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Ximelagatran is a novel, oral direct thrombin inhibitor designed to overcome the low and variable oral absorption of melagatran, its active form. The pharmacokinetics and pharmacodynamics of ximelagatran following single and repeated oral administration were investigated. The primary objectives were to determine the dose linearity and reproducibility of melagatran exposure and the influence of food intake. Two open-label studies were performed in healthy male subjects. Study I was a dose-escalation study, in which subjects received single oral doses of ximelagatran (1-98 mg). Study II was a randomised, two-way crossover study consisting of two 5-day treatment periods, in which subjects received a 20-mg oral dose of ximelagatran twice daily, either before breakfast and with dinner, or with breakfast and after dinner. Ximelagatran was rapidly absorbed and converted to melagatran, which was the predominant compound in plasma. The mean (+/- standard deviation) bioavailability of melagatran was 22.2+/-4.3% and 17.4+/-2.8% after single and repeated dosings, respectively. The maximum plasma concentration of melagatran and the area under the melagatran plasma concentration-time curve (AUC) increased linearly with dose. Inter- and intra-subject variability in melagatran AUC was 8% and 12%, respectively, with no relevant food- or time dependence. Anticoagulation, assessed as activated partial thromboplastin time, was correlated with melagatran plasma concentration. There was virtually no increase in capillary bleeding time over the dose range studied, and ximelagatran was well tolerated. After oral administration of ximelagatran to healthy male subjects, the pharmacokinetic and pharmacodynamic profile of melagatran is predictable and reproducible.

We propose two distinct AI-based approaches to smart heat pump control for domestic hot water and space heating heat pumps, which can consider various variable factors (such as load prediction from forecasting algorithms and weather), learn the system model and adapt to changing environmental conditions. Based on these factors, the controllers optimize the management of the heat pumps to reduce energy consumption while maintaining user comfort. We present initial insights gained from laboratory experiments and a real-world field test, highlighting the practical effectiveness and environmental impacts of AI-driven strategies for enhancing heat pump efficiency, while also identifying areas for further improvement.

Warfarin prevents ischaemic stroke in patients with non-valvular atrial fibrillation, but dose adjustment, coagulation monitoring, and bleeding risk limit its use. The oral direct thrombin inhibitor ximelagatran represents a potential alternative. We aimed to establish whether ximelagatran is non-inferior to warfarin, within a margin of 2% per year, for prevention of stroke and systemic embolism. We randomised 3410 patients with atrial fibrillation and one or more stroke risk factors to open-label warfarin (adjusted-dose, international normalised ratio [INR] 2·0-3·0) or ximelagatran (fixed-dose, 36 mg twice daily); patients were recruited from 259 hospitals, doctor's offices, or health-care clinics. Primary analysis was based on masked event assessment and was by intention to treat. Primary endpoint was stroke or systemic embolism. During 4941 patient-years of exposure (mean 17·4 months, SD 4·1), 96 patients had primary events (56 in the warfarin group vs 40 in the ximelagatran group). The primary event rate by intention to treat was 2·3% per year with warfarin and 1·6% per year with ximelagatran (absolute risk reduction 0·7% [95% Cl -0·1 to 1·4], p=0·10; relative risk reduction 29% [95% Cl -6·5 to 52]). Rates of disabling or fatal stroke, mortality, and major bleeding were similar between groups, but combined minor and major haemorrhages were lower with ximelagatran than with warfarin (29·8%vs 25·8% per year; relative risk reduction 14% [4 to 22]; p=0·007). Raised serum alanine amino-transferase was more common with ximelagatran. In high-risk patients with atrial fibrillation, fixed-dose oral ximelagatran was at least as effective as well-controlled warfarin for prevention of stroke and systemic embolism.

Objectives The purpose of this study is to compare the reproducibility of three-dimensional cephalometric landmarks on three-dimensional computed tomography (3D-CT) surface rendering using clinical protocols based on low-dose (35-mAs) spiral CT and cone-beam CT (I-CAT). The absorbed dose levels for radiosensitive organs in the maxillofacial region during exposure in both 3D-CT protocols were also assessed. Materials and methods The study population consisted of ten human dry skulls examined with low-dose CT and cone-beam CT. Two independent observers identified 24 cephalometric anatomic landmarks at 13 sites on the 3D-CT surface renderings using both protocols, with each observer repeating the identification 1 month later. A total of 1,920 imaging measurements were performed. Thermoluminescent dosimeters were placed at six sites around the thyroid gland, the submandibular glands, and the eyes in an Alderson phantom to measure the absorbed dose levels. Results When comparing low-dose CT and cone-beam CT protocols, the cone-beam CT protocol proved to be significantly more reproducible for four of the 13 anatomical sites. There was no significant difference between the protocols for the other nine anatomical sites. Both low-dose and cone-beam CT protocols were equivalent in dose absorption to the eyes and submandibular glands. However, thyroid glands were more irradiated with low-dose CT. Conclusions Cone-beam CT was more reproducible and procured less irradiation to the thyroid gland than low-dose CT. Clinical relevance Cone-beam CT should be preferred over low-dose CT for developing three-dimensional bony cephalometric analyses.

