Maternal sildenafil for severe fetal growth restriction (STRIDER): a multicentre, randomised, placebo-controlled, double-blind trial

Background Severe early-onset fetal growth restriction can lead to a range of adverse outcomes including fetal or neonatal death, neurodisability, and lifelong risks to the health of the affected child. Sildenafil, a phosphodiesterase type 5 inhibitor, potentiates the actions of nitric oxide, which leads to vasodilatation of the uterine vessels and might improve fetal growth in utero. Methods We did this superiority, placebo-controlled randomised trial in 19 fetal medicine units in the UK. We used random computer allocation (1:1) to assign women with singleton pregnancies between 22 weeks and 0 days' gestation and 29 weeks and 6 days' gestation and severe early-onset fetal growth restriction to receive either sildenafil 25 mg three times daily or placebo until 32 weeks and 0 days' gestation or delivery. We stratified women by site and by their gestational age at randomisation (before week 26 and 0 days or at week 26 and 0 days or later). We defined fetal growth restriction as a combination of estimated fetal weight or abdominal circumference below tenth percentile and absent or reversed end-diastolic blood flow in the umbilical artery on Doppler velocimetry. The primary outcome was the time from randomisation to delivery, measured in days. This study is registered with BioMed Central, number ISRCTN 39133303. Findings Between Nov 21, 2014, and July 6, 2016, we recruited 135 women and randomly assigned 70 women to sildenafil and 65 women to placebo. We found no difference in the median randomisation to delivery interval between women assigned to sildenafil (17 days [IQR 7–24]) and women assigned to placebo (18 days [8–28]; p=0·23). Livebirths (relative risk [RR] 1·06, 95% CI 0·84 to 1·33; p=0·62), fetal deaths (0·89, 0·54 to 1·45; p=0·64), neonatal deaths (1·33, 0·54 to 3·28; p=0·53), and birthweight (−14 g,–100 to 126; p=0·81) did not differ between groups. No differences were found for any other secondary outcomes. Eight serious adverse events were reported during the course of the study (six in the placebo group and two in the sildenafil group); none of these were attributed to sildenafil. Interpretation Sildenafil did not prolong pregnancy or improve pregnancy outcomes in severe early-onset fetal growth restriction and therefore it should not be prescribed for this indication outside of research studies with explicit participants' consent. Funding National Institute for Health Research and Medical Research Council

Blood Pressure Lowering With Nilvadipine in Patients With Mild-to-Moderate Alzheimer Disease Does Not Increase the Prevalence of Orthostatic Hypotension

BACKGROUND: Hypertension is common among patients with Alzheimer disease. Because this group has been excluded from hypertension trials, evidence regarding safety of treatment is lacking. This secondary analysis of a randomized controlled trial assessed whether antihypertensive treatment increases the prevalence of orthostatic hypotension (OH) in patients with Alzheimer disease. METHODS AND RESULTS: Four hundred seventy‐seven patients with mild‐to‐moderate Alzheimer disease were randomized to the calcium‐channel blocker nilvadipine 8 mg/day or placebo for 78 weeks. Presence of OH (blood pressure drop ≥20/≥10 mm Hg after 1 minute of standing) and OH‐related adverse events (dizziness, syncope, falls, and fractures) was determined at 7 follow‐up visits. Mean age of the study population was 72.2±8.2 years and mean Mini‐Mental State Examination score was 20.4±3.8. Baseline blood pressure was 137.8±14.0/77.0±8.6 mm Hg. Grade I hypertension was present in 53.4% (n=255). After 13 weeks, blood pressure had fallen by −7.8/−3.9 mm Hg for nilvadipine and by −0.4/−0.8 mm Hg for placebo (P<0.001). Across the 78‐week intervention period, there was no difference between groups in the proportion of patients with OH at a study visit (odds ratio [95% CI]=1.1 [0.8–1.5], P=0.62), nor in the proportion of visits where a patient met criteria for OH, corrected for number of visits (7.7±13.8% versus 7.3±11.6%). OH‐related adverse events were not more often reported in the intervention group compared with placebo. Results were similar for those with baseline hypertension. CONCLUSIONS: This study suggests that initiation of a low dose of antihypertensive treatment does not significantly increase the risk of OH in patients with mild‐to‐moderate Alzheimer disease. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov. Unique identifier: NCT02017340

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Biofilm cultivation of marine dinoflagellates under different temperatures and nitrogen regimes enhances DHA productivity

