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ABSTRACTDespite the low prevalence of each rare disease, the total burden is high. Patients with rare diseases encounter numerous barriers, including delayed diagnosis and limited access to high-quality treatments. In order to tackle these challenges, the European Commission launched the European Reference Networks (ERNs), cross-border networks of healthcare providers and patients representatives. In parallel, the aims and structure of these ERNs were translated at the federal and regional levels, resulting in the creation of the Flemish Network of Rare Diseases. In line with the mission of the ERNs and to ensure equal access to care, we describe as first patient pathways for systemic sclerosis (SSc), as a pilot model for other rare connective and musculoskeletal diseases. Consensus was reached on following key messages: 1. Patients with SSc should have multidisciplinary clinical and investigational evaluations in a tertiary reference expert centre at baseline, and subsequently every three to 5 years. Intermediately, a yearly clinical evaluation should be provided in the reference centre, whilst SSc technical evaluations are permissionably executed in a centre that follows SSc-specific clinical practice guidelines. In between, monitoring can take place in secondary care units, under the condition that qualitative examinations and care including interactive multidisciplinary consultations can be provided. 2. Patients with early diffuse cutaneous SSc, (progressive) interstitial lung disease and/or pulmonary arterial hypertension should undergo regular evaluations in specialised tertiary care reference institutions. 3. Monitoring of patients with progressive interstitial lung disease and/or pulmonary (arterial) hypertension will be done in agreement with experts of ERN LUNG.

Solar radiation modification (SRM) is increasingly discussed as a tool to reduce or avert global warming and concomitantly the risk of ice-sheet collapse, as is considered possible for the West Antarctic Ice Sheet (WAIS). Here we analyse the impact of stratospheric aerosol injections on the centennial-to-millennial Antarctic sea-level contribution using an ice-sheet model. We find that mid-twenty-first-century large-scale SRM could delay but ultimately not prevent WAIS collapse in a high-emissions scenario. On intermediate-emissions pathways, SRM could be an effective tool to delay or even prevent an instability of WAIS if deployed by mid-century. However, SRM interventions may be associated with substantial risks, commitments and unintended side effects; therefore, emissions reductions to prevent WAIS collapse seem to be the more practical and sensible approach at the current stage.

Abstract Objective--To determine whether, compared with fundamental imaging, second harmonic imaging can improve the accuracy of dobutamine stress echocardiography for identifying viable myocardium, using nuclear imaging as a reference. Patients--30 [...]

It is important to evaluate whether a new treatment for heart failure with reduced ejection fraction (HFrEF) provides additive benefit to background foundational treatments. As such, we aimed to evaluate the efficacy and safety of empagliflozin in patients with HFrEF in addition to baseline treatment with specific doses and combinations of disease-modifying therapies.

During the early to mid‐Miocene, benthic δ18O records indicate large ice volume fluctuations of the Antarctic ice sheet (AIS) on multiple timescales. Hitherto, research has mainly focused on how CO2and insolation changes control an equilibrated AIS. However, transient AIS dynamics remain largely unexplored. Here, we study Miocene AIS variability, using an ice sheet‐shelf model forced by climate model output with various CO2levels and orbital conditions. Besides equilibrium simulations, we conduct transient experiments, gradually changing the forcing climate state over time. We show that transient AIS variability is substantially smaller than equilibrium differences. This reduces the contribution of the AIS to δ18O fluctuations by more than two thirds on a 40‐kyr timescale, hence requiring a larger contribution by deep‐sea‐temperature variability. The growth rates are much slower than the decay rates, which ensures variability around a preferred small state. Finally, if the bedrock topography enlarges the West Antarctic land surface, AIS self‐sustenance increases. The contribution of transient Antarctic ice sheet variations to Miocene δ18O signals is smaller than indicated by equilibrium differencesTransient ice volume variability is centered around a preferred small state and is dependent on the timescale of the forcingEnlarging the West Antarctic land surface increases the self‐sustenance of the Miocene Antarctic ice sheet, decreasing the variability

Abstract Objective--To study the outcome of patients with arrhythmogenic right ventricular dysplasia treated with an implantable cardioverter-defibrillator (ICD) for ventricular tachyarrhythmias complicated by haemodynamic collapse. Design--Observational study. Setting--University hospital. Patients--Nine [...]

