleural covering. Bronchopleural fistula occurred in 11 patients within 21 days, in one after 2 months, and one after 6 months. Univariate analysis of comorbidities and risk factors did not show any significant differences between the groups. Advanced T stage and carcinomatous lymphangiosis at the resection margin were associated with a higher risk of bronchopleural fistula development, independent of the technique. Reinforcement of the bronchial stump by proximal pericardial fat pad coverage appears to be safe and feasible. It is comparable to coverage with pleura and surrounding tissues.

Objective: Tranexamic acid (TXA) and e-aminocaproic acid (EACA) are used for antifibrinolytic therapy in cardiac surgery, although data directly comparing their blood sparing effect and their side effects, especially in paediatric cardiac surgical patients, are still missing. Methods: We analysed perioperative data of 234 paediatric patients weighing less than 20 kg undergoing cardiac surgery. In a 5-month period, all patients (n = 114) received TXA (group TXA). During a second 5-month period, all patients (n = 120) were treated with EACA (group EACA). Primary outcome was blood loss at 24 h postoperatively; secondary outcome criteria were transfusion requirement, rate of revision for bleeding, postoperative complications and in-hospital mortality. Results: All descriptive and intra-operative parameters were well comparable. There was no evidence for a difference in blood loss at 24 h postoperatively (TXA 21 ml kg 1 (14—38) (median (interquartile range)) vs EACA 29 ml kg 1 (14— 40), p = 0.242), rate of re-operation for bleeding (TXA 9.6% vs EACA 8.3%, p = 0.725) and transfusion of blood products. The incidence of postoperative complications such as seizures (TXA 3.5% vs EACA 0.8%, p = 0.203) and other neurological complications (TXA 2.6% vs EACA 1.7%, p = 0.677), renal injury (TXA 9.6% vs EACA 13.3%, p = 0.378), renal failure (TXA 1.8% vs EACA 4.2%, p = 0.447), low cardiac output syndrome (TXA 12.3% vs EACA 10.8%, p = 0.729), and vascular thrombosis (TXA 4.4% vs EACA 5.0%, p = 0.824), as well as the in-hospital mortality (TXA 2.6% vs EACA 3.3%, p > 0.999) did not show any statistically significant difference. Conclusions: TXA and EACA are well comparable in their effect on perioperative blood loss as well as in major clinical outcome criteria. Although the fourfold risk for seizures using TXA was not significant, we currently use EACA in paediatric cardiac surgery. # 2010 European Association for Cardio-Thoracic Surgery. Published by Elsevier B.V. All rights reserved.

Introduction: Based on high-throughput transcriptional profiling and array comparative genomic hybridization, a three-gene predictor encompassing c-MYC, EGFR and FGFR2 has been identified to predict survival in cisplatin and fluorouracil (FU) – treated metastatic gastric cancer (GC) patients by others (1). The aim of our study was to determine the value of the expression of these three genes to predict response and/or survival for GC patients treated by a platin/5FU based chemotherapy in the neoadjuvant setting. Material and methods: Expression was analyzed in pretherapeutic tumor biopsies of 69 patients treated by platinum/5FU based neoadjuvant chemotherapy. Histopathological response was divided into three grades, tumor regression grade 1 (TRG1) corresponding to complete/major response, TRG2 corresponding to partial and TRG3 corresponding to minimal or no response. mRNA was isolated from manually microdissected formalin fixed and paraffin embedded tumor biopsies. Relative quantification of gene expression was performed by real time PCR using the delta-delta Ct method. As reference genes IPO8 and POLR2A were used and normalization was based on geometric averaging. Analyses were done in triplicates and the mean value was calculated. Fisher`s exact test or χ2-test (two sided) were used to test for an association with response. Overall survival was analyzed by log rank tests and Cox regression analyses. Results: Performing dichotomization of the patients based on median gene expression levels revealed a significant association of high c-MYC expression with minimal or no response (TRG3) (p=0.013). No other associations with response were observed for EGFR or FGFR2 expression in the study as a whole or in a separate analysis of patients with intestinal and nonintestinal type tumors. Testing various combinations of the expression of the three genes did not reveal a stronger association with response when compared to c-MYC expression alone. In the study as a whole, no statistically significant associations with overall survival were found. In the subgroup of nonintestinal-type tumors, univariate Cox regression analysis revealed a significantly increased risk of death for patients with a high expression of c-MYC (HR 59.56, 95%CI 1.28-2776.3; p=0.037). Conclusion: Our results indicate a prominent role of c-MYC expression to predict tumor shrinkage after platin/5FU-based neoadjuvant chemotherapy in GC and they suggest a prognostic relevance of this gene in particular for patients with nonintestinal-type gastric carcinomas. Reference: 1. Kim HK et al.: The Pharmacogenomics Journal (2012) 12: 119-127. Citation Format: Anna Munzig, Lukas Bauer, Julia Slotta-Huspenina, Alexander Novotny, Karen Becker, Alexander Hapfelmeier, Gisela Keller. c-MYC, EGFR, and FGFR2 expression and response and survival in neoadjuvant treated gastric cancer. [abstract]. In: Proceedings of the AACR Precision Medicine Series: Integrating Clinical Genomics and Cancer Therapy; Jun 13-16, 2015; Salt Lake City, UT. Philadelphia (PA): AACR; Clin Cancer Res 2016;22(1_Suppl):Abstract nr 12.

