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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.
To determine the preliminary feasibility, acceptability, and effects of Meaning-Centered Grief Therapy (MCGT) for parents who lost a child to cancer.
Parents who lost a child to cancer and who were between six months and six years after loss and reporting elevated levels of prolonged grief were enrolled in open trials of MCGT, a manualized, one-on-one cognitive-behavioral-existential intervention that used psychoeducation, experiential exercises, and structured discussion to explore themes related to meaning, identity, purpose, and legacy. Parents completed 16 weekly sessions, 60–90 minutes in length, either in person or through videoconferencing. Parents were administered measures of prolonged grief disorder symptoms, meaning in life, and other assessments of psychological adjustment preintervention, mid-intervention, postintervention, and at three months postintervention. Descriptive data from both the in-person and videoconferencing open trial were pooled.
Eight of 11 (72%) enrolled parents started the MCGT intervention, and six of eight (75%) participants completed all 16 sessions. Participants provided positive feedback about MCGT. Results showed postintervention longitudinal improvements in prolonged grief (d = 1.70), sense of meaning (d = 2.11), depression (d = 0.84), hopelessness (d = 1.01), continuing bonds with their child (d = 1.26), posttraumatic growth (ds = 0.29–1.33), positive affect (d = 0.99), and various health-related quality of life domains (d = 0.46–0.71). Most treatment gains were either maintained or increased at the three-month follow-up assessment.
Significance of results
Overall, preliminary data suggest that this 16-session, manualized cognitive-behavioral-existential intervention is feasible, acceptable, and associated with transdiagnostic improvements in psychological functioning among parents who have lost a child to cancer. Future research should examine MCGT with a larger sample in a randomized controlled trial.
Radiocarbon (14C or carbon-14, half-life 5730 yr) is a key radionuclide in the assessment of the safety of a geological disposal facility (GDF) for radioactive waste. In particular, the radiological impact of gaseous carbon-14 bearing species has been recognized as a potential issue. Irradiated steels are one of the main sources of carbon-14 in the United Kingdom’s radioactive waste inventory. However, there is considerable uncertainty about the chemical form(s) in which the carbon-14 will be released. The objective of the work was to measure the rate and speciation of carbon-14 release from irradiated 316L(N) stainless steel on leaching under high-pH anoxic conditions, representative of a cement-based near field for low-heat generating wastes. Periodic measurements of carbon-14 releases to both the gas phase and to solution were made in duplicate experiments over a period of up to 417 days. An initial fast release of carbon-14 from the surface of the steel is observed during the first week of leaching, followed by a drop in the rate of release at longer times. Carbon-14 is released primarily to the solution phase with differing fractions released to the gas phase in the two experiments: about 1% of the total release in one and 6% in the other. The predominant dissolved carbon-14 releases are in inorganic form (as 14C-carbonate) but also include organic species. The predominant gas-phase species are hydrocarbons with a smaller fraction of 14CO (which may include some volatile oxygen-containing carbon-species). The experiments are continuing, with final sampling and termination planned after leaching for a total of two years.
The OSU-FEI Electron Microscopy Collaboratory multiplies the number of individuals who can experience hands-on advanced microscopy techniques. The microscopy classroom allows up to 33 attendees to operate, individually and in real time, electron microscopes as if they were sitting in front of the actual instruments. The communications link, a fast backbone augmented by Internet2, allows various microscopes to be operated from the classroom or by collaborators in another city. This system transforms the training of new users from a one-person-at-a-time session with an expert operator to a group collaborative activity that can include users from around the world.
Hill (Twin Research and Human Genetics, Vol. 21, 2018, 84–88) presented a critique of our recently published paper in Cell Reports entitled ‘Large-Scale Cognitive GWAS Meta-Analysis Reveals Tissue-Specific Neural Expression and Potential Nootropic Drug Targets’ (Lam et al., Cell Reports, Vol. 21, 2017, 2597–2613). Specifically, Hill offered several interrelated comments suggesting potential problems with our use of a new analytic method called Multi-Trait Analysis of GWAS (MTAG) (Turley et al., Nature Genetics, Vol. 50, 2018, 229–237). In this brief article, we respond to each of these concerns. Using empirical data, we conclude that our MTAG results do not suffer from ‘inflation in the FDR [false discovery rate]’, as suggested by Hill (Twin Research and Human Genetics, Vol. 21, 2018, 84–88), and are not ‘more relevant to the genetic contributions to education than they are to the genetic contributions to intelligence’.
