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Background The GABA A -α5 receptor antagonist S44819 is a promising candidate to enhance functional recovery after acute ischemic stroke (IS). S44819 is currently evaluated in this indication; RESTORE brain study started in Dec 2016 and was completed in March 2019. Methods/design The study is a 3-month international, randomized, double-blind, parallel group, placebo-controlled phase II multicentre study. Patients in 14 countries who suffered an IS leading to a moderate or severe deficit defined by NIHSS score ranging from 7 to 20 and are aged between 18 to 85 years are included between 3 and 8 days after the stroke onset. Approximately 580 patients are to be included. The primary objective of the study is to demonstrate the superiority of at least one of the two doses of S44819 (150 or 300 mg bid) compared to placebo on top of usual care on functional recovery measured with the modified Rankin scale at 3 months. Comparisons between two doses of S44819 and placebo are assessed with ordinal logistic regression evaluating the odds of shifting from one category to the next in the direction of a better outcome at day 90. Secondary objectives include the evaluation of S44819 effects on neurological examination using the National Institute of Health Stroke Scale total score, activities of daily living using the Barthel Index total score, and cognitive performance using the Montreal Cognitive Assessment scale total score and Trail Making Test times. Safety and tolerability of the two doses of S44819 will also be analyzed. Discussion The RESTORE BRAIN study might represent the first proof of concept study of an innovative therapeutic approach that is primarily based on enhancing functional recovery after IS. Trial registration Randomized Efficacy and Safety Trial with Oral S 44819 after Recent ischemic cerebral Event, an international, multi-centre, randomized, double-blind placebo-controlled phase II study. ClinicalTrials.gov, NCT02877615 ; Eudract 2016–001005-16. Registered 24 August 2016

[...]there is an unmet need for therapies that allow enhancing neurological recovery and brain plasticity in the post-acute stroke phase (Hermann and Chopp, 2012). [...]this study fulfilled principles of a hypothesis-building study that was confirmed by a second independent data set.Stringent use of STAIR (Stroke Therapy Academic Industry Roundtable, 1999) and ARRIVE (Kilkenny et al., 2010) guidelines in the planning and conduction of animal experiments, including randomization and blinding, as well as in subsequent data reporting.Adequate statistical powering to detect drug effects with an alpha error of 5% and a beta error (1 – statistical power) of 20 % in each of both, the explorative and confirmation study.Solid behavioural assessments using comprehensive batteries of motor – coordination and cognitive tests that revealed neurological improvements which persisted after discontinuation of drug delivery.Rigorous histochemical assessments revealing structural brain remodelling and plasticity that accompany motor–coordination and cognitive improvements.Phase I dose escalation studies complemented by a TMS study in healthy humans, which revealed that S44819 at single doses of 100 mg reduced the active motor threshold and amplitude of the N45 potential (Darmani et al., 2016), thus indicating effects of S44819 on cortical function at doses very similar to those clinically applied. [13] The currently conducted RESTORE–Brain trial is unique in that it was designed very closely to the animal study. [...]it fulfils an important principle of translation strategies, which is that studies in animals and humans should mirror each other if possible one to one.

Background Antidepressant-induced liver injury is a major concern and a liver monitoring scheme has been recommended by the European Medicines Agency for agomelatine. Objective The objective of this study was to assess the liver safety and identify the characteristics of patients who developed a significant increase in transaminases whilst taking agomelatine. Method A retrospective pooled analysis of changes in transaminase levels in 9234 patients treated with agomelatine (25 or 50 mg/day; n  = 7605) or placebo ( n  = 1629) from 49 phase II and III studies was undertaken. A significant increase in transaminase levels was defined as an increase to >3 times the upper limit of normal (ULN) (>3 × ULN). Final causality was determined in a case-by-case review by five academic experts. Results Serum transaminases increased to >3 × ULN in 1.3 and 2.5 % of patients treated with 25 and 50 mg of agomelatine, respectively, compared with 0.5 % for placebo. The onset of increased transaminases occurred before 12 weeks in 64 % of patients. The median time to recovery (to ≤2 × ULN) was 14 days following treatment withdrawal. Liver function tests recovered in 36.1 % of patients despite continuation of agomelatine, suggesting the presence of a liver adaptive mechanism. No cases of acute liver failure or fatal outcome occurred. Patients with elevated transaminases at baseline, secondary to obesity/fatty liver disease, had an equally increased risk of developing further elevations of transaminases with agomelatine and placebo. Conclusion Incidence of abnormal transaminases was low and dose dependent. No specific population was identified regarding potential risk factors. Withdrawal of agomelatine led to rapid recovery, and some patients exhibited an adaptive phenomenon. Overall, in clinical trials, the liver profile of agomelatine seems safe when serum transaminases are monitored.

