A central question in neuroscience is how self-organizing dynamic interactions in the brain emerge on their relatively static structural backbone. Due to the complexity of spatial and temporal ...dependencies between different brain areas, fully comprehending the interplay between structure and function is still challenging and an area of intense research. In this paper we present a graph neural network (GNN) framework, to describe functional interactions based on the structural anatomical layout. A GNN allows us to process graph-structured spatio-temporal signals, providing a possibility to combine structural information derived from diffusion tensor imaging (DTI) with temporal neural activity profiles, like that observed in functional magnetic resonance imaging (fMRI). Moreover, dynamic interactions between different brain regions discovered by this data-driven approach can provide a multi-modal measure of causal connectivity strength. We assess the proposed model's accuracy by evaluating its capabilities to replicate empirically observed neural activation profiles, and compare the performance to those of a vector auto regression (VAR), like that typically used in Granger causality. We show that GNNs are able to capture long-term dependencies in data and also computationally scale up to the analysis of large-scale networks. Finally we confirm that features learned by a GNN can generalize across MRI scanner types and acquisition protocols, by demonstrating that the performance on small datasets can be improved by pre-training the GNN on data from an earlier study. We conclude that the proposed multi-modal GNN framework can provide a novel perspective on the structure-function relationship in the brain. Accordingly this approach appears to be promising for the characterization of the information flow in brain networks.
Between 1981 and 2000, 6609 children (<18 years of age) were treated in five consecutive trials of the Berlin-Frankfurt-Münster (BFM) study group for childhood acute lymphoblastic leukemia (ALL). ...Patients were treated in up to 82 centers in Germany, Austria and Switzerland. Probability of 10-year event-free survival (EFS) (survival) improved from 65% (77%) in study ALL-BFM 81 to 78% (85%) in ALL-BFM 95. In parallel to relapse reduction, major efforts focused on reducing acute and late toxicity through advanced risk adaptation of treatment. The major findings derived from these ALL-BFM trials were as follows: (1) preventive cranial radiotherapy could be safely reduced to 12 Gy in T-ALL and high-risk (HR) ALL patients, and eliminated in non- HR non-T-ALL patients, if it was replaced by high-dose and intrathecal (IT) MTX; (2) omission of delayed re-intensification severely impaired outcome of low-risk patients; (3) 6-month-less maintenance therapy caused an increase in systemic relapses; (4) slow response to an initial 7-day prednisone window was identified as adverse prognostic factor; (5) condensed induction therapy resulted in significant improvement of outcome; (6) the daunorubicin dose in induction could be safely reduced in low-risk patients and (7) intensification of consolidation/re-intensification treatment led to considerable improvement of outcome in HR patients.
Assessment of minimal residual disease (MRD) has acquired a prominent position in European treatment protocols for patients with acute lymphoblastic leukemia (ALL), on the basis of its high ...prognostic value for predicting outcome and the possibilities for implementation of MRD diagnostics in treatment stratification. Therefore, there is an increasing need for standardization of methodologies and harmonization of terminology. For this purpose, a panel of representatives of all major European study groups on childhood and adult ALL and of international experts on PCR- and flow cytometry-based MRD assessment was built in the context of the Second International Symposium on MRD assessment in Kiel, Germany, 18-20 September 2008. The panel summarized the current state of MRD diagnostics in ALL and developed recommendations on the minimal technical requirements that should be fulfilled before implementation of MRD diagnostics into clinical trials. Finally, a common terminology for a standard description of MRD response and monitoring was established defining the terms 'complete MRD response', 'MRD persistence' and 'MRD reappearance'. The proposed MRD terminology may allow a refined and standardized assessment of response to treatment in adult and childhood ALL, and provides a sound basis for the comparison of MRD results between different treatment protocols.
This paper reviews the literature on occupancy-based lighting control as a prelude to the application of sensor networks to building management. Many buildings include systems to detect occupancy and ...control building services. Current systems use single measurement points to detect occupancy, and there can be significant uncertainty associated with the measurement of occupancy. Long time delay and high detector sensitivity settings compensate for this uncertainty, but these diminish the savings that could be achieved with more accurate occupancy measurement. More effective control may be provided by more extensive sensing, using a network of occupancy sensors, and more extensive analysis of sensor data. The literature reviewed in this paper establishes the need for an investigation of the performance of sensor networks when used for lighting control.
Hypofibrinogenaemia is one of the main reasons for development of perioperative coagulopathy during major paediatric surgery. The aim of this study was to assess whether prophylactic maintenance of ...higher fibrinogen concentrations through administration of fibrinogen concentrate would decrease the volume of transfused red blood cell (RBCs).
In this prospective, randomised, clinical trial, patients aged 6 months to 17 yr undergoing craniosynostosis and scoliosis surgery received fibrinogen concentrate (30 mg kg−1) at two predefined intraoperative fibrinogen concentrations ROTEM® FIBTEM maximum clot firmness (MCF) of <8 mm (conventional) or <13 mm (early substitution). Total volume of transfused RBCs was recorded over 24 h after start of surgery.
Thirty children who underwent craniosynostosis surgery and 19 children who underwent scoliosis surgery were treated per protocol. During craniosynostosis surgery, children in the early substitution group received significantly less RBCs (median, 28 ml kg−1; IQR, 21 to 50 ml kg−1) compared with the conventional fibrinogen trigger of <8 mm (median, 56 ml kg−1; IQR, 28 to 62 ml kg−1) (P=0.03). Calculated blood loss as per cent of estimated total blood volume decreased from a median of 160% (IQR, 110–190%) to a median of 90% (IQR, 78–110%) (P=0.017). No significant changes were observed in the scoliosis surgery population. No bleeding events requiring surgical intervention, postoperative transfusions of RBCs, or treatment-related adverse events were observed.
