Book chapters will be unavailable on Saturday 24th August between 8am-12pm BST. This is for essential maintenance which will provide improved performance going forwards. Please accept our apologies for any inconvenience caused.
To send content items to your account,
please confirm that you agree to abide by our usage policies.
If this is the first time you use this feature, you will be asked to authorise Cambridge Core to connect with your account.
Find out more about sending content to .
To send content items to your Kindle, first ensure email@example.com
is added to your Approved Personal Document E-mail List under your Personal Document Settings
on the Manage Your Content and Devices page of your Amazon account. Then enter the ‘name’ part
of your Kindle email address below.
Find out more about sending to your Kindle.
Note you can select to send to either the @free.kindle.com or @kindle.com variations.
‘@free.kindle.com’ emails are free but can only be sent to your device when it is connected to wi-fi.
‘@kindle.com’ emails can be delivered even when you are not connected to wi-fi, but note that service fees apply.
To evaluate the long-term safety and tolerability of deutetrabenazine in patients with tardive dyskinesia (TD) at 2years.
In the 12-week ARM-TD and AIM-TD studies, deutetrabenazine showed clinically significant improvements in Abnormal Involuntary Movement Scale scores compared with placebo, and there were low rates of overall adverse events (AEs) and discontinuations associated with deutetrabenazine.
Patients who completed ARM-TD or AIM-TD were included in this open-label, single-arm extension study, in which all patients restarted/started deutetrabenazine 12mg/day, titrating up to a maximum total daily dose of 48mg/day based on dyskinesia control and tolerability. The study comprised a 6-week titration period and a long-term maintenance phase. Safety measures included incidence of AEs, serious AEs (SAEs), and AEs leading to withdrawal, dose reduction, or dose suspension. Exposure-adjusted incidence rates (EAIRs; incidence/patient-years) were used to compare AE frequencies for long-term treatment with those for short-term treatment (ARM-TD and AIM-TD). This analysis reports results up to 2 years (Week106).
343 patients were enrolled (111 patients received placebo in the parent study and 232 received deutetrabenazine). There were 331.4 patient-years of exposure in this analysis. Through Week 106, EAIRs of AEs were comparable to or lower than those observed with short-term deutetrabenazine and placebo, including AEs of interest (akathisia/restlessness [long-term EAIR: 0.02; short-term EAIR range: 0–0.25], anxiety [0.09; 0.13–0.21], depression [0.09; 0.04–0.13], diarrhea [0.06; 0.06–0.34], parkinsonism [0.01; 0–0.08], somnolence/sedation [0.09; 0.06–0.81], and suicidality [0.02; 0–0.13]). The frequency of SAEs (EAIR 0.15) was similar to those observed with short-term placebo (0.33) and deutetrabenazine (range 0.06–0.33) treatment. AEs leading to withdrawal (0.08), dose reduction (0.17), and dose suspension (0.06) were uncommon.
These results confirm the safety outcomes seen in the ARM-TD and AIM-TD parent studies, demonstrating that deutetrabenazine is well tolerated for long-term use in TD patients.
Presented at: American Academy of Neurology Annual Meeting; April 21–27, 2018, Los Angeles, California,USA
Funding Acknowledgements: Funding: This study was supported by Teva Pharmaceuticals, Petach Tikva, Israel
To evaluate long-term efficacy of deutetrabenazine in patients with tardive dyskinesia (TD) by examining response rates from baseline in Abnormal Involuntary Movement Scale (AIMS) scores. Preliminary results of the responder analysis are reported in this analysis.
In the 12-week ARM-TD and AIM-TD studies, the odds of response to deutetrabenazine treatment were higher than the odds of response to placebo at all response levels, and there were low rates of overall adverse events and discontinuations associated with deutetrabenazine.
Patients with TD who completed ARM-TD or AIM-TD were included in this open-label, single-arm extension study, in which all patients restarted/started deutetrabenazine 12mg/day, titrating up to a maximum total daily dose of 48mg/day based on dyskinesia control and tolerability. The study comprised a 6-week titration and a long-term maintenance phase. The cumulative proportion of AIMS responders from baseline was assessed. Response was defined as a percent improvement from baseline for each patient from 10% to 90% in 10% increments. AlMS score was assessed by local site ratings for this analysis.
343 patients enrolled in the extension study (111 patients received placebo in the parent study and 232 patients received deutetrabenazine). At Week 54 (n=145; total daily dose [mean±standard error]: 38.1±0.9mg), 63% of patients receiving deutetrabenazine achieved ≥30% response, 48% of patients achieved ≥50% response, and 26% achieved ≥70% response. At Week 80 (n=66; total daily dose: 38.6±1.1mg), 76% of patients achieved ≥30% response, 59% of patients achieved ≥50% response, and 36% achieved ≥70% response. Treatment was generally well tolerated.