The Neotoma Paleoecology Database is a community-curated data resource that supports interdisciplinary global change research by enabling broad-scale studies of taxon and community diversity, distributions, and dynamics during the large environmental changes of the past. By consolidating many kinds of data into a common repository, Neotoma lowers costs of paleodata management, makes paleoecological data openly available, and offers a high-quality, curated resource. Neotoma’s distributed scientific governance model is flexible and scalable, with many open pathways for participation by new members, data contributors, stewards, and research communities. The Neotoma data model supports, or can be extended to support, any kind of paleoecological or paleoenvironmental data from sedimentary archives. Data additions to Neotoma are growing and now include >3.8 million observations, >17,000 datasets, and >9200 sites. Dataset types currently include fossil pollen, vertebrates, diatoms, ostracodes, macroinvertebrates, plant macrofossils, insects, testate amoebae, geochronological data, and the recently added organic biomarkers, stable isotopes, and specimen-level data. Multiple avenues exist to obtain Neotoma data, including the Explorer map-based interface, an application programming interface, the neotoma R package, and digital object identifiers. As the volume and variety of scientific data grow, community-curated data resources such as Neotoma have become foundational infrastructure for big data science.
Whether monozygotic (MZ) and dizygotic (DZ) twins differ from each other in a variety of phenotypes is important for genetic twin modeling and for inferences made from twin studies in general. We analyzed whether there were differences in individual, maternal and paternal education between MZ and DZ twins in a large pooled dataset. Information was gathered on individual education for 218,362 adult twins from 27 twin cohorts (53% females; 39% MZ twins), and on maternal and paternal education for 147,315 and 143,056 twins respectively, from 28 twin cohorts (52% females; 38% MZ twins). Together, we had information on individual or parental education from 42 twin cohorts representing 19 countries. The original education classifications were transformed to education years and analyzed using linear regression models. Overall, MZ males had 0.26 (95% CI [0.21, 0.31]) years and MZ females 0.17 (95% CI [0.12, 0.21]) years longer education than DZ twins. The zygosity difference became smaller in more recent birth cohorts for both males and females. Parental education was somewhat longer for fathers of DZ twins in cohorts born in 1990–1999 (0.16 years, 95% CI [0.08, 0.25]) and 2000 or later (0.11 years, 95% CI [0.00, 0.22]), compared with fathers of MZ twins. The results show that the years of both individual and parental education are largely similar in MZ and DZ twins. We suggest that the socio-economic differences between MZ and DZ twins are so small that inferences based upon genetic modeling of twin data are not affected.
To determine whether antimicrobial-impregnated textiles decrease the acquisition of pathogens by healthcare provider (HCP) clothing.
We completed a 3-arm randomized controlled trial to test the efficacy of 2 types of antimicrobial-impregnated clothing compared to standard HCP clothing. Cultures were obtained from each nurse participant, the healthcare environment, and patients during each shift. The primary outcome was the change in total contamination on nurse scrubs, measured as the sum of colony-forming units (CFU) of bacteria.
PARTICIPANTS AND SETTING
Nurses working in medical and surgical ICUs in a 936-bed tertiary-care hospital.
Nurse subjects wore standard cotton-polyester surgical scrubs (control), scrubs that contained a complex element compound with a silver-alloy embedded in its fibers (Scrub 1), or scrubs impregnated with an organosilane-based quaternary ammonium and a hydrophobic fluoroacrylate copolymer emulsion (Scrub 2). Nurse participants were blinded to scrub type and randomly participated in all 3 arms during 3 consecutive 12-hour shifts in the intensive care unit.
