Heart rate variability does not discriminate between different levels of haemodynamic responsiveness during surgical anaesthesia

BACKGROUND: Hypnotic depth but not haemodynamic responsiveness is measured with EEG-based monitors. In this study we compared heart rate variability (HRV) in unstimulated patients and stimulation-induced HRV at different levels of anaesthesia. METHODS: A total of 95 ASA I or II patients were randomly assigned to five groups (Group 1: BIS 45(5), remifentanil 1 ng ml(-1); Group 2: BIS 45(5), remifentanil 2 ng ml(-1); Group 3: BIS 45(5), remifentanil 4 ng ml(-1); Group 4: BIS 30(5), remifentanil 2 ng ml(-1); Group 5: BIS 60(5), remifentanil 2 ng ml(-1)). A time- and frequency-domain analysis of the RR interval (RRI) from the electrocardiogram was performed. HRV before induction, before and after a 5 s tetanic stimulus of the ulnar nerve, and before and after tracheal intubation was compared between groups, between stimuli, and between responders to intubation [systolic arterial pressure (SAP) increase >20 mm Hg, a maximal heart rate (HR) after intubation >90 min(-1) or both] and non-responders (anova). RESULTS: Induction of anaesthesia significantly lowered HR and HRV. Mean RRI before stimulation was higher in G3 than in G1, G2, and G4 (P < 0.001), whereas the other HRV parameters were similar. Intubation induced a greater HRV response than tetanic stimulation. The mean RRI after intubation was lower in G3 compared with the other groups and the sd of the RRI after tetanic stimulation was lower in G3 compared with G5. Otherwise, unstimulated HRV and stimulation-induced HRV were similar in responders and non-responders. CONCLUSION: HRV parameters discriminate between awake and general anaesthesia, are different after tracheal intubation and a 5 s ulnar nerve stimulation, but do not discriminate between different levels of haemodynamic responsiveness during surgical anaesthesia.

Expression Analysis of the Theileria parva Subtelomere-Encoded Variable Secreted Protein Gene Family

Background The intracellular protozoan parasite Theileria parva transforms bovine lymphocytes inducing uncontrolled proliferation. Proteins released from the parasite are assumed to contribute to phenotypic changes of the host cell and parasite persistence. With 85 members, genes encoding subtelomeric variable secreted proteins (SVSPs) form the largest gene family in T. parva. The majority of SVSPs contain predicted signal peptides, suggesting secretion into the host cell cytoplasm. Methodology/Principal Findings We analysed SVSP expression in T. parva-transformed cell lines established in vitro by infection of T or B lymphocytes with cloned T. parva parasites. Microarray and quantitative real-time PCR analysis revealed mRNA expression for a wide range of SVSP genes. The pattern of mRNA expression was largely defined by the parasite genotype and not by host background or cell type, and found to be relatively stable in vitro over a period of two months. Interestingly, immunofluorescence analysis carried out on cell lines established from a cloned parasite showed that expression of a single SVSP encoded by TP03_0882 is limited to only a small percentage of parasites. Epitope-tagged TP03_0882 expressed in mammalian cells was found to translocate into the nucleus, a process that could be attributed to two different nuclear localisation signals. Conclusions Our analysis reveals a complex pattern of Theileria SVSP mRNA expression, which depends on the parasite genotype. Whereas in cell lines established from a cloned parasite transcripts can be found corresponding to a wide range of SVSP genes, only a minority of parasites appear to express a particular SVSP protein. The fact that a number of SVSPs contain functional nuclear localisation signals suggests that proteins released from the parasite could contribute to phenotypic changes of the host cell. This initial characterisation will facilitate future studies on the regulation of SVSP gene expression and the potential biological role of these enigmatic proteins.

Space–oriented EEG segmentation reveals changes in brain electric–field maps under the influence of a nootropic drug

Map landscape-based segmentation of the sequences of momentary potential distribution maps (42-channel recordings) into brain microstates during spontaneous brain activity was used to study brain electric field spatial effects of single doses of piracetam (2.9, 4.8, and 9.6 g Nootropil® UCB and placebo) in a double-blind study of five normal young volunteers. Four 15-second epochs were analyzed from each subject and drug condition. The most prominent class of microstates (covering 49% of the time) consisted of potential maps with a generally anterior-posterior field orientation. The map orientation of this microstate class showed an increasing clockwise deviation from the placebo condition with increasing drug doses (Fisher's probability product, p < 0.014). The results of this study suggest the use of microstate segmentation analysis for the assessment of central effects of medication in spontaneous multichannel electroencephalographic data, as a complementary approach to frequency-domain analysis.

