Effect of Deutetrabenazine on Chorea Among Patients With Huntington Disease A Randomized Clinical Trial

Importance Deutetrabenazine is a novel molecule containing deuterium, which attenuates CYP2D6 metabolism and increases active metabolite half-lives and may therefore lead to stable systemic exposure while preserving key pharmacological activity. Objective To evaluate efficacy and safety of deutetrabenazine treatment to control chorea associated with Huntington disease. Design, Setting, and Participants Ninety ambulatory adults diagnosed with manifest Huntington disease and a baseline total maximal chorea score of 8 or higher (range, 0-28; lower score indicates less chorea) were enrolled from August 2013 to August 2014 and randomized to receive deutetrabenazine (n = 45) or placebo (n = 45) in a double-blind fashion at 34 Huntington Study Group sites. Interventions Deutetrabenazine or placebo was titrated to optimal dose level over 8 weeks and maintained for 4 weeks, followed by a 1-week washout. Main Outcomes and Measures Primary end point was the total maximal chorea score change from baseline (the average of values from the screening and day-0 visits) to maintenance therapy (the average of values from the week 9 and 12 visits) obtained by in-person visits. This study was designed to detect a 2.7-unit treatment difference in scores. The secondary end points, assessed hierarchically, were the proportion of patients who achieved treatment success on the Patient Global Impression of Change (PGIC) and on the Clinical Global Impression of Change (CGIC), the change in 36-Item Short Form– physical functioning subscale score (SF-36), and the change in the Berg Balance Test. Results Ninety patients with Huntington disease (mean age, 53.7 years; 40 women [44.4%]) were enrolled. In the deutetrabenazine group, the mean total maximal chorea scores improved from 12.1 (95% CI, 11.2-12.9) to 7.7 (95% CI, 6.5-8.9), whereas in the placebo group, scores improved from 13.2 (95% CI, 12.2-14.3) to 11.3 (95% CI, 10.0-12.5); the mean between-group difference was –2.5 units (95% CI, –3.7 to –1.3) (P < .001). Treatment success, as measured by the PGIC, occurred in 23 patients (51%) in the deutetrabenazine group vs 9 (20%) in the placebo group (P = .002). As measured by the CGIC, treatment success occurred in 19 patients (42%) in the deutetrabenazine group vs 6 (13%) in the placebo group (P = .002). In the deutetrabenazine group, the mean SF-36 physical functioning subscale scores decreased from 47.5 (95% CI, 44.3-50.8) to 47.4 (44.3-50.5), whereas in the placebo group, scores decreased from 43.2 (95% CI, 40.2-46.3) to 39.9 (95% CI, 36.2-43.6), for a treatment benefit of 4.3 (95% CI, 0.4 to 8.3) (P = .03). There was no difference between groups (mean difference of 1.0 unit; 95% CI, –0.3 to 2.3; P = .14), for improvement in the Berg Balance Test, which improved by 2.2 units (95% CI, 1.3-3.1) in the deutetrabenazine group and by 1.3 units (95% CI, 0.4-2.2) in the placebo group. Adverse event rates were similar for deutetrabenazine and placebo, including depression, anxiety, and akathisia. Conclusions and Relevance Among patients with chorea associated with Huntington disease, the use of deutetrabenazine compared with placebo resulted in improved motor signs at 12 weeks. Further research is needed to assess the clinical importance of the effect size and to determine longer-term efficacy and safety

High Density SNP Screen in A Large Multiplex Neural Tube Defect Family Refines Linkage to Loci at 7p21-Pter And 2q33.1-35

Neural tube defects (NTDs) are considered complex with both genetic and environmental factors implicated. To date, no major causative genes have been identified in humans despite several investigations. The first genomewide screen in NTDs (Rampersaud et al. 2005) demonstrated evidence of linkage to chromosomes 7 and 10. This screen included forty-four multiplex families and consisted of 402 microsatellite markers spaced approximately 10 cM apart. Further investigation of the genomic screen data identified a single large multiplex family, pedigree 8776, as primarily driving the linkage results on chromosome 7

Effect of remote ischaemic conditioning on clinical outcomes in patients with acute myocardial infarction (CONDI-2/ERIC-PPCI): a single-blind randomised controlled trial.