Patients who received long-term treatment with deutetrabenazine achieved response rates higher than those observed in positive short-term studies, indicating clinically meaningful long-term treatment benefit.
Presented at: American Academy of Neurology Annual Meeting; April 21–27, 2018, Los Angeles, California, USA.
Funding Acknowledgements: This study was supported by Teva Pharmaceuticals, Petach Tikva, Israel.
Objectives: To examine academic performance in dystrophinopathy as a function of dystrophin gene mutation position as well as intellectual function, executive skills, socioeconomic status (SES), behavior, and physical ability. Methods: In a cross-sectional study, boys with dystrophinopathy (ages 5–17; n=50) completed tests of academics (Woodcock-Johnson-III: spelling, reading, calculation and total scores), executive functioning (selective attention/inhibitory control, set shifting, working memory, and processing speed), single word comprehension and nonverbal reasoning. Motor skills were assessed and parents provided demographic information and child behavioral assessments. Dystrophin gene mutation positions were dichotomized into groups (upstream versus downstream of exon 43, location of isoforms previously linked to intellectual impairment). Genetic mutation groups were compared on measures of academic achievement, and multiple regression analyses examined unique and joint contributions of executive skills, intelligence quotient (IQ), SES, motor abilities, behavior, and mutation positions to academic outcomes. Results: Academic performance was slightly, yet significantly, lower than IQ and varied as a function of dystrophin gene position, wherein boys possessing the downstream mutation exhibited greater impairment than boys with the upstream mutation. Digit span forward (indexing verbal span), but no other measure of executive function, contributed significant variance to total academic achievement, spelling and calculation. Conclusions: Weak academic performance is associated with dystrophinopathy and is more common in downstream mutations. A specific deficit in verbal span may underlie inefficiencies observed in children with dystrophinopathy and may drive deficits impacting academic abilities. (JINS, 2018, 24, 928–938)
The loss of methanesul phonic acid (MSA) from stored ice cores can be significant over typical storage times, with diffusion to the ice-core surface controlling the loss. Methods for minimizing this loss are discussed and it is shown how measurements can be corrected by calculating the amount of MSA lost. A revised diffusion coefficient for MSA in solid ice, (4.1 × 10−13) ± (2.5 × 10−14) m2 s−1, is derived to improve such MSA loss corrections.
To determine the scope, source, and mode of transmission of a multifacility outbreak of extensively drug-resistant (XDR) Acinetobacter baumannii.
SETTING AND PARTICIPANTS
Residents and patients in skilled nursing facilities, long-term acute-care hospital, and acute-care hospitals.
A case was defined as the incident isolate from clinical or surveillance cultures of XDR Acinetobacter baumannii resistant to imipenem or meropenem and nonsusceptible to all but 1 or 2 antibiotic classes in a patient in an Oregon healthcare facility during January 2012–December 2014. We queried clinical laboratories, reviewed medical records, oversaw patient and environmental surveillance surveys at 2 facilities, and recommended interventions. Pulsed-field gel electrophoresis (PFGE) and molecular analysis were performed.
We identified 21 cases, highly related by PFGE or healthcare facility exposure. Overall, 17 patients (81%) were admitted to either long-term acute-care hospital A (n=8), or skilled nursing facility A (n=8), or both (n=1) prior to XDR A. baumannii isolation. Interfacility communication of patient or resident XDR status was not performed during transfer between facilities. The rare plasmid-encoded carbapenemase gene blaOXA-237 was present in 16 outbreak isolates. Contact precautions, chlorhexidine baths, enhanced environmental cleaning, and interfacility communication were implemented for cases to halt transmission.
Interfacility transmission of XDR A. baumannii carrying the rare blaOXA-237 was facilitated by transfer of affected patients without communication to receiving facilities.
This study explored how coping with war-related traumatic events in Sierra Leone impacted mental health outcomes among 529 youth (aged 10–17 at baseline; 25% female) using longitudinal data from three time points (Time 1 in 2002, Time 2 in 2004, and Time 3 in 2008). We examined two types of coping items (approach and avoidance); used multiple regression models to test their relations with long-term mental health outcomes (internalizing behaviors, externalizing behaviors, adaptive/prosocial behaviors, and posttraumatic stress symptoms); and used mediation analyses to test whether coping explained the relation between previous war exposures (being raped, death of parent(s), or killing/injuring someone during the war) and those outcomes. We found that avoidance coping items were associated with lower internalizing and posttraumatic stress behaviors at Time 3, and provided some evidence of mediating the relation between death of parent(s) during the war and the two outcomes mentioned above. Approach coping was associated with higher Time 3 adaptive/prosocial behaviors, whereas avoidance coping was associated with lower Time 3 adaptive/prosocial behaviors. Avoidance coping may be a protective factor against mental illness, whereas approach coping may be a promotive factor for adaptive/prosocial behaviors in war-affected societies. This study has important implications for designing and implementing mental health interventions for youth in postconflict settings.