This important and first-of-its-kind collection addresses the emerging challenges in the field of media art preservation and exhibition, providing an outline for the training of professionals in this field.

This important and first-of-its-kind collection addresses the emerging challenges in the field of media art preservation and exhibition, providing an outline for the training of professionals in this field. Since the emergence of time-based media such as film, video and digital technology, artists have used them to experiment with their potential. The resulting artworks, with their basis in rapidly developing technologies that cross over into other domains such as broadcasting and social media, have challenged the traditional infrastructures for the collection, preservation and exhibition of art. Addressing these challenges, the authors provide a historical and theoretical survey of the field, and introduce students to the challenges and difficulties of preserving and exhibiting media art through a series of first-hand case studies. Situated at the threshold between archival practices and film and media theory, it also makes a strong contribution to the growing literature on archive theory and archival practices.|“A companion to media art” provides the first full-fledged introduction to the emerging new field of the preservation and presentation of media art from a truly international perspective. Bringing together contributions from authors from all over Europe and the United States and combining the rich insights of scholars, curators and artists the book addresses the history, theory and technical aspects of creating and curating media art. |“A companion to media art” is the first textbook for students in advanced degree programs that lead to careers in the field of preserving and curating media art in media archives and museum collections. For the general reader the book provides an introduction to this fascinating new field. |The combination of incisive scholarly articles and cases studies provides for a comprehensive view of the field that will interest scholars, artists, archivists and curators alike.

•The bioavailability of furosemide 80 mg/mL SC injection is equivalent to that of furosemide 80 mg IV.•Diuresis, natriuresis, and kaliuresis are similar with furosemide 80 mg/mL SC injection and furosemide 80 mg IV.•Furosemide 80 mg/mL SC injection was generally well tolerated. Furoscix (furosemide injection) 80 mg/10 mL is a pH neutral formulation administered subcutaneously (SC) over 5 hours to treat edema in adults with chronic HF or chronic kidney disease. Furosemide 80 mg/mL is a novel concentrated formulation administered as a single 1.0-mL SC injection that could improve convenience for patients. This randomized, open-label, phase 1 study assessed the pharmacokinetics, bioavailability, pharmacodynamics, and safety of furosemide 80 mg/mL SC versus furosemide 80 mg administered intravenously (IV). Healthy volunteers were randomized 1:1 to furosemide 80 mg/mL SC or furosemide 80 mg IV (two 40-mg boluses, 2 hours apart), and after a 3-day washout, received the opposite treatment. Plasma furosemide pharmacokinetics, urine output, and urinary sodium and potassium excretion were measured through 12 hours post-dose. Bioavailability (the primary endpoint) was assessed as the least-squares mean ratio (LSMR) of area under the curve (AUC) from time 0−last (AUClast) and 0−infinity (AUCinf) between furosemide SC and furosemide IV. Plasma furosemide pharmacokinetics were assessed noncompartmentally. Pharmacodynamics were assessed using a repeated measures, mixed model analysis. Safety was assessed through end of study. Twenty-one participants were randomized (furosemide SC/IV, n = 10; furosemide IV/SC, n = 11). The furosemide SC/IV LSMR (90% confidence interval [CI]) AUClast was 106.1% (102.7%, 109.6%), and LSMR (90% CI) AUCinf was 107.3% (103.9%, 110.8%). Furosemide 80 mg/mL SC had bioavailability equivalent to furosemide 80 mg IV, as the CIs fell within 80.0%–125.0%. Mean (SD) Cmax was 4532.9 (1497.7) ng/mL with furosemide 80 mg/mL SC and 10,087.6 (2804.7) ng/mL with furosemide IV. The therapeutic effects of furosemide 80 mg/mL SC on diuresis, natriuresis, and kaliuresis occurred within 1 hour of treatment and were consistent with those of furosemide IV at all time points. There was no significant difference between furosemide 80 mg/mL SC versus furosemide IV in total urine output or urinary sodium or potassium excretion at 0–6 hours, 0–8 hours, or 0–12 hours. Adverse events (AEs) occurred in 14 (66.7%) participants (furosemide SC, n = 11 [52.4%]; furosemide IV, n = 7 [35.0%]) and were mild or moderate. Ten (47.6%) participants had injection site AEs, all of which were treatment-related, mild, non-serious, and resolved. Injection site pain scores graded on a Likert 11-point scale remained low (mean, <0.4; median, 0) at all time points, were similar between groups, and decreased over time. Furosemide 80 mg/mL SC injection was generally well tolerated and had bioavailability, diuresis, natriuresis, and kaliuresis consistent with those of furosemide IV.