Heparins substantially reduce the risk of thromboembolic complications after total hip or knee replacement. However, they can be given only by injection and have several other drawbacks. We did a multicentre, randomised, double-blind study to examine the dose-response relation of subcutaneous melagatran, a direct thrombin inhibitor, followed by oral ximelagatran as thromboprophylaxis after total hip or knee replacement. We aimed to compare the efficacy and safety with that of dalteparin. Of 1900 patients, 1495 were assigned to four dose categories of subcutaneous melagatran from just before surgery (1·00 mg, 1·50 mg, 2·25 mg, or 3·00 mg twice daily) followed from the day after surgery by oral ximelagatran (8 mg, 12 mg, 18 mg, or 24 mg twice daily). 381 patients were assigned subcutaneous dalteparin 5000 IU once daily, from the evening before surgery. Bilateral venography was done at 7–10 days, and clinically suspected venous thromboembolism (VTE) was confirmed radiologically. The primary endpoint was the rate of deep-vein thrombosis and pulmonary embolism (PE). Analyses were by intention to treat. 1876 patients underwent total replacement of hip (n=1270) or knee (n=606); evaluable venograms were obtained in 1473 (79%). Four patients without evaluable venograms had PE. Overall, a significant dose-dependent decrease in VTE was seen with melagatran/ximelagatran (lowest to highest group: 111 [37·8%] 70 [24·1%], 71 [23·7%], and 43 [15·1%]; p=0·0001); there were also significant relations for both total hip and total knee replacement individually. The frequency of VTE was significantly lower with the highest dose of melagatran/ ximelagatran than with dalteparin (15·1% vs 28·2%, p<0·0001). There were no reoperations due to bleeding and no critical organ bleeding. Excessive surgical bleeding was uncommon but more frequent in the highest dose group. This sequential therapy was effective and safe in patients undergoing major joint replacement surgery. The findings should be confirmed in a large phase III trial.

The potentialities of ENVISAT ASAR (Advanced Synthetic Aperture Radar) multi-angle data for mapping surface soil moisture (SSM) in Sahelian rangelands are investigated at medium scale (30 000 km2). The Wide Swath data are selected to take advantage of their high temporal repetitivity (about 8 days at the considered scale) associated to a moderate spatial resolution (150 m). In the continuity of previous studies conducted at a local scale in the same region, SSM maps are here processed over the whole AMMA Gourma mesoscale site at 1 km resolution scale. Overall, the generated maps are found to be in good agreement with field data, EPSAT-SG (Estimation des Pluies par SATellite – Second Generation) rainfall estimates and ERS (European Remote Sensing) Wind Scatterometer (WSC) SSM products. The present study shows that the spatial pattern of SSM can be realistically estimated at a kilometric scale. The resulting SSM maps are expected to provide valuable information for initialisation of land surface models and the estimation of the spatial distribution of radiative fluxes. Particularly, SSM maps could help to desaggregate low-resolution products such as those derived from WSC data.

Objectives One of the key aspects of three-dimensional (3D) craniofacial cephalometry is the measurement of posterior cranial base angle as this area is deeply involved in craniofacial development. The purpose of our retrospective study was to define the best reproducible 3D posterior cranial base angles among five 3D angles transposed from 2D cephalometry (Cousin, BL1 of Ross and Ravosa, Bjork, Delaire, CBA4 of Liberman) and seven 3D angles based on physical anthropology studies and on new concepts (R1 to R7). The null hypothesis was that all 3D posterior cranial base angles were equally reproducible. Material and methods We used a preoperative low-dose computed tomography (CT) data from 20 adult patients undergoing orthognathic surgery after approval by local ethical committee. Two independent observers performed two series of 23 3D landmark identifications on 3D CT surface rendering of each patient using Maxilim software. Then, the same observers performed twice 3D cephalometric analyses (23 landmarks, 4 midpoints, 19 planes) that provided the automatic measurement of 12 posterior cranial base angles. Results Inter-observer correlation coefficient varied from 0.545 (Cousin) to 0.695 (CBA4 of Liberman) and from −0.177 (R2) to 0.827 (R4). Conclusions The null hypothesis was rejected. The most reproducible angle was 3D angle R4 based on “basion,” “superior optic” (right, left), and “crista galli inferior” landmarks. Clinical relevance R4 angle might be used as reference 3D posterior cranial base angle in further clinical studies involving 3D cephalometry as a diagnostic tool for orthodontics and for orthognathic surgery.