Gas-accepting ion sources for radiocarbon accelerator mass spectrometry (AMS) have permitted the direct analysis of CO2 gas, eliminating the need to graphitize samples. As a result, a variety of analytical instruments can be interfaced to an AMS system, processing time is decreased, and smaller samples can be analyzed (albeit with lower precision). We have coupled a gas chromatograph to a compact 14C AMS system fitted with a microwave ion source for real-time compound-specific 14C analysis. As an initial test of the system, we have analyzed a sample of fatty acid methyl esters and biodiesel. Peak shape and memory was better then existing systems fitted with a hybrid ion source while precision was comparable. 14C/12C ratios of individual components at natural abundance levels were consistent with those determined by conventional methods. Continuing refinements to the ion source are expected to improve the performance and scope of the instrument.
In 2008, a large African baobab (Adansonia digitata L.) from Makulu Makete, South Africa, split vertically into 2 sections, revealing a large enclosed cavity. Several wood samples collected from the cavity were processed and radiocarbon dated by accelerator mass spectrometry (AMS) for determining the age and growth rate dynamics of the tree. The 14C date of the oldest sample was found to be of 1016 ± 22 BP, which corresponds to a calibrated age of 1000 ± 15 yr. Thus, the Makulu Makete tree, which eventually collapsed to the ground and died, becomes the second oldest African baobab dated accurately to at least 1000 yr. The conventional growth rate of the trunk, estimated by the radial increase, declined gradually over its life cycle. However, the growth rate expressed more adequately by the cross-sectional area increase and by the volume increase accelerated up to the age of 650 yr and remained almost constant over the past 450 yr.
The article reports the first radiocarbon dating of a live African baobab (Adansonia digitata L.), by investigating wood samples collected from 2 inner cavities of the very large 2-stemmed Platland tree of South Africa. Some 16 segments extracted from determined positions of the samples, which correspond to a depth of up to 15–20 cm in the wood, were processed and analyzed by accelerator mass spectrometry (AMS). Calibrated ages of segments are not correlated with their positions in the stems of the tree. Dating results indicate that the segments originate from new growth layers, with a thickness of several centimeters, which cover the original old wood. Four new growth layers were dated before the reference year AD 1950 and 2 layers were dated post-AD 1950, in the post-bomb period. Formation of these layers was triggered by major damage inside the cavities. Fire episodes are the only possible explanation for such successive major wounds over large areas or over the entire area of the inner cavities of the Platland tree, able to trigger regrowth.
Percolation of blood and of interstitial fluids into implantable continuous glucose sensors (CGS) for diabetics presently limits sensor lifetime between 3 and 7 days. Na+ mobile ions in body fluids damage Si-based CGS sensors electronics. The direct detection of Na percolation is investigated by Ion Beam Analysis (IBA) and Proton Induced X-ray Emission (PIXE) in previously used CGS. Based on these results, a new technology called HemaDropTM is then tested to prepare small volume (5-10 µL) of blood for IBA. A species’s detectability by IBA scales with the square of the ratio of element’s atomic number Z to that of the substrate. Because Na has a low atomic number (Z=11), Si signals from sensor substrates can prevent Na detection in Si by 2 mega electron volt (MeV) IBA.
Using 4.7 MeV 23Na (α, α)23Na nuclear resonance (NR) can increase the 23Na scattering cross section and thus its detectability in Si. The NR energy, width, and resonance factor, is calibrated via two well-known alpha (α) particle signals with narrow energy spreads: a 5.486 ± 0.007 MeV 241Am α-source (ΔΕ = 0.12%) and the 3.038 ± 0.003 MeV 16O(α, α)16O NR (ΔΕ = 0.1%). Next, the NR cross section is calibrated via 100 nm NaF thin films on Si(100) by scanning the beam energy. The23Na (α, α) NR energy is found to be 4.696 ± 0.180 MeV, and the NR/RBS cross section 141 ± 7%. This is statistically significant but small compared to the 4.265 MeV 12C NR (1700%) and 3.038 MeV 16O NR (210%), and insufficient to detect small amounts of 23Na in Si. Next, a new method of sample preparation HemaDropTM, is tested for detection of elements in blood, such Fe, Ca, Na, Cl, S, K, C, N, and O, as an alternative to track fluid percolation and Na diffusion in damaged sensors. Detecting more abundant, heavier elements in blood and interstitial fluids can better track fluid percolation and Na+ ions in sensors. Both Na detection and accuracy of measured blood composition by IBA is greatly improved by using HemaDropTM sample preparation to create Homogeneous Thin Solid Films (HTSFs) of blood from 5-10 µL on most substrates. HTSF can be used in vacuo such as 10-8 –10-6 Torr).