Ridge alterations post-extraction in the esthetic zone: a 3D analysis with CBCT

Dimensional alterations of the facial bone wall following tooth extractions in the esthetic zone have a profound effect on treatment outcomes. This prospective study in 39 patients is the first to investigate three-dimensional (3D) alterations of facial bone in the esthetic zone during the initial 8 wks following flapless tooth extraction. A novel 3D analysis was carried out, based on 2 consecutive cone beam computed tomographies (CBCTs). A risk zone for significant bone resorption was identified in central areas, whereas proximal areas yielded only minor changes. Correlation analysis identified a facial bone wall thickness of ≤ 1 mm as a critical factor associated with the extent of bone resorption. Thin-wall phenotypes displayed pronounced vertical bone resorption, with a median bone loss of 7.5 mm, as compared with thick-wall phenotypes, which decreased by only 1.1 mm. For the first time, 3D analysis has allowed for documentation of dimensional alterations of the facial bone wall in the esthetic zone of humans following extraction. It also characterized a risk zone prone to pronounced bone resorption in thin-wall phenotypes. Vertical bone loss was 3.5 times more severe than findings reported in the existing literature.

Adjuvant bevacizumab-containing therapy in triple-negative breast cancer (BEATRICE): primary results of a randomised, phase 3 trial

BACKGROUND The addition of bevacizumab to chemotherapy improves progression-free survival in metastatic breast cancer and pathological complete response rates in the neoadjuvant setting. Micrometastases are dependent on angiogenesis, suggesting that patients might benefit from anti-angiogenic strategies in the adjuvant setting. We therefore assessed the addition of bevacizumab to chemotherapy in the adjuvant setting for women with triple-negative breast cancer. METHODS For this open-label, randomised phase 3 trial we recruited patients with centrally confirmed triple-negative operable primary invasive breast cancer from 360 sites in 37 countries. We randomly allocated patients aged 18 years or older (1:1 with block randomisation; stratified by nodal status, chemotherapy [with an anthracycline, taxane, or both], hormone receptor status [negative vs low], and type of surgery) to receive a minimum of four cycles of chemotherapy either alone or with bevacizumab (equivalent of 5 mg/kg every week for 1 year). The primary endpoint was invasive disease-free survival (IDFS). Efficacy analyses were based on the intention-to-treat population, safety analyses were done on all patients who received at least one dose of study drug, and plasma biomarker analyses were done on all treated patients consenting to biomarker analyses and providing a measurable baseline plasma sample. This trial is registered with ClinicalTrials.gov, number NCT00528567. FINDINGS Between Dec 3, 2007, and March 8, 2010, we randomly assigned 1290 patients to receive chemotherapy alone and 1301 to receive bevacizumab plus chemotherapy. Most patients received anthracycline-containing therapy; 1638 (63%) of the 2591 patients had node-negative disease. At the time of analysis of IDFS, median follow-up was 31·5 months (IQR 25·6-36·8) in the chemotherapy-alone group and 32·0 months (27·5-36·9) in the bevacizumab group. At the time of the primary analysis, IDFS events had been reported in 205 patients (16%) in the chemotherapy-alone group and in 188 patients (14%) in the bevacizumab group (hazard ratio [HR] in stratified log-rank analysis 0·87, 95% CI 0·72-1·07; p=0·18). 3-year IDFS was 82·7% (95% CI 80·5-85·0) with chemotherapy alone and 83·7% (81·4-86·0) with bevacizumab and chemotherapy. After 200 deaths, no difference in overall survival was noted between the groups (HR 0·84, 95% CI 0·64-1·12; p=0·23). Exploratory biomarker assessment suggests that patients with high pre-treatment plasma VEGFR-2 might benefit from the addition of bevacizumab (Cox interaction test p=0·029). Use of bevacizumab versus chemotherapy alone was associated with increased incidences of grade 3 or worse hypertension (154 patients [12%] vs eight patients [1%]), severe cardiac events occurring at any point during the 18-month safety reporting period (19 [1%] vs two [<0·5%]), and treatment discontinuation (bevacizumab, chemotherapy, or both; 256 [20%] vs 30 [2%]); we recorded no increase in fatal adverse events with bevacizumab (four [<0·5%] vs three [<0·5%]). INTERPRETATION Bevacizumab cannot be recommended as adjuvant treatment in unselected patients with triple-negative breast cancer. Further follow-up is needed to assess the potential effect of bevacizumab on overall survival.

