Ulipristal acetate versus levonorgestrel-releasing intrauterine system for heavy menstrual bleeding (UCON): a randomised controlled phase III trial.

Background: Heavy menstrual bleeding affects one in four women and negatively impacts quality of life. Ulipristal acetate is prescribed to treat symptoms associated with uterine fibroids. We compared the effectiveness of ulipristal acetate and the levonorgestrel-releasing intrauterine system at reducing the burden of heavy menstrual bleeding, irrespective of the presence of fibroids. Methods: This randomised, open-label, parallel group phase III trial enrolled women over 18 years with heavy menstrual bleeding from 10 UK hospitals. Participants were centrally randomised, in a 1:1 ratio, to either three, 12-week treatment cycles of 5 mg ulipristal acetate daily, separated by 4-week treatment-free intervals, or a levonorgestrel-releasing intrauterine system. The primary outcome, analysed by intention-to-treat, was quality of life measured by the Menorrhagia Multi-Attribute Scale at 12 months. Secondary outcomes included menstrual bleeding and liver function. The trial is registered with ISRCTN, 20426843. Findings: Between June 5th, 2015 and February 26th, 2020, 236 women were randomised, either side of a recruitment suspension due to concerns of ulipristal acetate hepatoxicity. Subsequent withdrawal of ulipristal acetate led to early cessation of recruitment but the trial continued in follow-up. The primary outcome substantially improved in both groups, and was 89, (interquartile range [IQR] 65 to 100, n = 53) and 94, (IQR 70 to 100, n = 50; adjusted odds ratio 0.55, 95% confidence interval [CI] 0.26-1.17; p = 0.12) in the ulipristal and levonorgestrel-releasing intrauterine system groups. Rates of amenorrhoea at 12 months were higher in those allocated ulipristal acetate compared to levonorgestrel-releasing intrauterine system (64% versus 25%, adjusted odds ratio 7.12, 95% CI 2.29-22.2). Other outcomes were similar between the two groups and there were no cases of endometrial malignancy or hepatotoxicity due to ulipristal acetate use. Interpretation: Our findings suggested that both treatments improved quality of life. Ulipristal was more effective at inducing amenorrhoea. Ulipristal has been demonstrated to be an effective medical therapeutic option but currently its use has restrictions and requires liver function monitoring. Funding: UK Medical Research Council and National Institute of Health Research EME Programme (12/206/52).

The effectiveness of methylphenidate in the management of Attention Deficit Hyperactivity Disorder (ADHD) in people with intellectual disabilities: A systematic review.

BACKGROUND: The effectiveness of psychostimulants, primarily methylphenidate (MPH), in the treatment of Attention Deficit Hyperactivity Disorder (ADHD) in the general population of typically growing children and adolescents is well established through many Randomised Controlled Trials (RCTs). AIMS AND METHODS: We carried out a systematic review of all the RCTs in people with intellectual disabilities (ID) that assessed effectiveness of MPH on the core ADHD symptoms. OUTCOMES AND RESULTS: We included 15 papers from 13 studies that were all on children and adolescents with ID (315 participants were on MPH and placebo respectively), 12 of which used a cross over design, and one used a parallel design. On average around 40-50% responded to MPH in the ID group whereas around 70-80% response rate is reported among the non-ID children. Because of the heterogeneity of the outcome data it was not possible to carry out a meta-analysis. Significant adverse events included sleep difficulties and poor appetite along with weight loss and also irritability, social withdrawal and increased motor activities including tic. CONCLUSIONS AND IMPLEMENTATION: On the basis of the poor quality evidence that is available, it seems that MPH may be effective in some but not all children and adolescents with ID and ADHD.

Spin-locking of half-integer quadrupolar nuclei in NMR of solids: The far off-resonance case.

Spin-locking of spin I=3/2 and I=5/2 nuclei in the presence of large resonance offsets has been studied using both approximate and exact theoretical approaches and, in the case of I=3/2, experimentally. We show the variety of coherences and population states produced in a far off-resonance spin-locking NMR experiment (one consisting solely of a spin-locking pulse) and how these vary with the radiofrequency field strength and offset frequency. Under magic angle spinning (MAS) conditions and in the "adiabatic limit", these spin-locked states acquire a time dependence. We discuss the rotor-driven interconversion of the spin-locked states, using an exact density matrix approach to confirm the results of the approximate model. Using conventional and multiple-quantum filtered spin-locking 23Na (I=3/2) NMR experiments under both static and MAS conditions, we confirm the results of the theoretical calculations, demonstrating the applicability of the approximate theoretical model to the far off-resonance case. This simplified model includes only the effects of the initial rapid dephasing of coherences that occurs at the start of the spin-locking period and its success in reproducing both experimental and exact simulation data indicates that it is this dephasing that is the dominant phenomenon in NMR spin-locking of quadrupolar nuclei, as we have previously found for the on-resonance and near-resonance cases. Potentially, far off-resonance spin-locking of quadrupolar nuclei could be of interest in experiments such as cross polarisation as a consequence of the spin-locking pulse being applied to a better defined initial state (the thermal equilibrium bulk magnetisation aligned along the z-axis) than can be created in a powdered solid with a selective radiofrequency pulse, where the effect of the pulse depends on the orientation of the individual crystallites.