Intraoperative administration of fibrinogen concentrate using a FIBTEM MCF trigger level of <13 mm can be successfully used to significantly decrease bleeding, and transfusion requirements in the setting of craniosynostosis surgery, but not scoliosis.
ClinicalTrials.gov NCT01487837.
This paper presents and discusses the methodology used in a numerical investigation of the aggregated effect of model predictive control (MPC) strategies implemented in hundreds of residential ...buildings on demand reduction in the electricity distribution feeder. This approach includes reduced order models for the homes and heating, ventilating and air conditioning systems, a model for typical group of buildings served by a distribution feeder, and a simple model for the description of real and reactive power flows. The methodology is demonstrated with a simple MPC example. This paper is intended to serve as the basis of a study, presented in the companion paper, on the effect of using residential predictive control strategies to complement the integration of renewable energy technologies in the grid.
Long-term survival of high-risk neuroblastoma patients is still below 50% despite intensive multimodal treatment. This trial aimed to address whether the addition of two topotecan-containing ...chemotherapy courses compared to standard induction therapy improves event-free survival (EFS) of these patients.
An open-label, multicenter, prospective randomized controlled trial was carried out at 58 hospitals in Germany and Switzerland. Patients aged 1–21 years with stage 4 neuroblastoma and patients aged 6 months to 21 years with MYCN-amplified tumors were eligible. The primary endpoint was EFS. Patients were randomly assigned to standard induction therapy with six chemotherapy courses or to experimental induction chemotherapy starting with two additional courses of topotecan, cyclophosphamide, and etoposide followed by standard induction chemotherapy (eight courses in total). After induction chemotherapy, all patients received high-dose chemotherapy with autologous hematopoietic stem cell rescue and isotretinoin for consolidation. Radiotherapy was applied to patients with active tumors at the end of induction chemotherapy.
Of 536 patients enrolled in the trial, 422 were randomly assigned to the control arm (n = 211) and the experimental arm (n = 211); the median follow-up time was 3.32 years (interquartile range 1.65–5.92). At data lock, the 3-year EFS of experimental and control patients was 34% and 32% 95% confidence Interval (CI) 28% to 40% and 26% to 38%; P = 0.258, respectively. Similarly, the 3-year overall survival of the patients did not differ 54% and 48% (95% CI 46% to 62% and 40% to 56%), respectively; P = 0.558. The response to induction chemotherapy was not different between the arms. The median number of non-fatal toxicities per patient was higher in the experimental group while the median number of toxicities per chemotherapy course was not different.
While the burden for the patients was increased by prolonging the induction chemotherapy and the toxicity, the addition of two topotecan-containing chemotherapy courses did not improve the EFS of high-risk neuroblastoma patients and thus cannot be recommended.
NCT number 03042429.
•Extension of induction chemotherapy for high-risk neuroblastoma by two courses did not increase event free and overall survival.•Response, surgical resectability, and need for radiotherapy were not improved by 2 topotecan/cyclophosphamide/etoposide courses.•Treatment time and number of toxicities were increased in the experimental arm.
This paper introduces a methodology, using model predictive control, for shaping the electric demand of residential distribution feeder. The methods are designed to result in a paradigm shift from ...generation that follows load to load that follows supply. First, a reference demand curve, obtained from "smoothing" a base case demand profile, is proposed. Then, in order to better match the availability of renewable energy resources, the reference demand curve is modified to consider residential rooftop photovoltaic systems and utility scale wind generation. A simulation framework introduced in a companion paper is employed. Simulation results suggest that the active load shaping methodology is very effective at providing demand flexibility at time scales shorter than two or three hours. At longer time scales, flexibility is limited by the thermal storage effectiveness of the residential building envelope, and to a large extent, the amount of load being shifted relative to total active cooling demand.
Four thousand, four hundred and forty eligible children of up to 18 years of age were treated in four consecutive trials between 1981 and 1995 with the treatment protocols of the ...Berlin-Frankfurt-Münster (BFM) study group for childhood acute lymphoblastic leukemia (ALL). The probability for event-free survival (pEFS) at 8 years improved from 65.8% in study ALL-BFM 81 to 75.9% in study ALL-BFM 90. The cumulative incidence of recurrences with CNS involvement was 10.1% and 9.3% in studies ALL-BFM 81 and 83, but was reduced to less than 5% in study ALL-BFM 90 (for isolated CNS relapses from 5.3% in study ALL-BFM 81 to 1.1% in study ALL-BFM 90). Four major findings were derived from this series of trials performed by 37 to 96 centers in Germany, Austria, and Switzerland: (1) Reintensification is a crucial part of treatment, even in low risk patients; (2) presymptomatic cranial radiotherapy can be safely reduced to 12 Gy, or even be eliminated if it is replaced by early intensive systemic and intrathecal methotrexate applied; (3) maintenance therapy given a total of 24 months from diagnosis provides a lower rate of systemic relapses than treatment for 18 months; (4) inadequate response to an initial 7-day prednisone window (combined with one intrathecal injection of methotrexate on day 1) defines about 10% of the patients with a very high risk of relapse. For patients with adequate early response (90% of all) an 8-year pEFS of 80% has been achieved in the most recent trial ALL-BFM 90. While it has proven so far to be impossible to improve the outcome for the small group of high risk patients, the number of recurrences could be effectively reduced for the large group of patients responding adequately to the prednisone in vivo sensitivity test. Apart from inadequate prednisone response, patients with hyperleukocytosis, age <1 year, or the presence of the Philadelphia-chromosome (Ph+ ALL) are at a particularly high risk of failure.
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