Overall IDSA/SIS intra-abdominal infection guideline compliance was not associated with improved outcomes; however, there was a longer time to active therapy (P=.024) and higher mortality (P=.077) if empiric therapy was too narrow per guidelines. These findings support the need for the implementation of customized institutional guidelines adapted from the IDSA/SIS guidelines.
In response to the increasing demand for 14C analysis of samples containing less than 25 μg C, ultra-small graphitization reactors with an internal volume of ∼0.8 mL were developed at NOSAMS. For samples containing 6 to 25 μg C, these reactors convert CO2 to graphitic carbon in approximately 30 min. Although we continue to refine reaction conditions to improve yield, the reactors produce graphite targets that are successfully measured by AMS. Graphite targets produced with the ultra-small reactors are measured by using the Cs sputter source on the CFAMS instrument at NOSAMS where beam current was proportional to sample mass. We investigated the contribution of blank carbon from the ultra-small reactors and estimate it to be 0.3 ± 0.1 μg C with an Fm value of 0.43 ± 0.3. We also describe equations for blank correction and propagation of error associated with this correction. With a few exceptions for samples in the range of 6 to 7 μg C, we show that corrected Fm values agree with expected Fm values within uncertainty for samples containing 6–100 μg C.
The present study is the first record of twinning in Lagenorhynchus acutus and indeed any Lagenorhynchus sp. Both foetuses were male and located in the left uterine horn, had distinct grossly normal placentas and amniotic sacs, and were therefore likely dizygotic twins. The twins were an incidental finding in an animal that died of a systemic Brucella ceti infection.
The National Ocean Sciences Accelerator Mass Spectrometry (NOSAMS) facility at the Woods Hole Oceanographic Institution has developed an automated system for high-throughput, low-cost analysis of radiocarbon in carbonate samples (e.g. corals, carbonaceous sediments, speleothems, etc.). The method bypasses graphitization and pretreatment, and reduces costs to about 1/5th the price of a graphite-based 14C carbonate analysis, with a throughput of 60 unknowns per day and an analytical precision of better than 2%. Additionally, a simple mixing experiment indicated that extensive cleaning of carbonate samples to remove organic material is not necessary.
Radiocarbon analysis is an important tool in quantifying soil organic matter (SOM) dynamics within the terrestrial carbon cycle. However, there is increasing appreciation that representing SOM as a single, homogeneous pool with a single, mean 14C concentration is inadequate. We investigate whether the differing patterns in CO2 release during ramped-temperature oxidation reflect organic matter of different ages, and hypothesize that thermally labile SOM (combusting at low temperatures) consists of younger carbon than thermally resistant organic matter. Topsoil samples under contrasting land uses (native vegetation and long-term cultivation) were selected for 14C analysis before and after acid fumigation for the removal of carbonates. Results of bulk 14C analyses showed a significant shift in 14C age from 0.944 Fm under native vegetation to 0.790 Fm under cultivation. Four to 5 “fractions” associated with different CO2-evolution regions were identified by thermal analysis and analyzed for 14C via modifications to NOSAMS' established “programmed temperature pyrolysis system,” in which discrete CO2 fractions evolved during ramped-temperature oxidation were isotopically characterized by a microwave gas ion source (GIS) continuous-flow AMS (CFAMS) system. Results showed that while acid fumigation removed soil carbonates, the treatment also significantly altered the thermograms and inferred SOM composition. While direct attribution of 14C values to individual peaks is somewhat confounded by overlapping temperature ranges for oxidation of unique populations of carbon, in general, thermally stable fractions of SOM appear to be 14C-depleted compared to thermally reactive (low temperature) fractions regardless of pretreatment.
Compound specific radiocarbon measurements can be made instantaneously using a gas chromatograph (GC) combustion system coupled to a 14C AMS system fitted with a gas ion source. Samples below 10 μg C can be analyzed but the precision is reduced to 5–10% because of lower source efficiency. We modified our GC for CH4 and CO2 analysis and injected samples multiple times to sum data and increase precision. We attained a maximum precision of 0.6% for modern CO2 from 25 injections of 27 μg C and a background of ≃0.5% (40 kyr) for ancient methane. The 14C content of dissolved CO2 and CH4 in water samples collected at a deep-sea hydrothermal vent and a serpentine mud volcano was measured and the results for the vent sample are consistent with previously published data. Further experiments are required to determine a calibration and correction procedure to maximize accuracy.