Safety and efficacy of fluoxetine on functional outcome after acute stroke (AFFINITY): a randomised, double-blind, placebo-controlled trial

Background Trials of fluoxetine for recovery after stroke report conflicting results. The Assessment oF FluoxetINe In sTroke recoverY (AFFINITY) trial aimed to show if daily oral fluoxetine for 6 months after stroke improves functional outcome in an ethnically diverse population. Methods AFFINITY was a randomised, parallel-group, double-blind, placebo-controlled trial done in 43 hospital stroke units in Australia (n=29), New Zealand (four), and Vietnam (ten). Eligible patients were adults (aged ≥18 years) with a clinical diagnosis of acute stroke in the previous 2–15 days, brain imaging consistent with ischaemic or haemorrhagic stroke, and a persisting neurological deficit that produced a modified Rankin Scale (mRS) score of 1 or more. Patients were randomly assigned 1:1 via a web-based system using a minimisation algorithm to once daily, oral fluoxetine 20 mg capsules or matching placebo for 6 months. Patients, carers, investigators, and outcome assessors were masked to the treatment allocation. The primary outcome was functional status, measured by the mRS, at 6 months. The primary analysis was an ordinal logistic regression of the mRS at 6 months, adjusted for minimisation variables. Primary and safety analyses were done according to the patient's treatment allocation. The trial is registered with the Australian New Zealand Clinical Trials Registry, ACTRN12611000774921. Findings Between Jan 11, 2013, and June 30, 2019, 1280 patients were recruited in Australia (n=532), New Zealand (n=42), and Vietnam (n=706), of whom 642 were randomly assigned to fluoxetine and 638 were randomly assigned to placebo. Mean duration of trial treatment was 167 days (SD 48·1). At 6 months, mRS data were available in 624 (97%) patients in the fluoxetine group and 632 (99%) in the placebo group. The distribution of mRS categories was similar in the fluoxetine and placebo groups (adjusted common odds ratio 0·94, 95% CI 0·76–1·15; p=0·53). Compared with patients in the placebo group, patients in the fluoxetine group had more falls (20 [3%] vs seven [1%]; p=0·018), bone fractures (19 [3%] vs six [1%]; p=0·014), and epileptic seizures (ten [2%] vs two [<1%]; p=0·038) at 6 months. Interpretation Oral fluoxetine 20 mg daily for 6 months after acute stroke did not improve functional outcome and increased the risk of falls, bone fractures, and epileptic seizures. These results do not support the use of fluoxetine to improve functional outcome after stroke

Systematic investigations of uranium carbide composites oxidation from micro- to nano-scale: Application to waste disposal

The production of radioisotope beams at the ISOLDE (Isotope Separator OnLine DEvice) facility at CERN is achieved by irradiating target materials (e.g. uranium carbides and metal foils) with protons. The materials are usually operated at temperatures above 2000°C to promote isotope release. However, materials are rapidly degraded due to sintering which results in a loss of radioisotope beam intensity. Moreover, some refractory elements are particularly difficult to extract using the conventional high temperature approach due to their low vapor pressure and high boiling point. The topic of this thesis deals with two types of target materials which were engineered to improve isotope release. The first part of this thesis concerns new micro- and nano-structured uranium carbide materials. New nanomaterials were found highly pyrophoric and not compatible with long-term storage requirements. Thus, a safe process for their conversion into oxide is investigated. However, the oxidation mechanism is not fully understood, notably the relationship between the material characteristics and its oxidation kinetics. In this thesis, characterization and thermal analysis techniques were used to study the oxidation of five different uranium carbide materials. For each material, the mechanism of the reaction was determined and the reaction rate was modeled. The model predictions were evaluated against experimental data. The influence of the materials characteristics on the oxidation kinetics was notably discussed. The reaction was found generally controlled by the diffusion of oxygen through the uranium oxide product layer. However, nanomaterials presented a shift in the rate controlling mechanism from diffusion to surface. Onset oxidation temperatures between 150°C and 280°C and activation energies between 78.9 and 128.6 kJ/mol were observed. Both values were lower for nanomaterials, which highlights the importance of materials characteristics. Other parameters such as the concentration of carbon can affect the rate of the reaction by forming an additional passivation barrier around uranium carbide. The study provided a better understanding of the oxidation properties of uranium carbides. The approach is general and can be used to investigate other actinide materials in the future. In particular, the collected data can be used to design a safe process for the conversion and disposal of target materials at ISOL facilities worldwide. The second part of this thesis dealt with the stability of graphene on metal foil target materials under irradiation. Refractory elements can be extracted from metal foils using reactive gases to form volatile molecules at room temperature. However, the gas could also react with the target material and prevent the extraction of isotopes. Protection of tantalum foils against corrosion and oxidation can be obtained using graphene coating. However, the stability of graphene under high energy proton beam irradiation was never evaluated. It was found that the coating was mainly degraded by the impact of primary protons while the contribution of secondary particles and the temperature rise induced by the interaction of the primary proton beam with the target were found negligible. The study showed that graphene is unstable under proton irradiation and cannot be used as a protection barrier against corrosion and oxidation on target materials at the fluences found in the present-day operating facilities

