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Valbenazine is a highly selective vesicular monoamine transporter 2 inhibitor indicated for tardive dyskinesia (TD), a persistent and potentially debilitating movement disorder associated with prolonged antipsychotic exposure. Given the paucity of data regarding the course of TD in patients no longer taking antipsychotics, a meta-analysis of 3 long-term valbenazine studies was conducted in subgroups with and without concomitant antipsychotic use at baseline.
Methods
KINECTTM-3 (NCT02274558), KINECTTM-4 (NCT02405091), and JKINECT (NCT03176771) data were analyzed in study completers taking antipsychotics at baseline (AP+) and those who were not (AP-). The Abnormal Involuntary Movement Scale (AIMS) total score was used to measure TD severity at baseline, Wk48 (end of valbenazine treatment), and Wk52 (4 weeks after valbenazine withdrawal). The meta-analysis implemented a random-effects model that weighted each study based on inverse variance, adjusted for between-study variance.
Results
Of 576 enrolled patients, 336 (58.3%) were study completers and included for analysis: AP+ (n=269); AP- (n=67). Mean baseline AIMS scores ranged from 7.9–14.9 (AP+) and 10.9–14.5 (AP-). Mean changes from baseline in AIMS scores indicated substantial TD improvements with valbenazine at Wk48 (AP+, 6.1; AP-, -6.5) and return towards baseline severity at Wk52 (AP+, -2.1; AP-, -1.4).
Conclusions
Once-daily valbenazine treatment resulted in substantial and sustained TD improvement through Wk48, with no meaningful differences between AP+ and AP- subgroups. The return towards baseline severity after valbenazine withdrawal shows TD is chronic and often irreversible, even in patients no longer taking antipsychotics. Continuous treatment with valbenazine may be warranted irrespective of antipsychotic therapy.
By applying a general procedure for analyzing a correlation coefficient into components, the lens model equation is extended to a) analyze the effects of different types of variation and b) analyze the relations between judgmental systems that are not based on the same set of cues.
Generalized Baumslag-Solitar groups are a class of combinatorially interesting groups. Their group theory is also closely associated to a the topology of a class of 2-dimensional spaces. These 2-dimensional spaces are Seifert fibred. We develop the basic topology of these fibrations and derive some of the most immediate group theoretic consequences of this topology.
This survey article has two components. The first part gives a gentle introduction to Serres notion of $G$-complete reducibility, where $G$ is a connected reductive algebraic group defined over an algebraically closed field. The second part concerns consequences of this theory when $G$ is simple of exceptional type, specifically its role in elucidating the subgroup structure of $G$. The latter subject has a history going back about sixty years. We give an overview of what is known, up to the present day. We also take the opportunity to offer several corrections to the literature.
Every four years leading researchers gather to survey the latest developments in all aspects of group theory. Since 1981, the proceedings of these meetings have provided a regular snapshot of the state of the art in group theory and helped to shape the direction of research in the field. This volume contains selected papers from the 2022 meeting held in Newcastle. It includes substantial survey articles from the invited speakers, namely the mini course presenters Michel Brion, Fanny Kassel and Pham Huu Tiep; and the invited one-hour speakers Bettina Eick, Scott Harper and Simon Smith. It features these alongside contributed survey articles, including some new results, to provide an outstanding resource for graduate students and researchers.
Bioturbation can increase time averaging by downward and upward movements of young and old shells within the entire mixed layer and by accelerating the burial of shells into a sequestration zone (SZ), allowing them to bypass the uppermost taphonomically active zone (TAZ). However, bioturbation can increase shell disintegration concurrently, neutralizing the positive effects of mixing on time averaging. Bioirrigation by oxygenated pore-water promotes carbonate dissolution in the TAZ, and biomixing itself can mill shells weakened by dissolution or microbial maceration, and/or expose them to damage at the sediment–water interface. Here, we fit transition rate matrices to bivalve age–frequency distributions from four sediment cores from the southern California middle shelf (50–75 m) to assess the competing effects of bioturbation on disintegration and time averaging, exploiting a strong gradient in rates of sediment accumulation and bioturbation created by historic wastewater pollution. We find that disintegration covaries positively with mixing at all four sites, in accord with the scenario where bioturbation ultimately fuels carbonate disintegration. Both mixing and disintegration rates decline abruptly at the base of the 20- to 40-cm-thick, age-homogenized surface mixed layer at the three well-bioturbated sites, despite different rates of sediment accumulation. In contrast, mixing and disintegration rates are very low in the upper 25 cm at an effluent site with legacy sediment toxicity, despite recolonization by bioirrigating lucinid bivalves. Assemblages that formed during maximum wastewater emissions vary strongly in time averaging, with millennial scales at the low-sediment accumulation non-effluent sites, a centennial scale at the effluent site where sediment accumulation was high but bioturbation recovered quickly, and a decadal scale at the second high-sedimentation effluent site where bioturbation remained low for decades. Thus, even though disintegration rates covary positively with mixing rates, reducing postmortem shell survival, bioturbation has the net effect of increasing the time averaging of skeletal remains on this warm-temperate siliciclastic shelf.
