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

Factors Affecting the Intention to Participate in Disaster Risk Insurance of Households in the North and North Central of Vietnam

The research was conducted with the aim to identify the factors affecting the intention to purchase disaster risk insurance in the North and North Central region of Vietnam.The study used quantitative methods, selected TPB model to conduct research with data collected from 291 subjects, the results showed that the attitude towards disaster risk insurance, subjective norm, perceived behavioral control has a positive influence on the central factor, which is intended. From the results of the analysis, the study gives recommendations for the government and businesses to improve services. Additionally, the research will provide a basis for raising awareness about participating in disaster risk insurance products to proactively protect lives, livelihoods, infrastructure, and homes from the impacts of natural disasters. Keywords: natural disaster insurance, disaster risk insurance, purchase intention. DOI: 10.7176/JESD/13-8-07 Publication date: April 30th 202

Procarcinogens – Determination and Evaluation by Yeast-Based Biosensor Transformed with Plasmids Incorporating RAD54 Reporter Construct and Cytochrome P450 Genes

International audienceIn Vietnam, a great number of toxic substances, including carcinogens and procarcinogens, from industrial and agricultural activities, food production, and healthcare services are daily released into the environment. In the present study, we report the development of novel yeast-based biosensor systems to determine both genotoxic carcinogens and procarcinogens by cotransformation with two plasmids. One plasmid is carrying human CPR and CYP (CYP3A4, CYP2B6, or CYP2D6) genes, while the other contains the RAD54-GFP reporter construct. The three resulting coexpression systems bearing both CPR-CYP and RAD54-GFP expression cassettes were designated as CYP3A4/CYP2B6/CYP2D6 + RAD54 systems, respectively and used to detect and evaluate the genotoxic potential of carcinogens and procarcinogens by selective activation and induction of both CPR-CYP and RAD54-GFP expression cassettes in response to DNA damage. Procarcinogens were shown to be predominantly, moderately or not bioactivated by one of the CYP enzymes and thus selectively detected by the specific coexpression system. Aflatoxin B-1 and benzo(a) pyrene were predominantly detected by the CYP3A4 + RAD54 system, while N-nitrosodimethylamine only moderately activated the CYP2B6 + RAD54 reporter system and none of them was identified by the CYP2D6 + RAD54 system. In contrast, the genotoxic carcinogen, methyl methanesulfonate, was detected by all systems. Our yeast-reporter system can be performed in 384-well microplates to provide efficient genotoxicity testing to identify various carcinogenic compounds and reduce chemical consumption to about 53% as compared with existing 96-well genotoxicity bioassays. In association with a liquid handling robot, this platform enables rapid, cost-effective, and high-throughput screening of numerous analytes in a fully automated and continuous manner without the need for user interaction

Summary and comparison of the results of the present study with the data from published report.

<p>Summary and comparison of the results of the present study with the data from published report.</p

Analysis and evaluation of fluorescence signals in different yeast strains in response to serial dilution concentrations of test compounds.

<p>Analysis and evaluation of fluorescence signals in different yeast strains in response to serial dilution concentrations of test compounds.</p

Primer pairs used for construction of plasmids pESC-<i>CPR-CYPs</i>

<p>Primer pairs used for construction of plasmids pESC-<i>CPR-CYPs</i></p

Procarcinogens – Determination and Evaluation by Yeast-Based Biosensor Transformed with Plasmids Incorporating <i>RAD54</i> Reporter Construct and Cytochrome <i>P450</i> Genes - Fig 1

<p><b>Activity test of recombinant human CPR (A) and recombinant human CYP3A4, CYP2B6, and CYP2D6 (B)</b>. 3A4+, 2B6+, and 2D6+ are microsomes of clones coexpressing both <i>CPR</i> and <i>CYP</i> genes; 3A4–, 2B6–, and 2D6– or CPR–are microsomes of clones expressing only one gene, the <i>CYPs</i> or <i>CPR</i>, respectively; NC (negative control) are microsomes of clones bearing the control pESC-URA plasmid. The standard deviation values of the measurements of fluorescence microplate assay (B) were all less than 5% of the calculated values and are thus not presented here.</p

Fluorescence induction in yeast cells transformed with different gene constructs in response to DNA damage.

<p>Yeast-based biosensors were either nontreated (NT, control) or exposed to increasing concentrations of AFB1 (A), BaP (B), NDMA (C), and MMS (positive genotoxin, D). CYP3A4 + RAD54: strain transformed with both <i>CPR-CYP3A4</i> and <i>RAD54-GFP</i> constructs; RAD54: strain transformed with only the <i>RAD54-GFP</i> construct; NCs (negative control) system: strain transformed with two control pESC-URA and pUMGP5 plasmids. The GFP fluorescence intensity of measurements was compared within linear range of GFP signals by calculation of GFP fold induction. The horizontal dashed line at 1.3 fold GFP induction is used as cutoff or genotoxicity threshold. Other negative (untransformed yeast cells) and process (medium) controls are not presented here.</p

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