In total, 40 nurses were enrolled and completed 3 shifts. Analyses of 2,919 cultures from the environment and 2,185 from HCP clothing showed that scrub type was not associated with a change in HCP clothing contamination (P=.70). Mean difference estimates were 0.118 for the Scrub 1 arm (95% confidence interval [CI], −0.206 to 0.441; P=.48) and 0.009 for the Scrub 2 rm (95% CI, −0.323 to 0.342; P=.96) compared to the control. HCP became newly contaminated with important pathogens during 19 of the 120 shifts (16%).
Antimicrobial-impregnated scrubs were not effective at reducing HCP contamination. However, the environment is an important source of HCP clothing contamination.
Planktonic foraminifera first evolved in the middle Jurassic but did not experience a major radiation until the mid-Cretaceous. The mid-Barremian to late Aptian was characterized by a steady increase in species richness and by the appearance of new morphological forms including planispiral coiling, clavate and radially elongate chambers, and culminating in the first appearance of taxa with complex apertural structures and the keeled morphotype in late Aptian time. This broad interval of radiation was abruptly ended by evolutionary turnover and low diversification rates in the latest Aptian and early Albian prior to a second explosive episode of radiation in the middle and late Albian. The evolutionary history of mid-Cretaceous calcareous nannofossils generally parallels the trends observed in planktonic foraminifera, although the latest Aptian-early Albian turnover event is not as pronounced. Reef communities in the Caribbean/Gulf of Mexico and Mediterranean provinces show a change in dominance from coral-algal-rudist reefs in the Barremian-early Albian to rudist domiance by the late Albian time. These changes in calcareous plankton and reef communities are related to complex oceanographic changes of the mid-Cretaceous including structure of the upper water column, productivity, sea level, atmospheric and oceanographic circulation, and changes in the chemistry of the ocean.
Changes in eustatic sea level influenced many of these factors including nutrient delivery to the oceans, climate, sites and rates of deep water formation, and ocean chemistry. What is the relationship between changes in sea level, as expressed by major seismic sequence boundaries, and the changes observed in marine biota? We have compared major changes of eustatic sea level within this interval of generally rising global sea level (Scott et al., 1988), with equivalent sequence boundaries (Haq et al., 1988) and the records of calcareous plankton (Roth, 1987; Leckie, 1989) and reef communities (Scott, 1988). What is most striking about these relationships is the apparent lack of direct correlation between sequence boundaries and turnover events in the marine biota. The calcareous plankton alternate in phase between relatively high rates of diversification and low rates of diversification, with the major sequence boundaries falling within intervals of change rather than at intervals of change. However, we acknowledge the potential of missing or condensed intervals in deep sea settings which may influence the record of evolutionary rates (e.g., Loutit, et al., 1988). Only the basal Albian sequence boundary appears to correlate with a major turnover event in the planktonic foraminifera, and the rapid change in Gulf Coast reef communites between the middle and upper Albian may correlate with a eustatic sea level change and a major sequence boundary. Based on high-resolution calcareous nannofossil, planktonic foraminiferal, sedimentologic, and geochemical data of Bralower et al. (submitted), the lower Aptian, basal Albian, and lower upper Albian sequence boundaries appear to correlate more closely with widespread oceanic dysoxic/anoxic events OAE1a, OAE1b, and OAE1c, respectively. The correlations between evolutionary events, anoxic events, and sequence boundaries must be considered tentative at this time because major disparities exist between the correlation of calcareous plankton zones and mid-Cretaceous chronostratigraphic units used by Haq et al. (1988) and Bralower et al. (submitted).
Strategies that reduce the time to antimicrobial administration, such as the availability of premix antimicrobials (PMAs) in the emergency department (ED), may better align with the goals of the Surviving Sepsis Campaign and improve outcomes in septic patients. The objective of this study was to evaluate the impact of antimicrobial preparation on time to administration in septic patients located in the emergency department (ED).