Background Despite the fact that subjects with established coronary heart disease (CHD) are at high risk of further events and deserve meticulous secondary prevention, current audits such as EUROASPIRE show poor control of major risk factors. Ongoing monitoring is required. We present a new risk factor audit system, SURF (Survey of Risk Factor management), that can be conducted much more quickly and easily than existing audit systems and has the potential to allow hospitals of all sizes to participate in a unified international audit system that will complement EUROASPIRE. Initial experience indicates that SURF is truly simple to undertake in an international setting, and this is illustrated with the results of a substantive pilot project conducted in Europe and Asia.Methods The data collection system was designed to allow rapid and easy data collection as part of routine clinic work. Consecutive patients (aged 18 and over) with established CHD attending outpatient cardiology clinics were included. Information on demographics, previous coronary medical history, smoking history, history of hypertension, dyslipidaemia or diabetes, physical activity, attendance at cardiac rehabilitation, cardiac medications, lipid and glucose levels (and HbA1c in diabetics) if available within the last year, blood pressure, heart rate, body mass index, and waist circumference were collected using a one-page data collection sheet. Years spent in full time education was added as an additional question during the pilot phase.Results Three European countries − Ireland (n= 251), Belgium (n= 122), and Croatia (n= 124) − and four Asian countries − Singapore (n= 142), Taiwan (n= 334), India (n= 97), and Korea (n= 45) − were included in the pilot study. The results of initial field testing were confirmed in that it proved possible to collect data within 60−90 seconds per subject. There was poor control of several risk factors including high levels of physical inactivity (41−45%), overweight and obesity (59−78%), and ongoing smoking (15%). There were lower levels of individuals attending cardiac rehabilitation in Asia. More Europeans than Asians reached the low-density lipoprotein cholesterol target of <2.5mmol/l (66 vs. 59%) reflecting differences in medication usage. However, blood pressure control was superior in Asia, with 71% <140/90 compared with 66% of Europeans (NS).Conclusions This phase of SURF has confirmed its ease of use which should allow wide participation and the collection of representative risk factor data in subjects with CHD as well as ongoing data collection to monitor secular trends in risk factor control. Notwithstanding that this is a pilot study, the results suggest that risk factor control, particularly for lifestyle-related measures, is poor in both Europe and Asia.

Over the last decades, more and more evidence is accumulated that physical activity (PA) and exercise interventions are essential components in primary and secondary prevention for cardiovascular disease. However, it is less clear whether and which type of PA and exercise intervention (aerobic exercise, dynamic resistive exercise, or both) or characteristic of exercise (frequency, intensity, time or duration, and volume) would yield more benefit in achieving cardiovascular health. The present paper, as the first of a series of three, will make specific recommendations on the importance of these characteristics for cardiovascular health in the population at large. The guidance offered in this series of papers is aimed at medical doctors, health practitioners, kinesiologists, physiotherapists and exercise physiologists, politicians, public health policy makers, and the individual member of the public. Based on previous and the current literature, recommendations from the European Association on Cardiovascular Prevention and Rehabilitation are formulated regarding type, volume, and intensity of PA and exercise.

