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Individuals with tardive dyskinesia (TD) who completed a long-term study (KINECT 3 or KINECT 4) of valbenazine (40 or 80 mg/day, once-daily for up to 48 weeks followed by 4-week washout) were enrolled in a subsequent study (NCT02736955) that was primarily designed to further evaluate the long-term safety of valbenazine.
Participants were initiated at 40 mg/day (following prior valbenazine washout). At week 4, dosing was escalated to 80 mg/day based on tolerability and clinical assessment of TD; reduction to 40 mg/day was allowed for tolerability. The study was planned for 72 weeks or until termination due to commercial availability of valbenazine. Assessments included the Clinical Global Impression of Severity-TD (CGIS-TD), Patient Satisfaction Questionnaire (PSQ), and treatment-emergent adverse events (TEAEs).
At study termination, 85.7% (138/161) of participants were still active. Four participants had reached week 60, and none reached week 72. The percentage of participants with a CGIS-TD score ≤2 (normal/not ill or borderline ill) increased from study baseline (14.5% [23/159]) to week 48 (64.3% [36/56]). At baseline, 98.8% (158/160) of participants rated their prior valbenazine experience with a PSQ score ≤2 (very satisfied or somewhat satisfied). At week 48, 98.2% (55/56) remained satisfied. Before week 4 (dose escalation), 9.4% of participants had ≥1 TEAE. After week 4, the TEAE incidence was 49.0%. No TEAE occurred in ≥5% of participants during treatment (before or after week 4).
Valbenazine was well-tolerated and persistent improvements in TD were found in adults who received once-daily treatment for >1 year.
Reconstructions of prehistoric vegetation composition help establish natural baselines, variability, and trajectories of forest dynamics before and during the emergence of intensive anthropogenic land use. Pollen–vegetation models (PVMs) enable such reconstructions from fossil pollen assemblages using process-based representations of taxon-specific pollen production and dispersal. However, several PVMs and variants now exist, and the sensitivity of vegetation inferences to PVM selection, variant, and calibration domain is poorly understood. Here, we compare the reconstructions, parameter estimates, and structure of a Bayesian hierarchical PVM, STEPPS, both to observations and to REVEALS, a widely used PVM, for the pre–Euro-American settlement-era vegetation in the northeastern United States (NEUS). We also compare NEUS-based STEPPS parameter estimates to those for the upper midwestern United States (UMW). Both PVMs predict the observed macroscale patterns of vegetation composition in the NEUS; however, reconstructions of minor taxa are less accurate and predictions for some taxa differ between PVMs. These differences can be attributed to intermodel differences in structure and parameter estimates. Estimates of pollen productivity from STEPPS broadly agree with estimates produced for use in REVEALS, while comparison between pollen dispersal parameter estimates shows no significant relationship. STEPPS parameter estimates are similar between the UMW and NEUS, suggesting that STEPPS parameter estimates are transferable between floristically similar regions and scales.
The diet of most adults is low in fish and, therefore, provides limited quantities of the long-chain, omega-3 fatty acids (LCn-3FAs), eicosapentaenoic and docosahexaenoic acids (EPA, DHA). Since these compounds serve important roles in the brain, we sought to determine if healthy adults with low-LCn-3FA consumption would exhibit improvements in neuropsychological performance and parallel changes in brain morphology following repletion through fish oil supplementation.
In a randomized, controlled trial, 271 mid-life adults (30–54 years of age, 118 men, 153 women) consuming ⩽300 mg/day of LCn-3FAs received 18 weeks of supplementation with fish oil capsules (1400 mg/day of EPA and DHA) or matching placebo. All participants completed a neuropsychological test battery examining four cognitive domains: psychomotor speed, executive function, learning/episodic memory, and fluid intelligence. A subset of 122 underwent neuroimaging before and after supplementation to measure whole-brain and subcortical tissue volumes.
Capsule adherence was over 95%, participant blinding was verified, and red blood cell EPA and DHA levels increased as expected. Supplementation did not affect performance in any of the four cognitive domains. Exploratory analyses revealed that, compared to placebo, fish oil supplementation improved executive function in participants with low-baseline DHA levels. No changes were observed in any indicator of brain morphology.
In healthy mid-life adults reporting low-dietary intake, supplementation with LCn-3FAs in moderate dose for moderate duration did not affect neuropsychological performance or brain morphology. Whether salutary effects occur in individuals with particularly low-DHA exposure requires further study.
