Effects of fluoxetine on functional outcomes after acute stroke (FOCUS): a pragmatic, double-blind, randomised, controlled trial

Background Results of small trials indicate that fluoxetine might improve functional outcomes after stroke. The FOCUS trial aimed to provide a precise estimate of these effects. Methods FOCUS was a pragmatic, multicentre, parallel group, double-blind, randomised, placebo-controlled trial done at 103 hospitals in the UK. Patients were eligible if they were aged 18 years or older, had a clinical stroke diagnosis, were enrolled and randomly assigned between 2 days and 15 days after onset, and had focal neurological deficits. Patients were randomly allocated fluoxetine 20 mg or matching placebo orally once daily for 6 months via a web-based system by use of a minimisation algorithm. The primary outcome was functional status, measured with the modified Rankin Scale (mRS), at 6 months. Patients, carers, health-care staff, and the trial team were masked to treatment allocation. Functional status was assessed at 6 months and 12 months after randomisation. Patients were analysed according to their treatment allocation. This trial is registered with the ISRCTN registry, number ISRCTN83290762. Findings Between Sept 10, 2012, and March 31, 2017, 3127 patients were recruited. 1564 patients were allocated fluoxetine and 1563 allocated placebo. mRS data at 6 months were available for 1553 (99·3%) patients in each treatment group. The distribution across mRS categories at 6 months was similar in the fluoxetine and placebo groups (common odds ratio adjusted for minimisation variables 0·951 [95% CI 0·839–1·079]; p=0·439). Patients allocated fluoxetine were less likely than those allocated placebo to develop new depression by 6 months (210 [13·43%] patients vs 269 [17·21%]; difference 3·78% [95% CI 1·26–6·30]; p=0·0033), but they had more bone fractures (45 [2·88%] vs 23 [1·47%]; difference 1·41% [95% CI 0·38–2·43]; p=0·0070). There were no significant differences in any other event at 6 or 12 months. Interpretation Fluoxetine 20 mg given daily for 6 months after acute stroke does not seem to improve functional outcomes. Although the treatment reduced the occurrence of depression, it increased the frequency of bone fractures. These results do not support the routine use of fluoxetine either for the prevention of post-stroke depression or to promote recovery of function. Funding UK Stroke Association and NIHR Health Technology Assessment Programme

Multi-modality imaging in hypertrophic cardiomyopathy: intermodal discrepancies in key prognostic parameters

Abstract Background/Introduction Multi-modality imaging is crucial for confirming diagnosis and assessing prognosis in patients with hypertrophic cardiomyopathy (HCM). However, inter-modality discrepancies in key parameters are commonly reported. Purpose To assess real-world inter-modal reporting discrepancies between transthoracic echocardiography (TTE) and cardiac magnetic resonance (CMR) imaging in the measurement of four key parameters in HCM patients. Methods Consecutive HCM patients with TTE and CMR performed within 6 months of each other at a tertiary centre were retrospectively assessed for reported maximum wall thickness (MWT), left atrial diameter (LAd), left ventricular ejection fraction (LVEF) and presence of left ventricular apical aneurysm (LVAA). The CMR report was considered gold standard. Data are reported as mean ± standard deviation (SD) or median and interquartile range (IQR) as appropriate. Results 353 consecutive HCM patients (72% male, median age 60.9 years, IQR 49.8–71.6 years) with TTE and CMR within 6 months (median difference 1.7 months, IQR 1.1–3.4 months) were assessed between 4th January 2018 and 9th April 2019. Of 284 patients with paired MWT data, median difference was 0.0 mm (IQR −1.0 to 3.0 mm, p=0.02), likely representing a difference in distributions of MWT. TTE both over and underestimated MWT (in 36% and 46% cases respectively). Of the 94 patients with paired LAd data, mean difference was 0.4±5.7 mm (95% CI −0.8010 to 1.546, p=0.5). N=320 patients with paired LVEF data (after excluding patients with atrial fibrillation (n=20)). Median difference in LVEF was 12% (IQR 5–19% p&amp;lt;0.0001). TTE underestimated LVEF in 88% of cases. CMR and TTE both identified 14 (5%) patients as having LVEF &amp;lt;50%. There were however 8 cases of disagreement in classification of LVEF &amp;lt;50%, due to over (n=4) or underestimation (n=4) by TTE. LVAA was accurately identified by TTE in only 9/30 (30%) of those patients with demonstrable LVAA by CMR (p=0.0008). TTE evidence of a discreet apical chamber (paradoxical jet on spectral or colour Doppler) was present in 16/21 (76%) cases where TTE failed to overtly identify LVAA. However, apical or mid-cavity obliteration was reported in 15/21 (71%) cases where TTE failed to identify LVAA. Conclusion(s) Echocardiography and CMR measurements are often used interchangeably in clinical practice but inter-modality discrepancies can affect diagnosis and sudden cardiac death (SCD) risk assessment. This is particularly important for binary risk factors such as LVEF&amp;lt;50% or LVAA which are considered major SCD risk factors in the latest American Heart Association guidelines. 25 (7%) patients in our cohort had major risk factors identified by CMR that were not identified on TTE. CMR is an important, recommended tool where TTE imaging is suboptimal, but attention to more subtle elements of abnormal intracavity blood flow may be able to increase LVAA detection during TTE. Funding Acknowledgement Type of funding sources: None. </jats:sec

Short-chain fatty acid producers in the gut are associated with pediatric multiple sclerosis onset.

OBJECTIVE: The relationship between multiple sclerosis and the gut microbiome has been supported by animal models in which commensal microbes are required for the development of experimental autoimmune encephalomyelitis. However, observational study findings in humans have only occasionally converged when comparing multiple sclerosis cases and controls which may in part reflect confounding by comorbidities and disease duration. The study of microbiome in pediatric-onset multiple sclerosis offers unique opportunities as it is closer to biological disease onset and minimizes confounding by comorbidities and environmental exposures. METHODS: A multicenter case-control study in which 35 pediatric-onset multiple sclerosis cases were 1:1 matched to healthy controls on age, sex, self-reported race, ethnicity, and recruiting site. Linear mixed effects models, weighted correlation network analyses, and PICRUSt2 were used to identify microbial co-occurrence networks and for predicting functional abundances based on marker gene sequences. RESULTS: Two microbial co-occurrence networks (one reaching significance after adjustment for multiple comparisons; q &lt; 0.2) were identified, suggesting interdependent bacterial taxa that exhibited association with disease status. Both networks indicated a potentially protective effect of higher relative abundance of bacteria observed in these clusters. Functional predictions from the significant network suggested a contribution of short-chain fatty acid producers through anaerobic fermentation pathways in healthy controls. Consistent family-level findings from an independent Canadian-US study (19 case/control pairs) included Ruminococaccaeae and Lachnospiraceae (p &lt; 0.05). Macronutrient intake was not significantly different between cases and controls, minimizing the potential for dietary confounding. INTERPRETATION: Our results suggest that short-chain fatty acid producers may be important contributors to multiple sclerosis onset