The formation, degree of crystallinity, and adherence of dense titania (TiO2) thin film coatings on a high-temperature polyimide resin (PMR-15) can be influenced by the chemical composition of the polymer surface. Furthermore, solution deposition conditions can be adjusted to provide additional control over the morphology and crystallinity of the titania films. Recipes for solution-based titania deposition that used a slowly hydrolyzing titanium fluoride salt in the presence of boric acid as a fluoride scavenger allowed growth of films up to 750 nm thick in 22 h. By adjusting solution pH and temperature, either amorphous titania or oriented crystalline anatase films could be formed. Surface sulfonate groups enhance the adhesion of solution-deposited oxide thin film coatings. While most sulfonation procedures severely damaged the PMR-15 surface, the use of chlorosulfonic acid followed by hydrolysis of the installed chlorosulfonyl groups provided effective surface sulfonation without significant surface damage. In some cases, the oxide deposition solution caused partial hydrolysis of the polymer surface, which itself was sufficient to allow adhesion of the titania film through chelation of titanium ions by exposed benzoic acid groups on the polymer surface.

Abstract: High-velocity oxyfuel (HVOF) sprayed polyimide/WC-Co functionally graded (FGM) coatings with flame-sprayed WC-Co topcoats have been investigated as solutions to improve the solid-particle erosion and oxidation resistance of polymer matrix composites (PMCs) in the gas flow path of advanced turbine engines. Porosity, coating thickness, and volume fraction of the WC-Co phase retained in the graded coating architecture were determined using standard metallographic techniques and computer image analysis. The adhesive bond strength of three different types of coatings was evaluated according to ASTM D 4541. Adhesive/cohesive strengths of the FGM coating were measured and compared with those of pure polyimide and polyimide/WC-Co composite coatings and also related to the tensile strength of the uncoated PMC substrate perpendicular to the thickness. The FGM coatings exhibited lower adhesive bond strengths (∼6.2 MPa) than pure polyimide coatings (∼8.4 MPa), and in all cases these values were lower than the tensile strength (∼17.6 MPa) of the reference uncoated PMC substrate. The nature and locus of the failures were characterized according to the percent adhesive and/or cohesive failure, and the interfaces tested and layers involved were analyzed by scanning electron microscopy.

In this work, a methodology has been presented for the evaluation of stiffness properties and temperature–dependent coefficients of thermal expansion of continuous fibres from the macroscopic properties of either unidirectional or woven composites. The methodology was used to determine the stiffness and thermal properties of T650–35 graphite fibres from the macroscopic input data of unidirectional and woven composites based on the same fibres embedded in a PMR–15 polyimide matrix. In the first part of the analysis, the fibre properties were determined directly from the unidirectional composite macro data using the inversed Eshelby–Mori–Tanaka approach. Subsequently, certain fibre properties were additionally evaluated indirectly from the woven composite, using the finite–element method and the concept of a representative unit cell.It has been shown that the temperature–dependent coefficients of thermal expansion of the fibres can be estimated from the unidirectional composite macro data with significantly smaller errors than in the case of the elastic properties. It has also been shown that the errors in the evaluation of the elastic properties of the fibres from the macro unidirectional composite data could be significantly reduced if the fibres were placed in a stiff matrix material: much stiffer than the polyimide resin. The longitudinal and transverse coefficients of thermal expansions and the shear modulus of the T650–35 fibres determined from the unidirectional composite analysis were successfully verified by investigating the woven composite.

The effect of LV properties on v p and the E/ v p ratio remains a matter of debate. Therefore, the objective of this study is to explore – in a new hydraulic model – the individual contributions of LV relaxation, filling pressure and compliance in changes of E, v p and E/ v p for different stages of diastolic function. A new hydraulic model, consisting of an open cylindrical LA connected to an ellipsoidal LV, is designed. E and v p are measured for varying values of t (45–60–90 ms), LV compliance (0.45–1.35 ml/mmHg) and filling pressure (3–10–30 mmHg). The results are used for predicting the evolution of E, v p and E/ v p during different stages of diastolic function. An increase in compliance decreases E, whereas it augments v p. v p is less load-dependent than E. E decreases with delayed relaxation, increases for the case of pseudonormalisation, and becomes higher than the reference values during restrictive filling. The v p value is lower for the case of delayed relaxation than for the reference situation. During pseudonormalisation, the value of v p remains lower than the reference value but higher than the value for delayed relaxation. . v p further decreases during restrictive filling. In conclusion, the effect of simultaneous changes in compliance and loading counterbalance changes in v p. Therefore, under normal physiologic conditions where load and compliance are coupled, v p is apparently load-insensitive and E/ v p increases as filling pressure increases. Moreover, in the different stages of diastolic dysfunction, due to the interference of the co-varying relaxation, the increase in E/ v p is more pronounced.