Dinoflagellates contain large amounts of omega-3 fatty acids, including the nutritionally important docosahexaenoic acid (DHA). However, their cultivation in suspensions is characterized by low growth rates. Twin-layer porous substrate photobioreactors (TL-PSBRs) have been shown to support growth of different microalgal species, including the robust dinoflagellate Symbiodinium voratum. In the present study, the potential of cultivating marine autotrophic dinoflagellate species in a TL-PSBR for DHA production was explored. Based on initial screening experiments, two Symbiodinium species with high biomass and DHA productivities were selected: the symbiotic Symbiodinium microadriaticum CCAC 2475 B and the free-living Symbiodinium voratum CCAC 3869 B. The effects of three different temperatures (17, 22 and 27 degrees C) and nitrogen regimes (nitrate, ammonium and nitrogen-free) on biomass growth, total lipid accumulation and fatty acid methyl esters (FAMEs) content, with emphasis on DHA, were evaluated. The two lower temperatures (17 and 22 degrees C) enhanced growth and total lipid accumulation of S. microadriaticum CCAC 2475 B and S. voratum CCAC 3869 B. Cultivation at 22 degrees C and nitrogen limitation led to a significant positive effect on DHA productivity. Symbiodinium. microadriaticum CCAC 2475 B reached a DHA productivity of 145.4 mg m(-2) day(-1) and DHA content in the dry biomass of 2% (w/w) after 4 days of nitrogen depletion. The results of the present study demonstrated that autotrophic dinoflagellates, when cultivated on a TL-PSBR, produce comparable amounts of lipids and fatty acids to other commercially used microalgal species including the valuable DHA

Disease Activity, Functional Ability and Nutritional Status in Patients with Rheumatoid Arthritis: An Observational Study in Greece

Aim: The aim of the present pilot study was to assess differences in the nutritional status, Mediterranean diet (MD) adherence, and functional ability among patients with rheumatoid arthritis (RA), according to disease activity. Methods: A total of 48 patients with RA, outpatients of a hospital in Athens, Greece were recruited. Disease activity was evaluated with DAS28, functional status with the Health Assessment Questionnaire (HAQ), MD adherence with the MedDietScore and malnutrition with the patient-generated subjective global assessment (PG-SGA). Results: A relationship was noted between DAS28 and HAQ, indicating a reduced functional status with increased RA activity. Although MD adherence differed between DAS28 categories, no specific differences were noted in the PG-SGA or the MedDietScore in the post-hoc analyses. According to the PG-SGA, no need for nutritional intervention was noted among participants. Conclusions: The origin of the participants might have reduced the differences between MD adherence and DAS28. In parallel, the PG-SGA does not appear sensitive in detecting muscle-related malnutrition among patients with RA. © Markaki AG, Gkiouras K, Papakitsos C, Grammatikopoulou MG, Papatsaraki A, Ioannou R, Tsagkari A, Papamitsou T, Bogdanos DP. This work is licensed under a Creative Commons Attribution 4.0 International License

Isolation, Characterization, and Computational Studies of the Novel [Mo₃(μ₃-Br)₂(μ-Br)₃Br ₆]²⁻ Cluster Anion

The novel trimolybdenum cluster [Mo3(μ 3-Br)2(μ -Br)3Br6]2- (1, {Mo3}9+, 9 d-electrons) has been isolated from the reaction of [Mo(CO)6] with 1,2-C2H4Br2 in refluxing PhCl. The compound has been characterized in solution by electrospray ionization mass spectrometry (ESI-MS), UV-vis spectroscopy, cyclic voltammetry, and in the solid state by X-ray analysis (counter-cations: (n-Bu)4N+ (1), Et4N+, Et3BzN+), electron paramagnetic resonance (EPR), magnetic susceptibility measurements, and infrared spectroscopy. The least disordered (n-Bu)4N+ salt crystallizes in the monoclinic space group C2/c, a = 20.077(2) Å, b = 11.8638(11) Å, c = 22.521(2) Å, α = 90 deg, β = 109.348(4) deg, γ = 90 deg, V = 5061.3(9) Å3, Z = 4 and contains an isosceles triangular metal arrangement, which is capped by two bromine ligands. Each edge of the triangle is bridged by bromine ions. The structure is completed by six terminal bromine ligands. According to the magnetic measurements and the EPR spectrum the trimetallic core possesses one unpaired electron. Electrochemical data show that oxidation by one electron of 1 is reversible, thus proceeding with retention of the trimetallic core, while the reduction is irreversible. The effective magnetic moment of 1 (μ eff, 1.55 μ B, r.t.) is lower than the spin-only value (1.73 μ B) for S = 1/2 systems, most likely because of high spin-orbit coupling of Mo(III) and/or magnetic coupling throughout the lattice. The ground electronic state of 1 was studied using density functional theory techniques under the broken symmetry formalism. The ground state is predicted to exhibit strong antiferromagnetic coupling between the three molybdenum atoms of the core. Moreover, our calculated data predict two broken symmetry states that differ only by 0.4 kcal/mol (121 cm-1). The antiferromagnetic character is delocalized over three magnetic orbitals populated by three electrons. The assignment of the infrared spectra is also provided