Astrophysics Telescope for Large Area Spectroscopy Probe is a concept for a National Aeronautics and Space Administration probe-class space mission that will achieve ground-breaking science in the fields of galaxy evolution, cosmology, Milky Way, and the Solar System. It is the follow-up space mission to Wide Field Infrared Survey Telescope (WFIRST), boosting its scientific return by obtaining deep 1–4 μm slit spectroscopy for ∼70% of all galaxies imaged by the ∼2 000 deg2 WFIRST High Latitude Survey at z > 0.5. Astrophysics Telescope for Large Area Spectroscopy will measure accurate and precise redshifts for ∼200 M galaxies out to z < 7, and deliver spectra that enable a wide range of diagnostic studies of the physical properties of galaxies over most of cosmic history. Astrophysics Telescope for Large Area Spectroscopy Probe and WFIRST together will produce a 3D map of the Universe over 2 000 deg2, the definitive data sets for studying galaxy evolution, probing dark matter, dark energy and modifications of General Relativity, and quantifying the 3D structure and stellar content of the Milky Way. Astrophysics Telescope for Large Area Spectroscopy Probe science spans four broad categories: (1) Revolutionising galaxy evolution studies by tracing the relation between galaxies and dark matter from galaxy groups to cosmic voids and filaments, from the epoch of reionisation through the peak era of galaxy assembly; (2) Opening a new window into the dark Universe by weighing the dark matter filaments using 3D weak lensing with spectroscopic redshifts, and obtaining definitive measurements of dark energy and modification of General Relativity using galaxy clustering; (3) Probing the Milky Way’s dust-enshrouded regions, reaching the far side of our Galaxy; and (4) Exploring the formation history of the outer Solar System by characterising Kuiper Belt Objects. Astrophysics Telescope for Large Area Spectroscopy Probe is a 1.5 m telescope with a field of view of 0.4 deg2, and uses digital micro-mirror devices as slit selectors. It has a spectroscopic resolution of R = 1 000, and a wavelength range of 1–4 μm. The lack of slit spectroscopy from space over a wide field of view is the obvious gap in current and planned future space missions; Astrophysics Telescope for Large Area Spectroscopy fills this big gap with an unprecedented spectroscopic capability based on digital micro-mirror devices (with an estimated spectroscopic multiplex factor greater than 5 000). Astrophysics Telescope for Large Area Spectroscopy is designed to fit within the National Aeronautics and Space Administration probe-class space mission cost envelope; it has a single instrument, a telescope aperture that allows for a lighter launch vehicle, and mature technology (we have identified a path for digital micro-mirror devices to reach Technology Readiness Level 6 within 2 yr). Astrophysics Telescope for Large Area Spectroscopy Probe will lead to transformative science over the entire range of astrophysics: from galaxy evolution to the dark Universe, from Solar System objects to the dusty regions of the Milky Way.
OBJECTIVES/SPECIFIC AIMS: The objective of this study is to assess the efficacy of combined AF and NP repairs to prevent degenerative changes and restore native disc morphology in an in vivo large animal model. We hypothesize that combined repairs will prevent disc degeneration following injury to a greater extent than the individual repairs after 6 weeks in vivo, as demonstrated through disc height measurements and disc morphology. METHODS/STUDY POPULATION: A total of 8 skeletally mature female Finn sheep were used in this study. Following a previously described method, IVDs from L1 to L6 of the lumbar spine were exposed using a lateral access, extraperitoneal approach5. IVDs were randomized into 5 treatment groups: 1) intact discs, 2) discs injured via a 3 cm x 1 cm box annulotomy and partial nucleotomy, 3) injury followed by a high density collagen (HDC) AF patch, 4) injury followed by injection of a modified hyaluronic acid (HA) into the NP, and 5) injury followed by both the HDC AF patch and HA NP injection. The HDC treatment was 15 mg/mL type-I collagen mixed with 0.06mM riboflavin, injected at the defect site and crosslinked in situ with blue light. The NP injection was HA modified with C16 side chains to increase the viscosity of the hydrogel (HYADD 4®)6. At 6 weeks post-operatively, sheep were sacrificed and had 3T magnetic resonance images (MRI) taken of their lumbar spine. Disc height analysis and Pfirrmann grading were performed on each segment using MR images. Additionally, quantitative MRI analyses were performed using a custom MATLAB algorithm that segments NP from the surrounding tissue and directly measures the NP volume. ANOVA with Tukey’s HSD was used to determine statistical significance between groups for disc height and quantitative MRI analyses, and the Kruskal-Wallis test with Mann-Whitney tests was used to statistically analyze Pfirrmann Grades. All animal use followed approved IACUC protocol. RESULTS/ANTICIPATED RESULTS: As shown in axial MR images (Figure 1A), intact discs had hyperintense NP with a distinct border to the AF. The discs receiving injury with no treatment had hypointense NP with no distinct border between the AF and NP. Individual and combined treatment with the HA NP injection and HDC AF patch appeared to preserve the hyperintense NP signal and AF/NP border. Intact control discs were not degenerated and had an average Pfirrmann grade of 1 (Figure 1B), while injured, untreated discs had significant degeneration with an average Pfirrmann grade of 3. Discs receiving the HA NP injection and collagen AF patch individually showed fewer signs of degeneration than the injured alone, and the combined treatment resulted in the least amount of degeneration with Pfirrmann grades not significantly different than the intact controls. Disc height index confirmed the trends seen in the Pfirrmann grades (Figure 1C), where injured discs lost 20% of the intact disc height, the individual NP and AF repairs restored 5-10% of intact disc height, and the combined repairs preserved 90% of the intact disc height. The NP voxel count of all treatment groups were similar to the intact controls (Figure 1D). DISCUSSION/SIGNIFICANCE OF IMPACT: The objective of this study was to determine how combined AF and NP can prevent degenerative changes to the disc in a large animal in vivo model. Pfirrmann grading and disc height index results show that the greatest preservation of disc morphology was seen with combined AF and NP repairs, while the individual strategies prevented degenerative changes better than injury with no treatment. It appears the HA NP injection restores lost water content to the disc following injury, and the AF collagen patch plays a role in maintaining the NP repair within the disc. This is the first study to our knowledge to attempt combined AF and NP repairs in an in vivo large animal model. Combining NP and AF repairs leads to significantly improved outcomes following disc injury, which warrants the translation of combined repairs into the clinic to improve patient outcomes with degenerative disc disease involving NP and AF.