Thermally sprayed coatings are being studied and developed as methods of enabling lightweight composites to be used more extensively as structural components in propulsion applications in order to reduce costs and improve efficiency through weight reductions. The primary goal of this work is the development of functionally graded material (FGM) polymer/metal matrix composite coatings to provide improved erosion/oxidation resistance to polyimide-based polymer matrix composite (PMC) substrates. The goal is to grade the coating composition from pure polyimide, similar to the PMC substrate matrix on one side, to 100% WC-Co on the other. Both step-wise and continuous gradation of the WC-Co loading in these coatings are being investigated. Details of the processing parameter development are presented, specifically the high velocity oxy-fuel (HVOF) combustion spraying of pure PMR-II matrix material and layers of various composition PMR-II/WC-Co blends onto steel and PMR-15 composite substrates. Results of the HVOF process optimization, microstructural characterization, and analysis will be presented. The sprayed coatings were evaluated using standard metallographic techniques - optical and scanning electron microscopy (SEM). An SEM + electron dispersive spectroscopy (EDS) technique has also been used to confirm retention of the PMR-II component.

Although there is increasing interest in the automatic processing of tomographic radionuclide ventriculography TRV studies, validation is mainly limited to a comparison of TRV results with data from planar radionuclide ventriculography PRV or gated perfusion single photon emission computed tomography SPECT. The aim of this study was to use a dynamic physical cardiac phantom to validate the ejection fraction EF and volumes from PRV and TRV studies. A new dynamic left ventricular phantom was constructed and used to obtain 21 acquisitions in the planar and tomographic mode. The directly measured volumes and EFs of the phantom during the acquisitions were considered as the gold standard for comparison with TRV and PRV. EFs were calculated from PRV by backgroundcorrected enddiastolic and endsystolic frames. Volumes and EFs were calculated from TRV by region growing with different lower thresholds to search for the optimal threshold. EF from PRV correlated significantly with the real EF r0.94, P0.00. The optimal threshold value for volume calculation from TRV in 336 cases was 50 r0.98, P0.00 yielding the best slope after linear regression. When considering these calculated enddiastolic and endsystolic volumes, EF correlated well r0.99, P0.00 with the real EF, and this correlation was significantly P0.04 higher than that of the EF from PRV. Our experiments prove that EF measured by TRV yields more accurate results compared with PRV in dynamic cardiac phantom studies.

The newly proposed atomic‐scale length standard, the wavelength of the 57Fe Mössbauer radiation [Shvyd'ko et al.(2000). Phys. Rev. Lett.45, 495–498], is used to measure the wavelengths of the Mössbauer radiation of 151Eu, 57.556185 (27) pm, 119Sn, 51.920811 (39) pm, and 161Dy, 48.334336 (19) pm, with a relative accuracy of ∼0.5 p.p.m. Also, the lattice constants of Al2O3are measured in a temperature range from 286 K to 374 K. At room temperature, = 295.65 K, their values are = 4.759213 (8) Å, = 12.991586 (4) Å.

