Opicapone as Adjunct to Levodopa Therapy in Patients With Parkinson Disease and Motor Fluctuations: A Randomized Clinical Trial

Importance: Catechol O-methyltransferase (COMT) inhibitors are an established treatment for end-of-dose motor fluctuations associated with levodopa therapy in patients with Parkinson disease (PD). Current COMT inhibitors carry a high risk for toxic effects to hepatic cells or show moderate improvement. Opicapone was designed to be effective without the adverse effects. Objective: To evaluate the efficacy and safety of 25- and 50-mg/d dosages of opicapone compared with placebo as adjunct to levodopa therapy in patients with PD experiencing end-of-dose motor fluctuations. Design: This phase 3 international, multicenter outpatient study evaluated a 25- and a 50-mg/d dosage of opicapone in a randomized, double-blind, 14- to 15-week, placebo-controlled clinical trial, followed by a 1-year open-label phase during which all patients received active treatment with opicapone. Patients with PD who experienced signs of end-of-dose deterioration and had a mean total awake off-time (state of akinesia or decreased mobility) of at least 1.5 hours, not including morning akinesia, were enrolled. Data were collected from March 18, 2011, through June 25, 2013. Data from the evaluable population were analyzed from July 31, 2013, to July 31, 2014. Main Outcomes and Measures: The primary efficacy outcome of the double-blind phase was the change from baseline in absolute off-time vs placebo based on patient diaries. The open-label phase focused on maintenance of treatment effect in off-time. Results: A total of 427 patients (258 men [60.4%] and 169 women [39.6%]; mean [SD] age, 63.1 [8.8] years) were randomized to a 25-mg/d (n = 129) or a 50-mg/d (n = 154) dosage of opicapone or to placebo (n = 144). Of these, 376 patients completed the double-blind phase and entered the open-label phase, of whom 286 completed 1 year of open-label treatment. At the end of the double-blind phase, the least squares mean change (SE) in off-time was -64.5 (14.4) minutes for the placebo group, -101.7 (14.9) minutes for the 25-mg/d opicapone group, and -118.8 (13.8) minutes for the 50-mg/d opicapone group. The adjusted treatment difference vs placebo was significant for the 50-mg/d opicapone group (treatment effect, -54.3 [95% CI, -96.2 to -12.4] minutes; P = .008), but not for the 25-mg/d opicapone group (treatment effect, -37.2 [95% CI, -80.8 to 6.4] minutes; P = .11). The off-time reduction was sustained throughout the open-label phase (-126.3 minutes at 1-year open-label end point). The most common adverse events in the opicapone vs placebo groups were dyskinesia, constipation, and dry mouth. Fifty-one patients (11.9%) discontinued from the study during the double-blind phase. Conclusions and Relevance: Treatment with a 50-mg once-daily dose of opicapone was associated with a significant reduction in mean daily off-time in levodopa-treated patients with PD and motor fluctuations, and this effect is maintained for at least 1 year. Opicapone was safe and well tolerated. Trial Registration: clinicaltrials.gov Identifier: NCT01227655

Perinatal and 2-year neurodevelopmental outcome in late preterm fetal compromise: the TRUFFLE 2 randomised trial protocol

Introduction Following the detection of fetal growth restriction, there is no consensus about the criteria that should trigger delivery in the late preterm period. The consequences of inappropriate early or late delivery are potentially important yet practice varies widely around the world, with abnormal findings from fetal heart rate monitoring invariably leading to delivery. Indices derived from fetal cerebral Doppler examination may guide such decisions although there are few studies in this area. We propose a randomised, controlled trial to establish the optimum method of timing delivery between 32 weeks and 36 weeks 6 days of gestation. We hypothesise that delivery on evidence of cerebral blood flow redistribution reduces a composite of perinatal poor outcome, death and short-term hypoxia-related morbidity, with no worsening of neurodevelopmental outcome at 2 years. Methods and analysis Women with non-anomalous singleton pregnancies 32+0 to 36+6 weeks of gestation in whom the estimated fetal weight or abdominal circumference is <10th percentile or has decreased by 50 percentiles since 18–32 weeks will be included for observational data collection. Participants will be randomised if cerebral blood flow redistribution is identified, based on umbilical to middle cerebral artery pulsatility index ratio values. Computerised cardiotocography (cCTG) must show normal fetal heart rate short term variation (≥4.5 msec) and absence of decelerations at randomisation. Randomisation will be 1:1 to immediate delivery or delayed delivery (based on cCTG abnormalities or other worsening fetal condition). The primary outcome is poor condition at birth and/or fetal or neonatal death and/or major neonatal morbidity, the secondary non-inferiority outcome is 2-year infant general health and neurodevelopmental outcome based on the Parent Report of Children’s Abilities-Revised questionnaire. Ethics and dissemination The Study Coordination Centre has obtained approval from London-Riverside Research Ethics Committee (REC) and Health Regulatory Authority (HRA). Publication will be in line with NIHR Open Access policy. Trial registration number Main sponsor: Imperial College London, Reference: 19QC5491. Funders: NIHR HTA, Reference: 127 976. Study coordination centre: Imperial College Healthcare NHS Trust, Du Cane Road, London, W12 0HS with Centre for Trials Research, College of Biomedical & Life Sciences, Cardiff University. IRAS Project ID: 266 400. REC reference: 20/LO/0031. ISRCTN registry: 76 016 200