Sensitivity of the WRF model to PBL parametrisations and nesting techniques: evaluation of wind storms over complex terrain

Simulating surface wind over complex terrain is a challenge in regional climate modelling. Therefore, this study aims at identifying a set-up of the Weather Research and Forecasting Model (WRF) model that minimises system- atic errors of surface winds in hindcast simulations. Major factors of the model configuration are tested to find a suitable set-up: the horizontal resolution, the planetary boundary layer (PBL) parameterisation scheme and the way the WRF is nested to the driving data set. Hence, a number of sensitivity simulations at a spatial resolution of 2 km are carried out and compared to observations. Given the importance of wind storms, the analysis is based on case studies of 24 historical wind storms that caused great economic damage in Switzerland. Each of these events is downscaled using eight different model set-ups, but sharing the same driving data set. The results show that the lack of representation of the unresolved topography leads to a general overestimation of wind speed in WRF. However, this bias can be substantially reduced by using a PBL scheme that explicitly considers the effects of non-resolved topography, which also improves the spatial structure of wind speed over Switzerland. The wind direction, although generally well reproduced, is not very sensitive to the PBL scheme. Further sensitivity tests include four types of nesting methods: nesting only at the boundaries of the outermost domain, analysis nudging, spectral nudging, and the so-called re-forecast method, where the simulation is frequently restarted. These simulations show that restricting the freedom of the model to develop large-scale disturbances slightly increases the temporal agreement with the observations, at the same time that it further reduces the overestimation of wind speed, especially for maximum wind peaks. The model performance is also evaluated in the outermost domains, where the resolution is coarser. The results demonstrate the important role of horizontal resolution, where the step from 6 to 2 km significantly improves model performance. In summary, the combination of a grid size of 2 km, the non-local PBL scheme modified to explicitly account for non-resolved orography, as well as analysis or spectral nudging, is a superior combination when dynamical downscaling is aimed at reproducing real wind fields.

Impact of anti-inflammatory treatment on the onset of uveitis in juvenile idiopathic arthritis: Longitudinal analysis from a nation-wide paediatric rheumatological database

PURPOSE Based on a nation-wide database, this study analysed the influence of methotrexate (MTX), TNF inhibitors and a combination of the two on uveitis occurrence in JIA patients. METHODS Data from the National Paediatric Rheumatological Database in Germany were used in this study. Between 2002 and 2013, data from JIA patients were annually documented at the participating paediatric rheumatological sites. Patients with JIA disease duration of less than 12 months at initial documentation and ≥2 years of follow-up were included in this study. The impact of anti-inflammatory treatment on the occurrence of uveitis was evaluated by discrete-time survival analysis. RESULTS A total of 3,512 JIA patients (mean age 8.3±4.8 years, female 65.7%, ANA-positive 53.2%, mean age at arthritis onset 7.8±4.8 years) fulfilled the inclusion criteria. Mean total follow-up time was 3.6±2.4 years. Uveitis developed in a total of 180 patients (5.1%) within one year after arthritis onset. Uveitis onset after the first year was observed in another 251 patients (7.1%). DMARD treatment in the year before uveitis onset significantly reduced the risk for uveitis: MTX (HR 0.63, p=0.022), TNF inhibitors (HR 0.56, p<0.001) and a combination of the two (HR 0.10, p<0.001). Patients treated with MTX within the first year of JIA had an even a lower uveitis risk (HR 0.29, p<0.001). CONCLUSION The use of DMARDs in JIA patients significantly reduced the risk for uveitis onset. Early MTX use within the first year of disease and the combination of MTX with a TNF inhibitor had the highest protective effect. This article is protected by copyright. All rights reserved.