Infarct size assessed by myocardial single-photon emission tomography (SPET) imaging is an important prognostic parameter after myocardial infarction (MI). We compared three commercially available automatic quantification algorithms that make use of normal templates for the evaluation of infarct extent and severity in a large population of patients with remote MI. We studied 100 consecutive patients (80 men, mean age 63±11 years, mean LVEF 47%±15%) with a remote MI who underwent resting technetium-99m tetrofosmin gated SPET study for infarct extent and severity quantification. The quantification algorithms used for comparison were a short-axis algorithm (Cedars-Emory quantitative analysis software, CEqual), a vertical long-axis algorithm (VLAX) and a three-dimensional fitting algorithm (Perfit). Semiquantitative visual infarct extent and severity assessment using a 20-segment model with a 5-point score and the relation of infarct extent and severity with rest LVEF determined by quantitative gated SPET (QGS) were used as standards to compare the different algorithms. Mean infarct extent was similar for visual analysis (30%±21%) and the VLAX algorithm (25%±17%), but CEqual (15%±11%) and Perfit (5%±6%) mean infarct extents were significantly lower compared with visual analysis and the VLAX algorithm. Moreover, infarct extent determined by Perfit was significantly lower than infarct extent determined by CEqual. Correlations between automatic and visual infarct extent and severity evaluations were moderate (r=0.47, P<0.0001 to r=0.62, P<0.0001) but comparable for all three algorithms. Correlations between LVEF and visual evaluation of infarct extent (r=–0.80, P<0.0001) and severity (r=–0.82, P<0.0001) were good but correlations were significantly lower for all three algorithms (r=–0.48, P<0.0001 to r=–0.65, P<0.0001). Systematically lower correlations were found in non-anterior infarctions (n=69) and obese patients (BMI ≥30 kg/m2, n=32) compared with anterior infarctions and non-obese patients for all three algorithms. In this large series of post-MI patients, results of infarct extent and severity determination by automatic quantification algorithms that make use of normal templates were not interchangeable and correlated only moderately with semiquantitative visual analysis and LVEF.

Abstract.: This study reports on the distribution and radiation dosimetry of iodine-123 labelled trans-Z-iodomethyl-N,N-diethyltamoxifen (123-ITX), a promising radioligand for prediction of the therapeutic efficacy of unlabelled tamoxifen in human breast carcinoma. Whole-body scans were performed up to 24 h after intravenous injection of 123-ITX (mean: 146 MBq, range: 142–148 MBq) in five female volunteers, four with and one without thyroid blockade. Blood samples were taken at various times up to 24 h after injection. Urine was also collected up to 24 h after injection, allowing calculation of renal clearance and interpretation of whole-body clearance. Time-activity curves were generated for the thyroid, heart, brain, breasts, liver and gallbladder by fitting the organ-specific geometric mean counts, obtained from regions of interest. The MIRD formulation was applied to calculate the absorbed radiation doses for various organs. The images showed rapid hepatobiliary excretion, resulting in good imaging conditions for the thoracic region, whereas imaging of the abdominal region was impeded by extensive bowel activity. The breast to non-specific uptake ratio increased over time. 123-ITX was cleared by both the kidneys and the gastrointestinal tract. At 50 h p.i. the mean excretion in the urine was 89.4% (SD 5.7%). If the thyroid was not blocked, it was one of the critical organs. The highest absorbed doses were received by the excretory organs, i.e. the urinary bladder wall, the lower and upper large intestine, and the gallbladder wall. The average effective dose of 123-ITX was estimated to be 0.0084 mSv/MBq. The amount of 123-ITX required for adequate imaging of tumoral uptake results in an acceptable effective dose to the patient.

