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

Assessing Groundwater Quality for Sustainable Drinking and Irrigation: A GIS-Based Hydro-Chemical and Health Risk Study in Kovilpatti Taluk, Tamil Nadu

The continuous investigation of water resources is essential to assess pollution risks. This study investigated a groundwater assessment in the coastal belt of Tamil Nadu’s Kovilpatti Taluk, Thoothukudi district. Twenty-one groundwater samples were collected during the pre-monsoon and post-monsoon seasons, analyzing water quality parameters, namely pH, EC, Cl−, SO42−, Ca2+, Mg2+, HCO3−, TH, Na2+, and K+. The Water Quality Index (WQI) was computed and it is observed that 5% of pre-monsoon and 9% of post-monsoon samples were unsuitable for drinking. SAR, MHR, RSC, %Na and Kelley’s index were used to determine irrigation suitability. Pre-monsoon shows 29% (MHR) and 71% (RSC) unsuitable, and post-monsoon shows 59% (MHR) and 9% (RSC) unsuitable. Coastal activity, urbanization, and industrialization in Kovilpatti resulted in the degradation of groundwater quality. Solving this coastal issue requires sustainable wastewater treatment and strict industrial discharge guidelines. Spatial distribution plots, Box plots, Gibbs plots, Piper plots, Wilcox plots and Correlation Matrices had similar results to the computed WQI and its physical–chemical parameters. According to the human health risk assessment, the Mooppanpatti, Illuppaiurani, and Vijayapuri regions show high health risks due to the nitrate and fluoride concentration in the groundwater. Kadambu, Melparaipatti, Therkuilandhaikulam, and Vadakku Vandanam have low levels, posing a minimal health risk

The endosomal escape vehicle platform enhances delivery of oligonucleotides in preclinical models of neuromuscular disorders

Biological therapeutic agents are highly targeted and potent but limited in their ability to reach intracellular targets. These limitations often necessitate high therapeutic doses and can be associated with less-than-optimal therapeutic activity. One promising solution for therapeutic agent delivery is use of cell-penetrating peptides. Canonical cell-penetrating peptides, however, are limited by low efficiencies of cellular uptake and endosomal escape, minimal proteolytic stability, and toxicity. To overcome these limitations, we designed a family of proprietary cyclic cell-penetrating peptides that form the core of our endosomal escape vehicle technology capable of delivering therapeutic agent-conjugated cargo intracellularly. We demonstrated the therapeutic potential of this endosomal escape vehicle platform in preclinical models of muscular dystrophy with distinct disease etiology. An endosomal escape vehicle-conjugated, splice-modulating oligonucleotide restored dystrophin protein expression in striated muscles in the mdx mouse, a model for Duchenne muscular dystrophy. Furthermore, another endosomal escape vehicle-conjugated, sterically blocking oligonucleotide led to knockdown of aberrant transcript expression levels in facioscapulohumeral muscular dystrophy patient-derived skeletal muscle cells. These findings suggest a significant therapeutic potential of our endosomal escape vehicle conjugated oligonucleotides for targeted upregulation and downregulation of gene expression in neuromuscular diseases, with possible broader application of this platform for delivery of intracellular biological agents