Estuaries are productive and ecologically important ecosystems, incorporating environmental drivers from water-sheds, rivers, and the coastal ocean. Climate change has potential to modify the physical properties of estuaries, with impacts on resident organisms. However, projections from general circulation models (GCMs) are generally too coarse to resolve important estuarine processes. Here, we statistically downscaled near-surface air temperature and precipitation projections to the scale of the Chesapeake Bay watershed and estuary. These variables were linked to Susquehanna River streamflow using a water balance model and finally to spatially resolved Chesapeake Bay surface temperature and salinity using statistical model trees. The low computational cost of this approach allowed rapid assessment of projected changes from four GCMs spanning a range of potential futures under a high CO₂ emission scenario, for four different downscaling methods. Choice of GCM contributed strongly to the spread in projections, but choice of downscaling method was also influential in the warmest models. Models projected a ~2-5.5 °C increase in surface water temperatures in the Chesapeake Bay by the end of the century. Projections of salinity were more uncertain and spatially complex. Models showing increases in winter-spring streamflow generated freshening in the Upper Bay and tributaries, while models with decreased streamflow produced salinity increases. Changes to the Chesapeake Bay environment have implications for fish and invertebrate habitats, as well as migration, spawning phenology, recruitment, and occurrence of pathogens. Our results underline a potentially expanded role of statistical downscaling to complement dynamical approaches in assessing climate change impacts in dynamically challenging estuaries.

Phenylketonuria is an inherited disease caused by impaired activity of phenylalanine hydroxylase, the enzyme that converts phenylalanine to tyrosine, leading to accumulation of phenylalanine and subsequent neurocognitive dysfunction. Phenylalanine ammonia lyase is a prokaryotic enzyme that converts phenylalanine to ammonia and trans-cinnamic acid. We aimed to assess the safety, tolerability, pharmacokinetic characteristics, and efficacy of recombinant Anabaena variabilis phenylalanine ammonia lyase (produced in Escherichia coli) conjugated with polyethylene glycol (rAvPAL-PEG) in reducing phenylalanine concentrations in adult patients with phenylketonuria. In this open-label, phase 1, multicentre trial, single subcutaneous injections of rAvPAL-PEG were given in escalating doses (0·001, 0·003, 0·010, 0·030, and 0·100 mg/kg) to adults with phenylketonuria. Participants aged 18 years or older with blood phenylalanine concentrations of 600 μmol/L or higher were recruited from among patients attending metabolic disease clinics in the USA. The primary endpoints were safety and tolerability of rAvPAL-PEG. Secondary endpoints were the pharmacokinetic characteristics of the drug and its effect on concentrations of phenylalanine. Participants and investigators were not masked to assigned dose group. This study is registered with ClinicalTrials.gov, number NCT00925054. 25 participants were recruited from seven centres between May 6, 2008, and April 15, 2009, with five participants assigned to each escalating dose group. All participants were included in the safety population. The most frequently reported adverse events were injection-site reactions and dizziness, which were self-limited and without sequelae. Two participants had serious adverse reactions to intramuscular medroxyprogesterone acetate, a drug that contains polyethylene glycol as an excipient. Three of five participants given the highest dose of rAvPAL-PEG (0·100 mg/kg) developed a generalised skin rash. By the end of the study, all participants had developed antibodies against polyethylene glycol, and some against phenylalanine ammonia lyase as well. Drug concentrations peaked about 89–106 h after administration of the highest dose. Treatment seemed to be effective at reducing blood phenylalanine in all five participants who received the highest dose (mean reduction of 54·2% from baseline), with a nadir about 6 days after injection and an inverse correlation between drug and phenylalanine concentrations in plasma. Phenylalanine returned to near-baseline concentrations about 21 days after the injection. Subcutaneous administration of rAvPAL-PEG in a single dose of up to 0·100 mg/kg was fairly safe and well tolerated in adult patients with phenylketonuria. At the highest dose tested, rAvPAL-PEG reduced blood phenylalanine concentrations. In view of the development of antibodies against polyethylene glycol (and in some cases against phenylalanine ammonia lyase), future studies are needed to assess the effect of repeat dosing. BioMarin Pharmaceutical.