165 research outputs found
Frontotemporal dementia caused by CHMP2B mutation is characterised by neuronal lysosomal storage pathology.
Mutations in the charged multivesicular body protein 2B (CHMP2B) cause frontotemporal dementia (FTD). We report that mice which express FTD-causative mutant CHMP2B at physiological levels develop a novel lysosomal storage pathology characterised by large neuronal autofluorescent aggregates. The aggregates are an early and progressive pathology that occur at 3Â months of age and increase in both size and number over time. These autofluorescent aggregates are not observed in mice expressing wild-type CHMP2B, or in non-transgenic controls, indicating that they are a specific pathology caused by mutant CHMP2B. Ultrastructural analysis and immuno- gold labelling confirmed that they are derived from the endolysosomal system. Consistent with these findings, CHMP2B mutation patient brains contain morphologically similar autofluorescent aggregates. These aggregates occur significantly more frequently in human CHMP2B mutation brain than in neurodegenerative disease or age-matched control brains. These data suggest that lysosomal storage pathology is the major neuronal pathology in FTD caused by CHMP2B mutation. Recent evidence suggests that two other genes associated with FTD, GRN and TMEM106B are important for lysosomal function. Our identification of lysosomal storage pathology in FTD caused by CHMP2B mutation now provides evidence that endolysosomal dysfunction is a major degenerative pathway in FTD
Comparison of treatment with insulin degludec and glargine U100 in patients with type 1 diabetes prone to nocturnal severe hypoglycaemia:The HypoDeg randomized, controlled, open-label, crossover trial
AIM: To investigate whether the longâacting insulin analogue insulin degludec compared with insulin glargine U100 reduces the risk of nocturnal symptomatic hypoglycaemia in patients with type 1 diabetes (T1D). METHODS: Adults with T1D and at least one episode of nocturnal severe hypoglycaemia during the last 2âyears were included in a 2âyear prospective, randomized, open, multicentre, crossover trial. A total of 149 patients were randomized 1:1 to basalâbolus therapy with insulin degludec and insulin aspart or insulin glargine U100 and insulin aspart. Each treatment period lasted 1âyear and consisted of 3âmonths of runâin or crossover followed by 9âmonths of maintenance. The primary endpoint was the number of blindly adjudicated nocturnal symptomatic hypoglycaemic episodes. Secondary endpoints included the occurrence of severe hypoglycaemia. We analysed all endpoints by intentionâtoâtreat. RESULTS: Treatment with insulin degludec resulted in a 28% (95% CI: 9%â43%; P = .02) relative rate reduction (RRR) of nocturnal symptomatic hypoglycaemia at level 1 (â¤3.9âmmol/L), a 37% (95% CI: 16%â53%; P = .002) RRR at level 2 (â¤3.0âmmol/L), and a 35% (95% CI: 1%â58%; P = .04) RRR in allâday severe hypoglycaemia compared with insulin glargine U100. CONCLUSIONS: Patients with T1D prone to nocturnal severe hypoglycaemia have lower rates of nocturnal symptomatic hypoglycaemia and allâday severe hypoglycaemia with insulin degludec compared with insulin glargine U100
Agents intervening against delirium in the intensive care unit trial-Protocol for a secondary Bayesian analysis
Background Delirium is highly prevalent in the intensive care unit (ICU) and is associated with high morbidity and mortality. The antipsychotic haloperidol is the most frequently used agent to treat delirium although this is not supported by solid evidence. The agents intervening against delirium in the intensive care unit (AID-ICU) trial investigates the effects of haloperidol versus placebo for the treatment of delirium in adult ICU patients. Methods This protocol describes the secondary, pre-planned Bayesian analyses of the primary and secondary outcomes up to day 90 of the AID-ICU trial. We will use Bayesian linear regression models for all count outcomes and Bayesian logistic regression models for all dichotomous outcomes. We will adjust for stratification variables (site and delirium subtype) and use weakly informative priors supplemented with sensitivity analyses using sceptical priors. We will present results as absolute differences (mean differences and risk differences) and relative differences (ratios of means and relative risks). Posteriors will be summarised using median values as point estimates and percentile-based 95% credibility intervals. Probabilities of any benefit/harm, clinically important benefit/harm and clinically unimportant differences will be presented for all outcomes. Discussion The results of this secondary, pre-planned Bayesian analysis will complement the primary frequentist analysis of the AID-ICU trial and facilitate a nuanced and probabilistic interpretation of the trial results.Peer reviewe
Agents intervening against delirium in the intensive care unit (AID-ICU) - Protocol for a randomised placebo-controlled trial of haloperidol in patients with delirium in the ICU
Background
Delirium among patients in the intensive care unit (ICU) is a common condition associated with increased morbidity and mortality. Haloperidol is the most frequently used pharmacologic intervention, but its use is not supported by firm evidence. Therefore, we are conducting Agents Intervening against Delirium in the Intensive Care Unit (AIDâICU) trial to assess the benefits and harms of haloperidol for the treatment of ICUâacquired delirium.
Methods
AIDâICU is an investigatorâinitiated, pragmatic, international, randomised, blinded, parallelâgroup, trial allocating adult ICU patients with manifest delirium 1:1 to haloperidol or placebo. Trial participants will receive intravenous 2.5 mg haloperidol three times daily or matching placebo (isotonic saline 0.9%) if they are delirious. If needed, a maximum of 20 mg/daily haloperidol/placebo is given. An escape protocol, not including haloperidol, is part of the trial protocol. The primary outcome is days alive out of the hospital within 90 days postârandomisation. Secondary outcomes are number of days without delirium or coma, serious adverse reactions to haloperidol, usage of escape medication, number of days alive without mechanical ventilation; mortality, healthârelated qualityâofâlife and cognitive function at 1âyear followâup. A sample size of 1000 patients is required to detect a 7âday improvement or worsening of the mean days alive out of the hospital, type 1 error risk of 5% and power 90%.
Perspective
The AIDâICU trial is based on gold standard methodology applied to a large sample of clinically representative patients and will provide pivotal highâquality data on the benefits and harms of haloperidol for the treatment ICUâacquired delirium
Mild Pd-Catalyzed Aminocarbonylation of (Hetero)Aryl Bromides with a Palladacycle Precatalyst
A palladacyclic precatalyst is employed to cleanly generate a highly active XantPhos-ligated Pd-catalyst. Its use in low temperature aminocarbonylations of (hetero)aryl bromides provides access to a range of challenging products in good to excellent yields with low catalyst loading and only a slight excess of CO. Some products are unattainable by traditional carbonylative coupling.National Institutes of Health (U.S.) (Award GM46059)Danish National Research Foundation (Grant DNRF59)Villum FoundationDanish Council for Independent Researc
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