The randomized, double-blind, placebo-controlled trial is the optimum method for clinical evaluation of new treatments, as assessed by clinicians and statisticians. However, if a known standard of therapy exists, it may be difficult to prove that a new therapy is superior. Equivalence and noninferiority clinical trial designs are now frequently utilized in clinical medical research. This article reviews the statistical differences between superiority, equivalence, and noninferiority design schemes, which pose specific ethical questions and have important implications for interpretation and clinical application of trial results. A guideline is proposed as a standard approach for reporting to facilitate qualitative assessment of the methodology of these trials.

New-onset trial fibrillation (AF) occurs commonly after acute myocardial infarction (MI) and is associated with a poor prognosis due to stroke or death. The optimal antithrombotic therapy is unknown. The aim of this study was to investigate whether an oral direct thrombin inhibitor, ximelagatran, added to aspirin, reduced the risk of death, myocardial infarction (MI), and stroke in patients who developed AF after their qualifying MI in the efficacy and safety of the oral direct thrombin inhibitor ximelagatran in patients with recent myocardial damage (ESTEEM) trial. The ESTEEM trial evaluated 6 months treatment with ximelagatran together with aspirin, compared to aspirin alone, for prevention of ischemic events in 1883 patients randomized within 14 days after an MI. After their qualifying MI, 174 (9%) patients developed AF in hospital. Multivariate hazard ratios for ximelagatran compared with placebo were calculated by presence AF. Of 101 patients with AF treated with ximelagatran 7 (6.9%) had either death, MI, or stroke, compared with 15 (20.6%) in 73 patients allocated to placebo. Ximelagatran reduced the risk of death, MI, or stroke by 70% (hazard ratio 0.30, 95% CI 0.12-0.74). For the separate outcome events, we found similar, nonsignificant trends. One major bleeding event occurred in each treatment group. For patients with MI complicated by AF, the combination of aspirin and an oral direct thrombin inhibitor seems beneficial. The high risk for death, MI, and stroke in this population and the increasing use of percutaneous interventions in MI patients may suggest a combination of long-term antiplatelet and anticoagulant therapy. Randomized clinical trials are warranted.

Satellite radar backscatter contains unique information on land surface moisture, vegetation features, and surface roughness and has thus been used in a range of Earth science disciplines. However, there is no single global radar data set that has a relatively long wavelength and a decades-long time span. We here provide the first long-term (since 1992), high-resolution (∼8.9 km instead of the commonly used ∼25 km resolution) monthly satellite radar backscatter data set over global land areas, called the long-term, high-resolution scatterometer (LHScat) data set, by fusing signals from the European Remote Sensing satellite (ERS; 1992–2001; C-band; 5.3 GHz), Quick Scatterometer (QSCAT, 1999–2009; Ku-band; 13.4 GHz), and the Advanced SCATterometer (ASCAT; since 2007; C-band; 5.255 GHz). The 6-year data gap between C-band ERS and ASCAT was filled by modelling a substitute C-band signal during 1999–2009 from Ku-band QSCAT signals and climatic information. To this end, we first rescaled the signals from different sensors, pixel by pixel. We then corrected the monthly signal differences between the C-band and the scaled Ku-band signals by modelling the signal differences from climatic variables (i.e. monthly precipitation, skin temperature, and snow depth) using decision tree regression. The quality of the merged radar signal was assessed by computing the Pearson r, root mean square error (RMSE), and relative RMSE (rRMSE) between the C-band and the corrected Ku-band signals in the overlapping years (1999–2001 and 2007–2009). We obtained high Pearson r values and low RMSE values at both the regional (r≥0.92, RMSE ≤ 0.11 dB, and rRMSE ≤ 0.38) and pixel levels (median r across pixels ≥ 0.64, median RMSE ≤ 0.34 dB, and median rRMSE ≤ 0.88), suggesting high accuracy for the data-merging procedure. The merged radar signals were then validated against the European Space Agency (ESA) ERS-2 data, which provide observations for a subset of global pixels until 2011, even after the failure of on-board gyroscopes in 2001. We found highly concordant monthly dynamics between the merged radar signals and the ESA ERS-2 signals, with regional Pearson r values ranging from 0.79 to 0.98. These results showed that our merged radar data have a consistent C-band signal dynamic. The LHScat data set (https://doi.org/10.6084/m9.figshare.20407857; Tao et al., 2023) is expected to advance our understanding of the long-term changes in, e.g., global vegetation and soil moisture with a high spatial resolution. The data set will be updated on a regular basis to include the latest images acquired by ASCAT and to include even higher spatial and temporal resolutions.