Increasing volumes of information are being collected via electronic health records and there is growing multi-site expertise in utlising these for research. This emerging field of healthcare data science is not only concerned with the technical challenges associated with complex data, but also with the need for effective security and governance in the use of sensitive information with robust structures for stakeholder input and guidance. To date, most of the focus has been on supporting observational cohort studies nested within clinical records data - particularly investigating research questions around treatment response and course/prognosis. It is likely that electronic health records will become increasingly integrated with clinical trials, providing opportunities for pre-study feasibility scoping, targeted recruitment, and enhanced and extended follow-up. In addition, there is interest in emulated trials using routine data. For mental health data science, key challenges lie in the quality and quantity of data made accessible, with a particular need for natural language processing to derive structured data from extensive clinical text. Many of the challenges have been addressed for observational research, creating exciting prospects for a transformed trials landscape.
Disclosure of Interest
R. Stewart Grant / Research support from: Janssen, GSK, Takeda
We show that, in some ranked ballot elections, it may be possible to violate the secret vote. There are so many ways to rank even a handful of candidates that many possible rankings might not be cast by any voter. So, a vote buyer could pay someone to rank the candidates a certain way and then use the announced election results to verify that the voter followed through. We examine the feasibility of this attack both theoretically and empirically, focusing on instant runoff voting (IRV). Although many IRV elections have few enough candidates that this scheme is not feasible, we use data from San Francisco and a proposed election rule change in Oakland to show that some important IRV elections can have large numbers of unused rankings. There is no evidence that this vote-buying scheme has ever been used. However, its existence has implications for the administration and security of IRV elections. This scheme is more feasible when more candidates can be ranked in the election and when the election results report all the ways that candidates were ranked.
Lithofacies and biostratigraphical analysis has enabled the establishment of a stratigraphic event framework for Ludfordian and Pridoli strata in south Wales and the Welsh Borderland. In SW Wales, the Golden Grove Axis acted as a structural hinge separating the shallow marine storm-influenced Cae’r mynach Seaway from a pediment surface above which Ludfordian colluvium (Abercyfor Formation) was deposited. The Axis seeded four NW-derived river-influenced delta progrades of Leintwardinian to early Pridoli age (Tilestones Formation). A NE-sourced early Pridoli wave-influenced delta deposited the Downton Castle Sandstone Formation (DCSF), coeval to the youngest Tilestones prograde, with a lateral interface existing between Mynydd Epynt and the Clun Forest area. Except for the Malverns area, the DCSF is no longer recognized south of the Neath Disturbance. Early Pridoli forced regression promoted widespread subaerial exposure north of the Neath Disturbance, with incision into tracts close to the Welsh Borderland Fault System. The basinward-shift in facies belts resulted in marine erosion and deposition of a phosphatic ravinement pebble lag. The wave-influenced Clifford’s Mesne Sandstone Formation delta subsequently seeded on the Gorsley Axis with tidally influenced Rushall Formation accumulating in a back-barrier setting. The Pwll-Mawr Formation records the easterly advance of coeval coastal deposits on the western side of the remnant Cae’r mynach Seaway. Behind migrating delta coastlines, green muds accumulated on coastal plains (Temeside Mudstone Formation) with better drained red dryland alluvium (Moor Cliffs Formation) charting expansion of Old Red Sandstone lithofacies. Mid-Pridoli incision preserves the Pont ar Llechau Formation estuarine valley fill.
Cognitive behavioural therapy (CBT) is an empirically supported treatment for generalized anxiety disorder (GAD). Little is known about the effectiveness of CBT for GAD in real-world treatment settings.
Aim:
This study investigated the effectiveness of group CBT and predictors of treatment response in an out-patient hospital clinic.
Method:
Participants (n = 386) with GAD participated in 12 sessions of group CBT at an out-patient clinic. Of those who provided at least partial data (n = 326), 84.5% completed treatment. Most questionnaires were completed at pre- and post-treatment; worry severity was assessed weekly.
Results:
Group CBT led to improvements in chronic worry (d = –0.91, n = 118), depressive symptoms (d = –1.22, n = 172), GAD symptom severity (d = –0.65, n = 171), intolerance of uncertainty (IU; d = –0.46, n = 174) and level of functional impairment (d = –0.35, n = 169). Greater pre-treatment GAD symptom severity (d = –0.17, n = 293), chronic worry (d = –0.20, n = 185), functional impairment (d = –0.12, n = 292), and number of comorbid diagnoses (d = –0.13, n = 299) predicted greater improvement in past week worry over treatment. Biological sex, age, depression symptom severity, number of treatment sessions attended, and IU did not predict change in past week worry over time.