Palladium(II) and ruthenium(II) complexes containing aminoxyl radical-substituted triphenylphosphine ligands are reported. The novel spin-labeled phosphine ligands [(p-(4,4,5,5,-tetramethylimidazolinyl-1-oxyl-3-oxide)phenyl)diphenylphosphine] (1) and [(p-(N-oxyl-tert-butylamino-2-)phenyl)diphenylphosphine] (2) react with PdCl2 to yield trans-Pd[1]2Cl2 and trans-Pd[2]2Cl2 (complexes 3 and 4, respectively), which show exchange-coupled EPR spectra. This through-space, intramolecular coupling provides a method of determining the number of radical phosphines coordinated to the Pd(II) center. Systems with only one coordinated phosphine show EPR spectra typical of the ligand. Phosphine 2 reacts with [(η³-C3H5)PdCl]2 and [(η⁶-p-cymene)RuCl2]2 to form the mononuclear metal phosphine adducts (η³-C3H5)Pd[2]Cl (5) and (η⁶-p-cymene)Ru[2]Cl2 (6). All complexes show broad, shifted ¹H NMR spectra, and magnetic susceptibility measurements confirm the presence of one (complexes 5, 6) or two (complexes 3, 4) radicals per complex accordingly. The X-ray crystal structures of Pd[2]2Cl2 and (η³-C3H5)Pd[2]Cl are also reported. Complexes 5 and 6 are unusual examples of stable organometallic systems with peripheral free radicals, i.e., spin-labeled organometallics.

Hornblende and biotite $$^{40}Ar/^{39}Ar$$age spectra from rocks in south-central Connecticut help define a Permian-Trias sic cooling curve for the area. Together with petrologic and structural information, a time-temperature-pressure-strain path is established. Similar data for the Narragansett basin in Rhode Island and Massachusetts allow correlation of the late Paleozoic histories of the two areas. Together, these data suggest that in the late Paleozoic, south-central New England was part of a fold-thrust belt, and the Narragansett basin was a retroarc foreland basin. NW-SE compression during the final assembly of Pangaea resulted in SE directed thrusting, causing the development of clastic wedges in adjacent Rhode Island and Massachusetts in the Late Carboniferous-Early Permian. A clockwise rotation of this deformation from NW to NNE led to northward underthrusting and concomitant uplift of both eastern Connecticut and Rhode Island in the Permian and Triassic.

The monoanionic ligand [C6H3(CH2NMe2)2-2,6]^-, a potentially terdentate N,C,N bonding system, has been employed to synthesize a series of new ruthenium(II) complexes [Ru{C6H3(CH2NMe2)2-2,6}X(L)] (L = PPh3, X = Cl (2a), I (2b); L = norbornadiene (nbd), X = Cl (4), η¹-OSO2CF3 (5)) and [Ru{C6H3(CH2NMe2)2-2,6}(2,2‘:6‘,2‘‘-terpyridine)]Cl (3). X-ray crystal structures of 2b and 3−5 have been determined, in which the N,C,N coordination geometry with respect to the metal center is found to differ considerably. In each complex the aryldiamine ligand is terdentate, η³-N,C,N-bonded as a six electron donor system. However, depending on the other ligands in the Ru(II) coordination sphere, this ligand demonstrates considerable flexibility in adopting coordination geometries which range from meridional in 3 through pseudomeridional in 2b to pseudofacial in 4 and 5. In the structures of 4 and 5 significant distortions of the aryl ring, involving bending of the six-membered ring into a boatlike conformation, are found. The different combinations of the N,C,N ligand with sets of other ligands lead to a range of metal geometries, i.e. square pyramidal in 2b, octahedral in 3, and bicapped tetrahedral in 4 and 5.

The primary goal of a quantitative structure−property relationship (QSPR) is to identify a set of structurally based numerical descriptors that can be mathematically linked to a property of interest. The types of descriptors fall into three categories:  topological, electronic, and geometric. In this study, 140 organic compounds with diverse structures were split into a training set, a cross-validation set, and a prediction set. The training set was used to build multiple linear regression and computational neural network models, the cross-validation set was used to prevent overtraining of the neural network, and the prediction set was used to validate the mathematical models. A set of nine descriptors was found that effectively linked the aqueous solubility to each structure. However, the polychlorinated biphenyls (PCBs) had a large root-mean-square (rms) error associated with them. Therefore models were also built using a training set that contained no PCBs. A set of nine descriptors was found with a significant improvement of the rms error of the training set as well as the prediction set.