Fetal cerebral Doppler changes and outcome in late preterm fetal growth restriction: prospective cohort study

Objectives To explore the association between fetal umbilical and middle cerebral artery (MCA) Doppler abnormalities and outcome in late preterm pregnancies at risk of fetal growth restriction. Methods This was a prospective cohort study of singleton pregnancies at risk of fetal growth restriction at 32 + 0 to 36 + 6 weeks of gestation, enrolled in 33 European centers between 2017 and 2018, in which umbilical and fetal MCA Doppler velocimetry was performed. Pregnancies were considered at risk of fetal growth restriction if they had estimated fetal weight and/or abdominal circumference (AC) < 10th percentile, abnormal arterial Doppler and/or a fall in AC growth velocity of more than 40 percentile points from the 20-week scan. Composite adverse outcome comprised both immediate adverse birth outcome and major neonatal morbidity. Using a range of cut-off values, the association of MCA pulsatility index and umbilicocerebral ratio (UCR) with composite adverse outcome was explored. Results The study population comprised 856 women. There were two (0.2%) intrauterine deaths. Median gestational age at delivery was 38 (interquartile range (IQR), 37–39) weeks and birth weight was 2478 (IQR, 2140–2790) g. Compared with infants with normal outcome, those with composite adverse outcome (n = 93; 11%) were delivered at an earlier gestational age (36 vs 38 weeks) and had a lower birth weight (1900 vs 2540 g). The first Doppler observation of MCA pulsatility index < 5th percentile and UCR Z-score above gestational-age-specific thresholds (1.5 at 32–33 weeks and 1.0 at 34–36 weeks) had the highest relative risks (RR) for composite adverse outcome (RR 2.2 (95% CI, 1.5–3.2) and RR 2.0 (95% CI, 1.4–3.0), respectively). After adjustment for confounders, the association between UCR Z-score and composite adverse outcome remained significant, although gestational age at delivery and birth-weight Z-score had a stronger association. Conclusion In this prospective multicenter study, signs of cerebral blood flow redistribution were found to be associated with adverse outcome in late preterm singleton pregnancies at risk of fetal growth restriction. Whether cerebral redistribution is a marker describing the severity of fetal growth restriction or an independent risk factor for adverse outcome remains unclear, and whether it is useful for clinical management can be answered only in a randomized trial. © 2020 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of the International Society of Ultrasound in Obstetrics and Gynecology

Electroweak measurements in electron–positron collisions at w-boson-pair energies at lep

Contains fulltext : 121524.pdf (preprint version ) (Open Access

Evidencing sexual assault: women in the witness box

Drawing on recent research conducted in Scottish criminal courts, this article discusses the evidencing of sexual crimes through victim testimony. Despite significant reforms, complainers in sexual offence trials still find the process traumatic; the amount of sexual evidence introduced into the trial has increased; and the nature of such evidence draws on pervasive and outmoded rape myths

Results from the BaBar Fully Inclusive Measurement of B→XsγB\to X_s\gamma

We present preliminary results from a lepton-tagged fully-inclusive measurement of $B \to X_{s}\gamma$ decays, where $X_{s}$ is any strange hadronic state. Results are based on a BaBar data set of 88.5 million $B\bar{B}$ pairs at the $\Upsilon(4S)$ resonance. We present a reconstructed photon energy spectrum in the $\Upsilon(4S)$ frame, and partial branching fractions above minimum reconstructed photon energies of 1.9, 2.0, 2.1 and 2.2 GeV. We then convert these to measurements of partial branching fractions and truncated first and second moments of the true photon energy distribution in the B rest frame, above the same minimum photon energy values. The full correlation matrices between the first and second moments are included to allow fitting to any parameterized theoretical calculation. We also measure the direct CP asymmetry $A_{cp}(B \to X_{s+d}\gamma)$ (based on the charge of the tagging lepton) above a reconstructed photon energy of 2.2 Ge

A Study of Production and Decays of Omega_c0 Baryons at BABAR

Production and decay of $\Omega_c^0$ baryons is studied with $\sim230 \mathrm{fb}^{-1}$ of data recorded with the BABAR detector at the PEP-II $e^+e^-$ asymmetric-energy storage ring at SLAC. The $\Omega_c^0$ is reconstructed through its decays into $\Omega^-\pi^+$, $\Omega^-\pi^+\pi^+\pi^-$, and $\Xi^-K^-\pi^+\pi^+$ final states. The invariant mass spectra are presented and the signal yields are extracted. Ratios of branching fractions are measured relative to the $\Omega^-\pi^+$ mode \frac{{\cal B}(\Xi^-K^-\pi^+\pi^+)}{{\cal B}(\Omega^-\pi^+)} &= 0.31 \pm 0.15\mathrm{(stat.)} \pm 0.04\mathrm{(syst.)}, \frac{{\cal B}(\Omega^-\pi^+\pi^+\pi^-)}{{\cal B}(\Omega^-\pi^+)} &< 0.30\qquad (90%\mathrm{CL}). The momentum spectrum (not corrected for efficiency) of $\Omega_c^0$ baryons is extracted from decays into $\Omega^-\pi^+$, establishing the first observation of $\Omega_c^0$ production from B decays