This was a retrospective, single-center, cohort study and adult patients with a diagnosis of sepsis who received at least one initial intravenous (IV) antimicrobial in the ED were included. Time to complete an empiric antimicrobial therapy was defined as the time between prescriber order entry and the infusion initiation time of the final antimicrobial agent of a patient’s antimicrobial regimen. Appropriate, empiric antimicrobial therapy was based on treatment recommendations by nationally accepted guidelines for the specific indication.
The first antimicrobial was initiated earlier when available as a PMA preparation (median (IQR): premix 25 minutes (16.5-42.3) vs. non-premix 46 minutes (20-102), p=0.027). When comparing complete, empiric antimicrobial regimen administration, there was no difference in time to administration between regimens containing one or more non-premix antimicrobials and regimens containing all PMAs (median (IQR): premix 69 minutes (21-115) vs. non-premix 65 minutes (38.5-133.8); p=0.455).
PMA preparations significantly reduced time to administration of the first antimicrobial agent for septic patients treated in the ED, but time to administration of subsequent antimicrobials were not improved.
For the first time, valence electron energy-loss spectroscopy (VEELS) was applied to individual single-crystalline SnO2 nanowires to investigate the dielectric function, band gap, and optical absorption coefficient. The results are compared with data from optical techniques such as spectroscopic ellipsometry and UV-Vis, and theoretical calculations from variations of density functional theory. The data obtained agree well with the standard optical and theoretical techniques. The dielectric function and optical absorption coefficient are given up to 20 eV, which otherwise requires a synchrotron source and large single crystals via optical methods. The energy loss function is given up to 40 eV, which gives a useful comparison to previous theoretical studies in an energy range that cannot be achieved via optical measurements. The comparison gives confidence in the accuracy of this method for exploring spatially-resolved measurements in individual nanoparticles or more complex nanostructures that are otherwise difficult to measure accurately using optical techniques.
Given its positive relationship with valued organizational outcomes, worker-related engagement has become a prominent issue for practitioners and for scholars. While recent research has begun to validate various engagement antecedents and outcomes, little is known about the effects that work orientation and supportive leadership have on engagement, particularly among millennial workers, the soon to be dominant generational work group globally. To explore these gaps, we studied a particular form of work orientation – those indicating having a ‘calling’ – along with perceptions of how supportive leadership is for study subjects’ current work. Specifically, we posited positive worker engagement relationships for both worker calling and perceptions of leadership support, as well as for their interaction. Drawing upon a United States-based sample of 297 millennial workers, we found a positive relationship for each hypothesis. This study contributes to the expanding literature on the value of understanding how work orientation and leadership perceptions impact important organizational outcomes.
The luminosity of a spiral arm is believed to originate primarily in the very young, newly forming stars; and the spiral arm itself to be a spiral wave which is capable of triggering the formation of the young stars selectively along the wave crest. A semi-empirical study of the density wave patterns predicted in the density wave models of twenty-five external galaxies has been made and one result of this study is presented here. It is found that those galaxies of the sample whose models predict the possibility of strong shock waves are also the galaxies which exhibit long, well-developed spiral arms; and those galaxies whose models predict weak shock waves are also the galaxies which exhibit less-developed spiral structure. This trend is seen through a correlation between w⊥0, the velocity component of basic rotation normal to a spiral arm, which is an important parameter in determining the shock strength on the one hand, and luminosity class, which is a measure of the degree of development of spiral structure on the other.
Steady-state creep-rates of polycrystalline ice were investigated as a function of temperature, grain-size, and inclusion concentration through uniaxial compression in the laboratory. Samples were run at a constant load with the temperature systematically varied between about —5°C and —40°C. The presence of inclusions inhibits dynamic recrystallization and grain growth; the average crystal size produced by recrystallization is inversely proportional to the inclusion concentration. At temperatures above —8°C, creep-rate is enhanced by about a factor of two. This appears to be the result of the combined effects of recrystallization with accompanying grain growth and grain-boundary sliding. Over the temperature range —10°C to —40°C, the apparent activation energy for creep increases with increasing volume fraction of inclusions. This is apparently due to a thermally activated process which is modified by internal stresses created by the inclusions.