A pre-registered short-term forecasting study of COVID-19 in Germany and Poland during the second wave.

Disease modelling has had considerable policy impact during the ongoing COVID-19 pandemic, and it is increasingly acknowledged that combining multiple models can improve the reliability of outputs. Here we report insights from ten weeks of collaborative short-term forecasting of COVID-19 in Germany and Poland (12 October-19 December 2020). The study period covers the onset of the second wave in both countries, with tightening non-pharmaceutical interventions (NPIs) and subsequently a decay (Poland) or plateau and renewed increase (Germany) in reported cases. Thirteen independent teams provided probabilistic real-time forecasts of COVID-19 cases and deaths. These were reported for lead times of one to four weeks, with evaluation focused on one- and two-week horizons, which are less affected by changing NPIs. Heterogeneity between forecasts was considerable both in terms of point predictions and forecast spread. Ensemble forecasts showed good relative performance, in particular in terms of coverage, but did not clearly dominate single-model predictions. The study was preregistered and will be followed up in future phases of the pandemic.

Quantitative imaging of tumour blood flow by contrast-enhanced magnetic resonance imaging.

Tumour blood flow plays a key role in tumour growth, formation of metastasis, and detection and treatment of malignant tumours. Recent investigations provided increasing evidence that quantitative analysis of tumour blood flow is an indispensable prerequisite for developing novel treatment strategies and individualizing cancer therapy. Currently, however, methods for noninvasive, quantitative and high spatial resolution imaging of tumour blood flow are rare. We apply here a novel approach combining a recently established ultrafast MRI technique, that is T(1)-relaxation time mapping, with a tracer kinetic model. For validation of this approach, we compared the results obtained in vivo with data provided by iodoantipyrine autoradiography as a reference technique for the measurement of tumour blood flow at a high resolution in an experimental tumour model. The MRI protocol allowed quantitative mapping of tumour blood flow at spatial resolution of 250 x 250 microm(2). Correlation of data from the MRI method with the iodantipyrine autoradiography revealed Spearman's correlation coefficients of Rs = 0.851 (r = 0.775, P < 0.0001) and Rs = 0.821 (r = 0.72, P = 0.014) for local and global tumour blood flow, respectively. The presented approach enables noninvasive, repeated and quantitative assessment of microvascular perfusion at high spatial resolution encompassing the entire tumour. Knowledge about the specific vascular microenvironment of tumours will form the basis for selective antivascular cancer treatment in the future.

Tumor microcirculation evaluated by dynamic magnetic resonance imaging predicts therapy outcome for primary rectal carcinoma.

Contrast enhanced dynamic studies of malignant tumors performed by computed tomography or magnetic resonance imaging (MRI) are increasingly applied to characterize tumor microcirculation for the prediction of therapy outcome. The aim of our study was to correlate perfusion index (PI) values determined in primary rectal carcinoma before chemoradiation with therapy outcome. In 17 patients with clinically staged T3 primary rectal carcinoma, dynamic MRI was performed before the onset of therapy using an ultrafast T1-mapping sequence. On the basis of the acquired data sets, PI values were calculated on a pixel-by-pixel basis. To characterize the heterogeneity of tumor microcirculation, relative cumulative frequency histograms of PI values within the tumors were computed. Subsequent resection of the tumors allowed correlating PI with histopathological classification. In 12 of 17 patients, T-downstaging as a response to therapy was found, whereas in the remaining 5 patients no therapy response was observed after chemoradiation. A statistically significant difference between both groups was found for the mean PI (P < 0.001; 8.5+/-1.7 ml/min/100 g versus 11.4+/-0.7 ml/min/100 g). Analyzing the cumulative frequency histograms for both groups revealed an optimal discrimination for a P1 value of 12.6 ml/min/100 g. The fraction of pixels in the tumor with PI values larger than 12.6 ml/min/100 g was significantly different (P < 0.001) between therapy-responding (3+/-3.6%) and therapy-nonresponding tumors (21+/-4.3%). The results indicate either a reduced supply of nutrients as well as chemotherapeutic agents attributable to increased shunt flow or highly aggressive tumor cell clusters characterized by increased angiogenic activity. Noninvasive PI measurements by dynamic MRI in rectal carcinoma before therapy seem to be of predictive value for therapy outcome in patients scheduled for preoperative chemoradiation.