Flavonoids with hepatoprotective activity from the leaves of <i>Cleome viscosa</i> L.

<p>One new flavonol glycoside named visconoside C (<b>1</b>), together with seven known flavonol glycosides, quercetin 3-O-β-d-glucopyranoside 7-O-α-l-rhamnopyranoside (<b>2</b>), quercetin 7-O-α-l-rhamnopyranoside (<b>3</b>), astragalin (<b>4</b>), kaempferol 3-<i>O</i>-(4-<i>O</i>-acetyl)-<i>α</i>-l-rhamnopyranoside (<b>5</b>), kaempferol 7-<i>O</i>-<i>α</i>-l-rhamnopyranoside (<b>6</b>), kaempferitrin (<b>7</b>) and kaempferol 3-<i>O</i>-<i>β</i>-d-glucopyranoside 7-<i>O</i>-<i>α</i>-l-rhamnopyranoside (<b>8</b>) were isolated by various chromatography methods from the leaves of <i>Cleome viscosa</i> L. Their structures were elucidated by IR, UV, HR-ESI-MS and NMR (1D & 2D) experiments. The cytotoxicity and hepatoprotective activities using HepG2 human hepatoma cell line of <b>1</b> were measured by MTT assay. At the concentration of 25 μM and 50 μM, <b>1</b> showed cytotoxic activity against HepG2 cells (cell viability was decreased to 22.2 and 23.0%, respectively, compared with doxorubicin control), while at the concentration of 100 μM, <b>1</b> showed hepatoprotective activity against CCl₄-induced hepatotoxicity on HepG2 cells (34.3%, compared with quercetin control).</p

CERN-MEDICIS: A Unique Facility for the Production of Non-Conventional Radionuclides for the Medical Research

The MEDICIS facility is a unique facility located at CERN dedicated to the production of non-conventional radionuclides for research and development in imaging, diagnostics and radiation therapy. It exploits in a Class A work sector, a dedicated isotope separator beam line, a target irradiation station at the 1.4 GeV Proton Synchroton Booster (PSB) and receives activated targets from external institutes during CERN Long Shut-Downs. The target is heated up at high temperatures to allow for the diffusion and effusion of the atoms out of the target that are subsequently ionized. The ions are accelerated and sent through an off-line mass separator. The radionuclide of interest is extracted through mass separation and implanted into a thin metallic collection foil. After collection, the batch is prepared to be dispatched to a research center. In the near-future, the radiochemistry process will also be performed in MEDICIS. Since its commissioning in December 2017, the facility has provided novel radionuclides such as Tb-149, Tb-155, Tm-165, Er-169 and Yb-175 with high specific activity, some for the first time, to European research institutes part of the collaboration