BACKGROUND: Remote ischaemic conditioning with transient ischaemia and reperfusion applied to the arm has been shown to reduce myocardial infarct size in patients with ST-elevation myocardial infarction (STEMI) undergoing primary percutaneous coronary intervention (PPCI). We investigated whether remote ischaemic conditioning could reduce the incidence of cardiac death and hospitalisation for heart failure at 12 months. METHODS: We did an international investigator-initiated, prospective, single-blind, randomised controlled trial (CONDI-2/ERIC-PPCI) at 33 centres across the UK, Denmark, Spain, and Serbia. Patients (age >18 years) with suspected STEMI and who were eligible for PPCI were randomly allocated (1:1, stratified by centre with a permuted block method) to receive standard treatment (including a sham simulated remote ischaemic conditioning intervention at UK sites only) or remote ischaemic conditioning treatment (intermittent ischaemia and reperfusion applied to the arm through four cycles of 5-min inflation and 5-min deflation of an automated cuff device) before PPCI. Investigators responsible for data collection and outcome assessment were masked to treatment allocation. The primary combined endpoint was cardiac death or hospitalisation for heart failure at 12 months in the intention-to-treat population. This trial is registered with ClinicalTrials.gov (NCT02342522) and is completed. FINDINGS: Between Nov 6, 2013, and March 31, 2018, 5401 patients were randomly allocated to either the control group (n=2701) or the remote ischaemic conditioning group (n=2700). After exclusion of patients upon hospital arrival or loss to follow-up, 2569 patients in the control group and 2546 in the intervention group were included in the intention-to-treat analysis. At 12 months post-PPCI, the Kaplan-Meier-estimated frequencies of cardiac death or hospitalisation for heart failure (the primary endpoint) were 220 (8·6%) patients in the control group and 239 (9·4%) in the remote ischaemic conditioning group (hazard ratio 1·10 [95% CI 0·91-1·32], p=0·32 for intervention versus control). No important unexpected adverse events or side effects of remote ischaemic conditioning were observed. INTERPRETATION: Remote ischaemic conditioning does not improve clinical outcomes (cardiac death or hospitalisation for heart failure) at 12 months in patients with STEMI undergoing PPCI. FUNDING: British Heart Foundation, University College London Hospitals/University College London Biomedical Research Centre, Danish Innovation Foundation, Novo Nordisk Foundation, TrygFonden

Causes of sulfur isotope variability in the seagrass, Zostera capricorni

Sulfur has been proposed as a useful element to employ in addition to carbon and nitrogen in stable isotope studies of marine food webs, but variability in δ34S of primary producers may prevent food web resolution. δ34S values in green leaves of the seagrass, Zostera capricorni, showed considerable variability (12.7–17.6‰) in a survey in Moreton Bay, Australia. We demonstrated that δ34S values were correlated with sediment organic matter (OM) content and height of seagrass on the tidal gradient, but these relationships were opposite to those expected from work elsewhere. In our survey, δ34S values were relatively depleted at sites higher on the shore and with lower OM content. We did find the expected relationship of depleted δ34S values where sediment porewater sulfide concentrations were higher. Any influence of OM content on δ34S values would have been confounded in the survey by the relationship between height on shore and OM content itself. We separated the effects of height and OM content by creating the following treatments at one height on the shore: (1) OM added, (2) procedural control, and (3) untouched control. δ34S values of seagrass in OM added plots were significantly depleted (5.6‰) relative to procedural (10.1‰) and untouched (11.0‰) controls 8 weeks after the manipulation. This demonstrated that OM content on its own does have the expected effect on δ34S values of seagrass, so in the initial survey another factor, probably related to height on shore, must have overridden the influence of OM content. Seagrass roots are able to exude excess oxygen produced during photosynthesis, reoxidising sulfides in surrounding porewater. We demonstrated that the above and below-ground biomass of seagrass was higher low on the shore, and contend that higher seagrass productivity low on the shore results in greater reoxidation of sulfides and leads to more enriched δ34S values of seagrass

Wastewater nitrogen and trace metal uptake by biota on a high-energy rocky shore detected using stable isotopes