Monitoring of tumor microcirculation during fractionated radiation therapy in patients with rectal carcinoma: preliminary results and implications for therapy.

PURPOSE: To measure microcirculatory changes during chemoirradiation and to correlate perfusion index (PI) values with therapy outcome. MATERIALS AND METHODS: Perfusion data in 11 patients with cT3 (clinical staging, tumor invaded the perirectal tissue) rectal carcinoma who underwent preoperative chemoirradiation were analyzed. Perfusion data were acquired by using a T1 mapping sequence with a whole-body magnetic resonance (MR) imager. After contrast medium was intravenously infused at a constant rate, concentration-and-time curves were evaluated for arterial blood and tumor. All patients underwent MR imaging before and at constant intervals during chemoirradiation. Clinical stages before therapy were compared with surgical stages after therapy. RESULTS: Spatial and temporal resolution on dynamic T1 maps were sufficient to reveal changes in contrast medium accumulation in the tumor. Comparison of PI values and radiation dose showed a significant increase in the 1st (P: =.003) and 2nd weeks (P: =.01) of treatment; values subsequently returned to pretreatment levels or showed a renewed increase. High initial PI values correlated with greater lymph node downstaging (P: =.042). CONCLUSION: Dynamic T1 mapping provides a suitable tool for monitoring tumor microcirculation during chemoirradiation and offers the potential for individual optimization of therapeutic procedures. Furthermore, these results indicate that the PI map may serve as a prognostic factor.

[Perfusion-index values evaluated by dynamic magnetic resonance imaging in advanced rectal carcinoma. A new predictor of response to preoperative radiochemotherapy?]. / Mittels dynamischer Magnetresonanztomographie erhaltene Perfusionsindexwerte beim fortgeschrittenen Rektumkarzinom. Eine neue Voraussagemöglichkeit über ein Therapieansprechen bei präoperativer Radiochemotherapie?

PURPOSE: The aim of our study was to evaluate in vivo the influence of tumor microcirculation data on therapy outcome. PATIENTS AND METHODS: Tumor perfusion data of primary rectal carcinoma (n = 14, cT3) who underwent preoperative chemoradiation have been analyzed (Table 1). The perfusion data were acquired at the beginning and at the end of therapy by use of an ultrafast T1-mapping sequence on a whole-body magnetic resonance imager. The gadolinium-DTPA concentration-time-curves were evaluated for arterial blood and tumor before, during and after intravenous constant rate infusion and from that the perfusion index (PI) was calculated. Subsequent resection of the tumors allowed for a correlation of perfusion index values with the pathological classification. RESULTS: Nine patients showed a T downstaging (ypT0-2, group 1), 5 patients did not (ypT3, group 2). The initial mean perfusion index value of group 1 (n = 9) was 8.2 ml/min/100 g (+/- 2) and for group 2 (n = 5) 10.4 ml/min/100 g (+/- 0.4). The difference in perfusion index values before chemoradiation between group 1 and group 2 was significant different (p = 0.012, Mann-Whitney test). The perfusion index value at the end of therapy of group 1 (n = 6) was 9.6 ml/min/100 g (+/- 2.8) and for group 2 (n = 4) 10.7 ml/min/100 g (+/- 1.6). The difference in perfusion index values after chemoradiation between group 1 and group 2 was not significant different (Table 2). CONCLUSION: Our used perfusion index value combines 2 parameters: tumor perfusion and extraction fraction. Therefore a significant negative influence on therapy outcome of high perfusion index values could be explained possibly by areas with a high portion of high perfusion (e.g. av-shunts) and a low extraction fraction (= low exchange of nutrients). However, we could show a significant negative influence of high perfusion index values on therapy outcome (p = 0.012). Because the tumor stage has a significant influence on tumor-free survival, there is a possibility for using initial perfusion index values as a new prognostic factor in rectal carcinoma without sphincter infiltration undergoing a preoperative chemoradiation. To examine this hypotheses a prospective trial is in preparation.