Background Monitoring cardiovascular function in acutely ill patients in the emergency department (ED) is of paramount importance. Arterial pressure (AP) is usually monitored using intermittent oscillometric measurements with an upper arm cuff. The vascular unloading technique (VUT) allows continuous noninvasive AP monitoring. In this study, we compare continuous AP measurements obtained by VUT with intermittent oscillometric AP measurements in ED patients. In addition, we aimed to investigate whether continuous noninvasive AP monitoring allows detection of relevant hypotensive episodes that might be missed with intermittent AP monitoring. Methods In a German university hospital, 130 ED patients who required AP monitoring were analyzed in this prospective method comparison study. Continuous AP monitoring was performed using VUT (CNAP technology; CNSystems Medizintechnik AG, Graz, Austria) over a 2-hour period. The oscillometric AP values were recorded simultaneously every 15 minutes for the comparison of both methods. For statistical evaluation, Bland-Altman plots accounting for repeated AP measurements per individual were used. Results The mean difference (±standard deviation) between AP measurements obtained by VUT and oscillometric AP measurements was -5 mmHg (±22 mmHg) for systolic AP (SAP), -2 mmHg (±15 mmHg) for diastolic AP (DAP), and -6 mmHg (±16 mmHg) for mean AP (MAP), respectively. In the interval between two oscillometric measurements, the VUT device detected hypotensive episodes (≥4 minutes) defined as either SAP

Purpose Accurate prediction of fluid responsiveness is of importance in the treatment of patients admitted to the intensive care unit (ICU). We investigated whether physical examination, central venous pressure (CVP), central venous oxygen saturation (ScvO 2 ), passive leg raising (PLR) test, and transpulmonary thermodilution (TPTD)–derived parameters can predict volume responsiveness in patients admitted to the ICU. Materials and Methods In this prospective study, structured clinical examination, measurement of CVP and ScvO 2 , a PLR test, and TPTD measurements were performed in 31 patients. A fluid challenge test was performed in 24 patients ( fluid responsiveness was defined as a cardiac index [CI] increase of ≥15%). Results Physical examination, CVP, ScvO 2 , the PLR test, and the TPTD-derived volumetric preload parameter global end-diastolic volume index showed poor prognostic capabilities regarding prediction of fluid responsiveness. Twenty-nine percent of patients were fluid responsive. There was a statistically significant correlation between the fluid challenge–induced increase in CI and changes in global end-diastolic volume index ( r = 0.666, P Conclusions Prediction of fluid responsiveness is difficult using physical examination, CVP, ScvO 2 , PLR maneuver, or TPTD-derived variables in critically ill patients. A volume challenge test should be considered for the assessment of fluid responsiveness in critically ill patients admitted to the ICU.

581 Background: Adjuvant therapy decisions in breast cancer patients are based on accurate risk assessment. UPA/PAI-1 can be used for risk evaluation. Recently, the EndoPredict-clin score (EPclin), a second generation multigene test has been introduced into clinical practice. Aim of this prospective study is to compare risk assessment by uPA/PAI-1 and EPclin and to determine, how these parameters influence treatment decisions. Methods: 100 consecutive cases of ER-pos, HER2neg, intermediate risk breast cancer cases were enrolled in this study. EPclin and uPA/PAI-1 (for G2-tumors) were obtained by central pathology assessment of the patients´ surgical specimen. Type of adjuvant treatment was chosen after case discussion in an interdisciplinary tumor conference. Results: 94 Patients (pt) have been evaluated. Tumor grading within the presented cohort was as follows: G1: 15 pt (16%), G2: 66 pt (70%), G3: 13 pt (14%). 20 pt (21%) had positive axillary lymph node involvement. Tumor size was less than 1 cm in 27 pt (29%). EPclin could be assessed in 94 pt (100%). 32 pt (34%) were classified as “high risk” whereas 62 pt (66%) were classified as “low risk”. uPA/PAI was obtained from 54 pt (57%). 36 pt (67%) out of these 54 pt had high uPA/PAI-1 levels whereas 18 pt (33%) showed low uPA/PAI-1 levels. Only 2 pt (4%) with low uPA/PAI-1 levels were classified as “high risk” with EPclin, whereas 17 pt (32%) with high uPA/PAI-1 were classified as “low risk” via EPclin (p=0,003). In 29 cases (31%) treatment decision was influenced by EPclin: In 26 pt (28%) adjuvant chemotherapy (ctx) was omitted whereas in 3 pt (3%) ctx was added following the EPclin. Conclusions: This prospective study shows for the first time, that high risk status according to the EPclin score is strongly associated with a high risk status as defined by uPA/PAI-1. Providing analytically valid results for all patients evaluated EPclin’s clinical practicability was clearly superior to uPA/PAI-1. This finding, combined with the fact that EPclin assigns twice as many patients to the low risk group indicated that EPclin is a more versatile and powerful tool to help spare patients from chemotherapy than uPA/PAI-1.