With more long-acting injectable (LAI) antipsychotics available for treating schizophrenia, each with variable durations of action (2 weeks to 3 months), it is important to have clear management strategies for patients developing breakthrough psychotic symptoms or experiencing symptomatic worsening on LAIs. However, no treatment guidelines or clinical practice pathways exist; health-care providers must rely on their own clinical judgment to manage these patients. This article provides practical recommendations—based on a framework of clinical, pharmacokinetic, and dosing considerations—to guide clinicians’ decisions regarding management of breakthrough psychotic symptoms. Management options include ruling out/addressing medical illness or substance abuse/misuse as a contributing factor, addressing stressors, optimizing nonpharmacologic treatments, treating medical/psychiatric comorbidities, ensuring proper LAI administration technique, addressing missed LAI doses or lack of steady-state attainment, and increasing LAI dose directly or indirectly by shortening the injection interval (off-label). If these strategies do not work sufficiently with frequent monitoring, the LAI could be supplemented with a low dose of the corresponding oral formulation for fast symptom control (off-label). However, caution should be exercised with this strategy, because data on the safety of concomitant use of LAI and oral antipsychotics (OAPs) are limited, especially over extended periods. If symptoms abate, therapy optimization could be continued and slow discontinuation of the OAP could be considered. For persistent/worsening symptoms, the OAP should be increased to optimum effective dose while intensifying the initial steps used before it was added. If this fails, switching the OAP or LAI could be considered. We believe that these strategies will help clinicians manage breakthrough psychotic symptoms during LAI treatment and improve overall outcomes among those who can benefit from LAIs.
Infants with prenatally diagnosed CHD are at high risk for adverse outcomes owing to multiple physiologic and psychosocial factors. Lack of immediate physical postnatal contact because of rapid initiation of medical therapy impairs maternal–infant bonding. On the basis of expected physiology, maternal–infant bonding may be safe for select cardiac diagnoses.
This is a single-centre study to assess safety of maternal–infant bonding in prenatal CHD.
In total, 157 fetuses with prenatally diagnosed CHD were reviewed. On the basis of cardiac diagnosis, 91 fetuses (58%) were prenatally approved for bonding and successfully bonded, 38 fetuses (24%) were prenatally approved but deemed not suitable for bonding at delivery, and 28 (18%) were not prenatally approved to bond. There were no complications attributable to bonding. Those who successfully bonded were larger in weight (3.26 versus 2.6 kg, p<0.001) and at later gestation (39 versus 38 weeks, p<0.001). Those unsuccessful at bonding were more likely to have been delivered via Caesarean section (74 versus 49%, p=0.011) and have additional non-cardiac diagnoses (53 versus 29%, p=0.014). There was no significant difference regarding the need for cardiac intervention before hospital discharge. Infants who bonded had shorter hospital (7 versus 26 days, p=0.02) and ICU lengths of stay (5 versus 23 days, p=0.002) and higher survival (98 versus 76%, p<0.001).
Fetal echocardiography combined with a structured bonding programme can permit mothers and infants with select types of CHD to successfully bond before ICU admission and intervention.
The Pueblo population of Chaco Canyon during the Bonito Phase (AD 800–1130) employed agricultural strategies and water-management systems to enhance food cultivation in this unpredictable environment. Scepticism concerning the timing and effectiveness of this system, however, remains common. Using optically stimulated luminescence dating of sediments and LiDAR imaging, the authors located Bonito Phase canal features at the far west end of the canyon. Additional ED-XRF and strontium isotope (87Sr/86Sr) analyses confirm the diversion of waters from multiple sources during Chaco’s occupation. The extent of this water-management system raises new questions about social organisation and the role of ritual in facilitating responses to environmental unpredictability.
Based on the data from the Next Generation Virgo cluster Survey (NGVS), we statistically study the photometric properties of globular clusters (GCs), ultra-compact dwarfs (UCDs) and dwarf nuclei in the Virgo core (M87) region. We found an obvious negative color (g - z) gradient in GC system associate with M87, i.e. GCs in the outer regions are bluer. However, such color gradient does not exist in UCD system, neither in dwarf nuclei system around M87. In addition, we found that many UCDs are surrounded by extended, low surface brightness envelopes. The dwarf nuclei and UCDs show different spatial distributions from GCs, with dwarf nuclei and UCDs (especially for the UCDs with visible envelopes) lying at larger distances to the Virgo center. These results support the view that UCDs (at least for a fraction of UCDs) are more tied to dwarf nuclei than to GCs.