[Development and application of dynamic MR imaging in the evaluation of perfusion changes in rectal carcinoma during radiotherapy in clinical routine. Preliminary results]. / Entwicklung und Anwendung dynamischer MRT-Messungen zur Evaluierung von Perfusionsveränderungen bei Rektumkarzinomen unter Bestrahlung in der klinischen Routine. Erste Ergebnisse.

PURPOSE: This study was aimed at measuring microcirculatory parameters and contrast medium accumulation within the rectal carcinoma during fractionated radiotherapy in the clinical setting. MATERIAL AND METHODS: Perfusion data were observed in patients with rectal carcinoma (n = 8) who underwent a pre-operative combined chemo/radiotherapy. To acquire perfusion data, an ultrafast T1 mapping sequence was carried out on a 1.5-Tesla whole body imager to obtain T1 maps at intervals of 14 or 120 seconds. The overall measurement time was 40 minutes. The transaxial slice thickness (5 mm) was chosen in such a way that both arterial vessels and the tumor could be clearly identified. The gadolinium-DTPA (Gd-DTPA) concentration time curve was evaluated for arterial blood and tumor after intravenous constant rate infusion. The method allows a spatial resolution of 2 x 2 x 5 mm and a temporal resolution of 14 seconds. Patients underwent MR imaging before and at constant intervals during fractionated radiotherapy. RESULTS: Spatial and temporal resolution of dynamic T1 mapping was sufficient to reveal varying CM accumulation levels within the tumor and to identify the great arteries in the pelvis. In 6 patients Gd-DTPA concentration-time-curves were evaluated within the tumor during radiation. Pi index of Gd-DTPA versus radiation dose showed a significant increase in the first or second week of treatment, then either returned slowly to pretreatment level or a renewed increase was observed. The average Pi-value at the beginning was 0.16 (+/- 0.049), reaching highest level of 0.23 (+/- 0.058). In all groups the rise from the Pi-value to the Pi-maximum was statistically significant. The relative increase in perfusion ranged between 20 to 83%. CONCLUSION: The results show, that the ultrafast MR-technique described above provide a suitable tool for monitoring tumor microcirculation during therapeutic interventions and offers the potential for an individualized optimization of therapeutic procedures.

Lectin intravital perfusion studies in tumor-bearing mice: micrometer-resolution, wide-area mapping of microvascular labeling, distinguishing efficiently and inefficiently perfused microregions in the tumor.

Intravital lectin perfusion was combined with computer-guided scanning digital microscopy to map the perfused elements of the vasculature in tumor-bearing mice. High-precision composite images (spatial precision 1.3 micron and optical resolution 1.5 micron) were generated to permit exact positioning, reconstruction, analysis, and mapping of entire tumor cross-sections (c. 1 cm in diameter). Collation of these mosaics with nuclear magnetic resonance maps in the same tumor plane identified sites of rapid contrast medium uptake as tumor blood vessels. Digitized imaging after intravital double labeling allowed polychromatic visualization of two different types of mismatched staining. First, simultaneous application of two lectins, each bearing a different fluorochrome, revealed organ-specific differential processing in the microvascular wall. Second, sequential application of two boluses of one lectin, bearing different fluorochromes successively, distinguished between double-labeled microvessels, representing efficiently perfused vascular segments, and single-labeled microvessels, with inefficient or intermittent perfusion. Intravital lectin perfusion images of blood vessels in the vital functional state thus highlighted biologically significant differences in vessel function and served as high-resolution adjuncts to MR imaging.

Assessment of tumor microcirculation: a new role of dynamic contrast MR imaging.