CERN-MEDICIS: A Review Since Commissioning in 2017

The CERN-MEDICIS (MEDical Isotopes Collected from ISolde) facility has delivered its first radioactive ion beam at CERN (Switzerland) in December 2017 to support the research and development in nuclear medicine using non-conventional radionuclides. Since then, fourteen institutes, including CERN, have joined the collaboration to drive the scientific program of this unique installation and evaluate the needs of the community to improve the research in imaging, diagnostics, radiation therapy and personalized medicine. The facility has been built as an extension of the ISOLDE (Isotope Separator On Line DEvice) facility at CERN. Handling of open radioisotope sources is made possible thanks to its Radiological Controlled Area and laboratory. Targets are being irradiated by the 1.4 GeV proton beam delivered by the CERN Proton Synchrotron Booster (PSB) on a station placed between the High Resolution Separator (HRS) ISOLDE target station and its beam dump. Irradiated target materials are also received from external institutes to undergo mass separation at CERN-MEDICIS. All targets are handled via a remote handling system and exploited on a dedicated isotope separator beamline. To allow for the release and collection of a specific radionuclide of medical interest, each target is heated to temperatures of up to 2,300°C. The created ions are extracted and accelerated to an energy up to 60 kV, and the beam steered through an off-line sector field magnet mass separator. This is followed by the extraction of the radionuclide of interest through mass separation and its subsequent implantation into a collection foil. In addition, the MELISSA (MEDICIS Laser Ion Source Setup At CERN) laser laboratory, in service since April 2019, helps to increase the separation efficiency and the selectivity. After collection, the implanted radionuclides are dispatched to the biomedical research centers, participating in the CERN-MEDICIS collaboration, for Research & Development in imaging or treatment. Since its commissioning, the CERN-MEDICIS facility has provided its partner institutes with non-conventional medical radionuclides such as Tb-149, Tb-152, Tb-155, Sm-153, Tm-165, Tm-167, Er-169, Yb-175, and Ac-225 with a high specific activity. This article provides a review of the achievements and milestones of CERN-MEDICIS since it has produced its first radioactive isotope in December 2017, with a special focus on its most recent operation in 2020

Twelve-Month Outcomes of the AFFINITY Trial of Fluoxetine for Functional Recovery After Acute Stroke: AFFINITY Trial Steering Committee on Behalf of the AFFINITY Trial Collaboration

Background and Purpose: The AFFINITY trial (Assessment of Fluoxetine in Stroke Recovery) reported that oral fluoxetine 20 mg daily for 6 months after acute stroke did not improve functional outcome and increased the risk of falls, bone fractures, and seizures. After trial medication was ceased at 6 months, survivors were followed to 12 months post-randomization. This preplanned secondary analysis aimed to determine any sustained or delayed effects of fluoxetine at 12 months post-randomization. Methods: AFFINITY was a randomized, parallel-group, double-blind, placebo-controlled trial in adults (n=1280) with a clinical diagnosis of stroke in the previous 2 to 15 days and persisting neurological deficit who were recruited at 43 hospital stroke units in Australia (n=29), New Zealand (4), and Vietnam (10) between 2013 and 2019. Participants were randomized to oral fluoxetine 20 mg once daily (n=642) or matching placebo (n=638) for 6 months and followed until 12 months after randomization. The primary outcome was function, measured by the modified Rankin Scale, at 6 months. Secondary outcomes for these analyses included measures of the modified Rankin Scale, mood, cognition, overall health status, fatigue, health-related quality of life, and safety at 12 months. Results: Adherence to trial medication was for a mean 167 (SD 48) days and similar between randomized groups. At 12 months, the distribution of modified Rankin Scale categories was similar in the fluoxetine and placebo groups (adjusted common odds ratio, 0.93 [95% CI, 0.76–1.14]; P =0.46). Compared with placebo, patients allocated fluoxetine had fewer recurrent ischemic strokes (14 [2.18%] versus 29 [4.55%]; P =0.02), and no longer had significantly more falls (27 [4.21%] versus 15 [2.35%]; P =0.08), bone fractures (23 [3.58%] versus 11 [1.72%]; P =0.05), or seizures (11 [1.71%] versus 8 [1.25%]; P =0.64) at 12 months. Conclusions: Fluoxetine 20 mg daily for 6 months after acute stroke had no delayed or sustained effect on functional outcome, falls, bone fractures, or seizures at 12 months poststroke. The lower rate of recurrent ischemic stroke in the fluoxetine group is most likely a chance finding. REGISTRATION: URL: http://www.anzctr.org.au/ ; Unique identifier: ACTRN12611000774921