Discussion:
These findings provide support for the effectiveness of group CBT for GAD and suggest the outcomes are robust and are either not impacted or are slightly positively impacted by several demographic and clinical factors.
Phase three trials of the monoclonal antibodies lecanemab and donanemab, which target brain amyloid, have reported statistically significant differences in clinical end-points in early Alzheimer's disease. These drugs are already in use in some countries and are going through the regulatory approval process for use in the UK. Concerns have been raised about the ability of healthcare systems, including those in the UK, to deliver these treatments, considering the resources required for their administration and monitoring.
Aims
To estimate the scale of real-world demand for monoclonal antibodies for Alzheimer's disease in the UK.
Method
We used anonymised patient record databases from two National Health Service trusts for the year 2019 to collect clinical, demographic, cognitive and neuroimaging data for these cohorts. Eligibility for treatment was assessed using the inclusion criteria from the clinical trials of donanemab and lecanemab, with consideration given to diagnosis, cognitive performance, cerebrovascular disease and willingness to receive treatment.
Results
We examined the records of 82 386 people referred to services covering around 2.2 million people. After applying the trial criteria, we estimate that a maximum of 906 people per year would start treatment with monoclonal antibodies in the two services, equating to 30 200 people if extrapolated nationally.
Conclusions
Monoclonal antibody treatments for Alzheimer's disease are likely to present a significant challenge for healthcare services to deliver in terms of the neuroimaging and treatment delivery. The data provided here allows health services to understand the potential demand and plan accordingly.
The Jamaican flower bat Phyllonycteris aphylla is categorized as Critically Endangered on the IUCN Red List. It is endemic to Jamaica and formerly known only from Stony Hill Cave, where there are an estimated c. 500 individuals. Previously declared extinct twice, its rediscovery in 2010 at Stony Hill Cave marked new hope for the conservation of this important species. Although little is known about its ecology, the species is presumed to be a cave-obligate rooster and to rely exclusively on so-called hot caves, which are defined by high ambient temperatures and low air quality. In March–April 2023, we surveyed bats at seven caves throughout Jamaica. At two of these, Green Grotto Caves, St. Ann, and Rock Spring Caverns, St. Mary, we captured both male and pregnant female P. aphylla. At Green Grotto Caves, we captured 24 P. aphylla, and 66 at Rock Spring Caverns. We believe Rock Spring Caverns to be one of the largest known roosts of P. aphylla. Neither of these sites are hot caves as both are moderated by flowing water, although warmer chambers may be more important to this bat than to other species. Further monitoring of these populations and continued exploration of other potential roosts are vital for the protection of this species.
Annual bluegrass is a troublesome weed in turfgrass, with reported resistance to at least 12 herbicide sites of action. The mitotic-inhibiting herbicide pronamide has both preemergence and postemergence activity on susceptible annual bluegrass populations. Previous studies suggest that postemergence activity may be compromised due to lack of root uptake, as well as target-site- and translocation-based mechanisms. Research was conducted to determine the effects of spray droplet spectra on spray coverage and control of annual bluegrass with pronamide, flazasulfuron, and a mixture of pronamide plus flazasulfuron. Herbicides were delivered to annual bluegrass plants having two to three leaves via five different spray spectra based on volume median diameters (VMD) of 200, 400, 600, 800, and 1,000 µm. Fluorescent tracer dye was added to each treatment solution to quantify the effects of herbicide and spray droplet spectra on herbicide deposition. In another experiment, the efficacy of 0.58, 1.16, and 2.32 kg pronamide ha−1; 0.022, 0.044, and 0.088 kg flazasulfuron ha−1, or a combination of the two, were assessed in iteration with droplet spectrum sprays of 400 and 1,000 µm on two pronamide-resistant and two pronamide-susceptible annual bluegrass populations. Spray droplet spectrum affected the deposition of pronamide and flazasulfuron, applied alone and in combination. Pronamide foliar deposition decreased with increasing droplet spectra. Pronamide efficacy was affected by droplet spectrum, with the largest (1,000 µm) exhibiting improved control. Flazasulfuron efficacy and pronamide plus flazasulfuron efficacy were not affected by droplet spectra. Pronamide plus flazasulfuron mixture controlled all four populations more effectively than pronamide alone, regardless of droplet spectra. A mixture of pronamide plus flazasulfuron applied with relatively large droplets may be optimal for annual bluegrass control, which offers valuable insights for optimizing herbicide application and combatting herbicide resistance. However, applications in this controlled-growth pot study may not mimic conditions in which thatch and turfgrass canopy limit the soil deposition of pronamide.
This book uses qualitative longitudinal data, from repeat interviews with people subject to compulsion and sanction in their everyday lives, to analyse the effectiveness and ethicality of welfare conditionality in promoting and sustaining behaviour change in the UK.