On high-energy rocky shores receiving treated wastewater, impacts are difficult to distinguish against a highly variable background and are localised due to rapid dilution. We demonstrate that nitrogen stable isotope values (δ15N) of rocky shore biota are highly sensitive to wastewater inputs. For macroalgae (Ulva lactuca and Endarachne binghamiae), grazing snails (Bembicium nanum and Nerita atramentosa), and predatory snails (Morula marginalba), δ15N was enriched near a wastewater outfall and declined with distance, returning to background levels within 290 m. Any of these species therefore indicates the extent of influence of wastewater, allowing identification of an appropriate scale for studies of ecosystem impacts. For M. marginalba, significant regressions between δ15N and tissue copper, manganese, and zinc concentrations indicate a possible wastewater source for these metals. This suggests that δ15N is a proxy for exposure to wastewater contaminants, and may help to attribute variations in rocky shore communities to wastewater impacts

Uptake of dissolved organic and inorganic nitrogen in microalgae-dominated sediment: comparing dark and light in situ and ex situ additions of 15N

Microbial communities within bare intertidal sediment have an active role in uptake of inorganic and organic nitrogen as it is transported through estuaries. 15N-labeled dissolved inorganic nitrogen (DIN, NH4 +; 250 µmol l−1, 500 µmol l−1) and dissolved organic nitrogen (DON, algalderived; 125 µmol l−1, 250 µmol l−1) were applied to diatom-dominated sandy intertidal sediment under light and dark conditions to investigate short-term N uptake (24 h). Two experiments compared uptake in intact sediments (in situ) and homogenized slurries (ex situ). In both experiments, N uptake was similar in light and dark conditions, and benthic microalgae (BMA) dominated both biomass and DIN and DON uptake over heterotrophic bacteria. Substantially lower uptake of DON than DIN occurred for both experiments, likely because organic molecules require extra - cellular processing before uptake by BMA. Compared to intact sediments, sediment slurries had higher N uptake into sediment organic matter (3−36×), lower bacterial biomass (13.6 ± 3.5% versus 41.1 ± 7.6% intact) and low bacterial contribution to 15N uptake (14 ± 0.8% versus 14 ± 3.0%). Differences are likely due to shifts within the microbial community and sediment environment caused by sediment homogenization or incubation effects. Consistently, uptake rates within slurries were greater than within intact sediments, and patterns of significant differences among treatments were different. Slurry incubations are therefore not reliable for quantification or comparison of in situ uptake rates across different N substrates, but biomarkers appear robust between the 2 methods, indicating low bacterial contribution to N uptake in BMA-dominated sediment

Fate of microphytobenthos nitrogen in subtropical subtidal sediments : A 15N pulse-chase study

Microphytobenthos (MPB) are an important nitrogen (N) sink in coastal systems, but little is known about the fate of this N after it has been assimilated. We used an in situ 15N pulse-chase experiment in subtidal sands to follow the assimilation, trophic transfer, transformation, and flux pathways of MPB-N over 33 d. Throughout the study MPB dominated 15N uptake, on average representing only 18.1% of the biomass but 63.9% of the 15N within 0–2 cm sediment. Following assimilation, 15N was rapidly transferred to deeper sediment, with 32.1% below 2 cm and 16.5% below 5 cm after 60 h. In contrast to MPB, bacteria represented 39.5% of sediment biomass but accounted for only up to 27.3% of assimilated 15N. Foraminifera accumulated and stored 15N more than bacteria; their contribution to the 15N remaining in 0–2 cm sediment at the end of the study was more than double their biomass contribution. Thirty-three days after the 15N was assimilated by MPB 27% remained in the sediment, 16.5% had been effluxed as inline image, 20.8% had been effluxed as inline image, 20.7% had been effluxed as N2 and 15.1% was missing. Most (12.6%) of 15N label that was missing at the end of the study was probably lost as dissolved organic N (DON) fluxes. Of the 15N remaining in 0–2 cm sediment, 80.4% was in MPB, 2.7% in bacteria, 1% in foraminifera and the remaining 15.9% was uncharacterized. Overall there was little benthic trophic transfer with most of the MPB-assimilated N remineralized over 33 d