e15042 Background: Cetuximab (CET), an antibody directed against epidermal growth factor receptor (EGFR) has proved efficacy in squamous cell cancer (SCC) of the head and neck in vitro and in vivo by enhancing the activity of chemo- and radiotherapy. The aim was to investigate the early metabolic response in esophageal SCC induced by single agent CET. Methods: Patients with cT3 Nx esophageal SCC received single agent CET for two weeks (400mg/m2 i. v. d -15 followed by 250mg/m2 d -8) before entering a neoadjuvant dose escalation protocol of weekly cetuximab plus weekly oxaliplatin (starting dose level 45mg/m²; d1,8,15,22,29), plus 5-FU cont. i.v. (starting dose level 180mg/m²/d; d1-5, 8-12, 15-19, 22-26, 29-33) and radiotherapy (45Gy cumulative dose; 1.8Gy/d). Surgery was scheduled 4-6 weeks after chemoradiation (CRT). Tumor FDG uptake was assessed by PET at baseline, two weeks after start of CET and two weeks after start of CRT. Standard uptake values (SUV) of the two response PETs were compared with SUVs measured at baseline and correlated with the histopathological response data. Results: 11 patients are assessable for metabolic and histopathological response. Decreases in the SUVs two weeks after the start of CET compared with baseline SUV ranged from -16% to -70% (median -24%) and from 0% to -72% (median -39%) two weeks after start of CRT. Three patients were classified as complete histopathological responders. One patient had a subtotal ( can lead to a marked and early decrease in tumor glucose uptake. Our findings suggest that there may be an association between the early decrease in FDG uptake during CET monotherapy, indicating a growth dependency of some tumors from the EGFR signal pathway. These preliminary observations require confirmation in a larger patient cohort. Clinical trial information: 2006-001097-24.

Background Clinical trials evaluating anti-CD20-mediated B-cell depletion in multiple sclerosis (MS) and neuromyelitis optica (NMO) generated encouraging results. Our recent studies in the MS model experimental autoimmune encephalomyelitis (EAE) attributed clinical benefit to extinction of activated B-cells, but cautioned that depletion of naïve B-cells may be undesirable. We elucidated the regulatory role of un-activated B-cells in EAE and investigated whether anti-CD20 may collaterally diminish regulatory B-cell properties in treatment of neuroimmunological disorders. Methods Myelin oligodendrocyte glycoprotein (MOG) peptide-immunized C57Bl/6 mice were depleted of B-cells. Functional consequences for regulatory T-cells (Treg) and cytokine production of CD11b+ antigen presenting cells (APC) were assessed. Peripheral blood mononuclear cells from 22 patients receiving anti-CD20 and 23 untreated neuroimmunological patients were evaluated for frequencies of B-cells, T-cells and monocytes; monocytic reactivity was determined by TNF-production and expression of signalling lymphocytic activation molecule (SLAM). Results We observed that EAE-exacerbation upon depletion of un-activated B-cells closely correlated with an enhanced production of pro-inflammatory TNF by CD11b+ APC. Paralleling this pre-clinical finding, anti-CD20 treatment of human neuroimmunological disorders increased the relative frequency of monocytes and accentuated pro-inflammatory monocyte function; when reactivated ex vivo, a higher frequency of monocytes from B-cell depleted patients produced TNF and expressed the activation marker SLAM. Conclusions These data suggest that in neuroimmunological disorders, pro-inflammatory APC activity is controlled by a subset of B-cells which is eliminated concomitantly upon anti-CD20 treatment. While this observation does not conflict with the general concept of B-cell depletion in human autoimmunity, it implies that its safety and effectiveness may further advance by selectively targeting pathogenic B-cell function.