Imaging of the B1 distribution and background signal in a MAS NMR probehead using inhomogeneous B0 and B1 fields.

Several widely used methods for suppressing the "background" signal in (1)H magic angle spinning (MAS) NMR spectroscopy are based on the assumption of a significant difference between the B1 radiofrequency field experienced by the sample (within the MAS rotor) and that felt by static components of the probehead (where the background signal is believed to originate). In this work, a two-dimensional correlation experiment employing inhomogeneous B0 and B1 fields is used to image the B1 distribution in a MAS NMR probehead. The experiment, which can be performed on any spectrometer, allows the distribution of the B1 field to be measured and also correlated with the spatial location of the NMR signal within the probehead. The method can also readily be combined with various "depth pulse" techniques for background suppression, allowing their performances to be more rigorously evaluated.

Dual-compensated antisymmetric composite refocusing pulses for NMR.

Novel antisymmetric composite 180° pulses are designed for use in nuclear magnetic resonance (NMR) and verified experimentally. The pulses are simultaneously broadband with respect to both inhomogeneity of the radiofrequency (B(1)) field and resonance offset and, as a result of their antisymmetric phase schemes, can be used to form spin echoes without the introduction of a phase error. The new dual-compensated pulses are designed analytically, using symmetry arguments and a graphical interpretation of average Hamiltonian theory. Two families of composite refocusing pulses are presented, one (ASBO-9) consisting of sequences made up of 9 simple 180° pulses and one (ASBO-11) of sequences made up of 11 simple 180° pulses. There are an infinite number of composite pulses in each family owing to a free phase variable in the solution to the average Hamiltonian equations and this allows selection of individual composite pulses with particular properties. Finally, a comparison is made between composite pulses designed using average Hamiltonian theory and those proposed for use in quantum computing by NMR.

Improved background suppression in ¹H MAS NMR using composite pulses.

A well known feature of ¹H MAS NMR spectroscopy, particularly of solids where the concentration of ¹H nuclei is low, is the presence in the spectrum of a significant broad "background" signal arising from ¹H nuclei that are outside the MAS rotor and radiofrequency coil, probably located on the surfaces of the static components of the probehead. A popular method of suppressing this unwanted signal is the "depth pulse" method, consisting of a 90° pulse followed by one or two 180° pulses that are phase cycled according to the "Exorcycle" scheme, which removes signal associated with imperfect 180° pulses. Consequently, only spins in the centre of the radiofrequency coil contribute to the ¹H MAS spectrum, while those experiencing a low B1 field outside the coil are suppressed. Although very effective at removing background signal from the spectrum, one drawback with this approach is that significant loss of the desired signal from the sample also occurs. Here we investigate the ¹H background suppression problem and, in particular, the use of novel antisymmetric passband composite pulses to replace the simple pulses in a depth pulse experiment. We show that it is possible to improve the intensity of the ¹H signals of interest while still maintaining effective background suppression. We expect that these results will be relevant to ¹H MAS NMR studies of, for example, nominally perdeuterated biological samples or nominally anhydrous inorganic materials.

Use of composite refocusing pulses to form spin echoes.

The radiofrequency pulses used in NMR are subject to a number of imperfections such as those caused by inhomogeneity of the radiofrequency (B(1)) field and an offset of the transmitter frequency from precise resonance. The effect of these pulse imperfections upon a refocusing pulse in a spin-echo experiment can be severe. Many of the worst effects, those that distort the phase of the spin echo, can be removed completely by selecting the echo coherence pathway using either the "Exorcycle" phase cycle or magnetic field gradients. It is then tempting to go further and try to improve the amplitude of the spin-echo signal by replacing the simple refocusing pulse with a broadband composite 180° pulse that compensates for the relevant pulse imperfection. We show here that all composite pulses with a symmetric or asymmetric phase shift scheme will reintroduce phase distortions into the spin echo, despite the selection of the echo coherence pathway. In contrast, all antisymmetric composite pulses yield no phase distortion whatsoever, both on and off resonance, and are therefore the correct symmetry of composite refocusing pulse to use. These conclusions are verified using simulations and (31)P MAS NMR spin-echo experiments performed on a microporous aluminophosphate.