With the advances in MR techniques, information related to tumor microcirculation now can be obtained in the clinical setting. This information can be valuable in the assessment of tumor blood supply/oxygenation status and tumor response to therapy. In this article, we review the tracer-kinetic modeling for tumor microcirculatory parameters derived from dynamic contrast MR imaging and report several preliminary results from both an animal model and early experience with human tumors. Despite the application of different MR protocols and tracer-kinetic models, the initial results of these pioneer studies consistently support the role of MR-derived microcirculatory tumor parameters, in providing prognostic information to assess and predict the response of cancers to cytotoxic therapy.

Magnetic resonance imaging investigation of blood-brain barrier damage in adoptive transfer experimental autoimmune encephalomyelitis.

Recent advances in fast magnetic resonance imaging (MRI) techniques have allowed quantification of parameters such as T1 relaxation time, which can be modified by changes in the water content of a tissue. We have used this new method to study the evolution of blood-brain barrier (BBB) changes after adoptive transfer of MBP-specific (AT-EAE) and ovalbumin-specific T cell lines in Lewis rats. Measurable changes in T1 relaxation time suggesting widespread increase in BBB permeability were found, starting on day 3 post inoculation (p.i.), in the midbrain and brainstem of AT-EAE rats. In addition, we noted a significant decrease in T1 relaxation time before injection of a paramagnetic agent, in the cisternal cerebrospinal fluid (CSF) of diseased animals, starting on day 5 p.i. In vitro measurement of T1 in CSF containing various concentrations of albumin, IgM and glucose showed that, at physiological concentrations, a T1 decrease is mainly associated with an increase in albumin concentration. A moderate increase in BBB and blood-CSF barrier permeability was found as early as 4-8 h p.i., in rats injected with MBP-specific as in animals injected with ovalbumin-specific T cell lines, suggesting a non-specific mechanism. Experimental MRI may become a powerful tool to sequentially analyse changes in barrier dynamics, for example following pharmacological intervention.

T1 maps by K-space reduced snapshot-FLASH MRI.

The T1 maps evaluated from k-space reduced Snapshot fast low angle shot (FLASH) images provide high contrast parameter images for tissue characterization in vivo of any body region. An algorithm for computing T1 values that allows a fast and reliable evaluation of T1 maps and yields reproducible values of tissue parameters in MR imaging is presented. The algorithm combined with the Snapshot FLASH inversion recovery imaging sequence permits a precise determination of T1 values, even for T1 times as low as 50 ms. Comparison with a spectroscopical inversion recovery method on identical phantoms demonstrates the accuracy of this technique. With its total acquisition time of approximately 2 s, IR Snapshot FLASH is fast enough to be used in monitoring fast T1 dynamics.

Fluctuations, exchange processes, and water diffusion in aqueous protein systems: A study of bovine serum albumin by diverse NMR techniques.

Experimental frequency, concentration, and temperature dependences of the deuteron relaxation times T(1) and T(2) of D(2)O solutions of bovine serum albumin are reported and theoretically described in a closed form without formal parameters. Crucial processes of the theoretical concept are material exchange, translational diffusion of water molecules on the rugged surfaces of proteins, and tumbling of the macromolecules. It is also concluded that, apart from averaging of the relaxation rates in the diverse deuteron phases, material exchange contributes to transverse relaxation by exchange modulation of the Larmor frequency. The rate limiting factor of macromolecular tumbling is determined by the free water content. In a certain analogy to the classical free-volume theory, a "free-water-volume theory" is presented. There are two characteristic water mass fractions indicating the saturation of the hydration shells (C(s) approximately 0.3) and the onset of protein tumbling (C(0) approximately 0.6). The existence of the translational degrees of freedom of water molecules in the hydration shells has been verified by direct measurement of the diffusion coefficient using an NMR field-gradient technique. The concentration and temperature dependences show phenomena indicating a percolation transition of clusters of free water. The threshold water content was found to be C(c) (w) approximately 0.43.