ObjectiveTo investigate the hypothesis that vaccination is a risk factor for multiple sclerosis (MS) by use of German ambulatory claims data in a case-control study.MethodsUsing the ambulatory claims data of the Bavarian Association of Statutory Health Insurance Physicians covering 2005–2017, logistic regression models were used to assess the relation between MS (n = 12,262) and vaccinations in the 5 years before first diagnosis. Participants newly diagnosed with Crohn disease (n = 19,296) or psoriasis (n = 112,292) and participants with no history of these autoimmune diseases (n = 79,185) served as controls.ResultsThe odds of MS were lower in participants with a recorded vaccination (odds ratio [OR] 0.870, p < 0.001 vs participants without autoimmune disease; OR 0.919, p < 0.001 vs participants with Crohn disease; OR 0.973, p = 0.177 vs participants with psoriasis). Lower odds were most pronounced for vaccinations against influenza and tick-borne encephalitis. These effects were consistently observed for different time frames, control cohorts, and definitions of the MS cohort. Effect sizes increased toward the time of first diagnosis.ConclusionsResults of the present study do not reveal vaccination to be a risk factor for MS. On the contrary, they consistently suggest that vaccination is associated with a lower likelihood of being diagnosed with MS within the next 5 years. Whether this is a protective effect needs to be addressed by future studies.

Background Women have unfavorable prognosis after myocardial infarction (MI). This text describes sex differences in mortality and in the power of risk predictors in contemporarily-treated MI patients. Methods A population of 4141 MI patients (26.5% females) was followed up for 5 years. Effects of sex and age on total mortality were investigated by multivariable Cox analysis. Mortality predictors were investigated by receiver-operator characteristics analysis. Stepwise multivariable Cox regression was used to create sex-specific predictive models. Results Thirty-day mortality was 1.5-fold higher in women. However, sex was not a significant mortality predictor in a model adjusted for age. Predictors for 5-year mortality performed differently in male and female patients. In women, a sex-specific model provided better risk stratification than a sex-neutral model. Conclusion The unfavorable prognosis of female MI patients can be explained by advanced age. Sex-specific predictive models might improve risk stratification in female survivors of acute MI.

ObjectiveTo explore the occurrence of diseases and symptoms in the 5 years before diagnosis in patients with multiple sclerosis (MS) in a case-control study.MethodsUsing ambulatory claims data, we systematically assessed differences in the occurrence of diseases and symptoms in the 5 years before first diagnosis in patients with MS (n = 10,262) compared to patients with 2 other autoimmune diseases, Crohn disease (n = 15,502) and psoriasis (n = 98,432), and individuals without these diseases (n = 73,430).ResultsForty-three ICD-10 codes were recorded more frequently for patients with MS before diagnosis compared to controls without autoimmune disease. Many of these findings were confirmed in a comparison to the other control groups. A high proportion of these ICD-10 codes represent symptoms suggestive of demyelinating events or other neurologic diagnoses. In a sensitivity analysis excluding patients with such recordings before first diagnosis, no association remained significant. Seven ICD-10 codes were associated with lower odds ratios of MS, 4 of which represent upper respiratory tract infections. Here, the relations with MS were even more pronounced in the sensitivity analysis.ConclusionsOur analyses suggest that patients with MS are frequently not diagnosed at their first demyelinating event but often years later. Symptoms and physician encounters before MS diagnosis seem to be related to already ongoing disease rather than a prodrome. The observed association of upper respiratory tract infections with lower odds ratios of MS diagnosis suggests a link between protection from infection and MS that, however, needs to be validated and further investigated.

Due to their well-established fracture risk reduction, bisphosphonates are the most frequently used therapeutic agent to treat osteoporosis. Bisphosphonates reduce fracture risk by suppressing bone resorption, but the lower bone turnover could have a negative impact on bone quality at the tissue level. Here, we directly assess the structural and mechanical characteristics of cancellous bone from the lumbar vertebrae (L5) in non-treated osteoporotic controls (n = 21), mid-term alendronate-treated osteoporotic patients (n = 6), and long-term alendronate-treated osteoporotic patients (n = 7). The strength and toughness of single trabeculae were evaluated, while the structure was characterised through measurements of microdamage accumulation, mineralisation distribution, and histological indices. The alendronate-treated cases had a reduced eroded surface (ES/BS, p < 0.001) and a higher bone mineralisation in comparison to non-treated controls (p = 0.037), which is indicative of low turnover associated with treatment. However, the amount of microdamage and the mechanical properties were similar among the control and treatment groups. As the tissue mineral density (TMD) increased significantly with alendronate treatment compared to non-treated osteoporotic controls, the reduction in resorption cavities could counterbalance the higher TMD allowing the alendronate-treated bone to maintain its mechanical properties and resist microdamage accumulation. A multivariate analysis of the possible predictors supports the theory that multiple factors (e.g., body mass index, TMD, and ES/BS) can impact the mechanical properties. Our results suggest that long-term alendronate treatment shows no adverse impact on mechanical cancellous bone characteristics.