Multivariate Tie-breaker Designs

In a tie-breaker design (TBD), subjects with high values of a running variable are given some (usually desirable) treatment, subjects with low values are not, and subjects in the middle are randomized. TBDs are intermediate between regression discontinuity designs (RDDs) and randomized controlled trials (RCTs) by allowing a tradeoff between the resource allocation efficiency of an RDD and the statistical efficiency of an RCT. We study a model where the expected response is one multivariate regression for treated subjects and another for control subjects. For given covariates, we show how to use convex optimization to choose treatment probabilities that optimize a D-optimality criterion. We can incorporate a variety of constraints motivated by economic and ethical considerations. In our model, D-optimality for the treatment effect coincides with D-optimality for the whole regression, and without economic constraints, an RCT is globally optimal. We show that a monotonicity constraint favoring more deserving subjects induces sparsity in the number of distinct treatment probabilities and this is different from preexisting sparsity results for constrained designs. We also study a prospective D-optimality, analogous to Bayesian optimal design, to understand design tradeoffs without reference to a specific data set. We apply the convex optimization solution to a semi-synthetic example involving triage data from the MIMIC-IV-ED database

Social identification, identity integration and wellbeing in people who hear voices

Objectives Hearing voices is associated with public stigma and this can influence readiness to identify as a voice hearer (VH) and psychological wellbeing. In this study, we investigated the relationships between a VH social identity, the integration of that identity with other important social identities and wellbeing. Design Cross-sectional study, with a subset of longitudinal data across three time points. Methods People who self-identified as voice hearers completed questionnaires (VH social identity, identity integration, wellbeing and perceptions of in-group and out-group empathy) at three time points, spaced at 3-monthly intervals. The final sample comprised 182 participants at T1, 91 at T2 and 75 at T3. Hierarchical linear multiple regression analyses were used to test all hypotheses. Results The integration of a VH social identity was strongly associated with better psychological wellbeing at T1. Identity integration was also associated with static wellbeing scores at 6 months. Effects on wellbeing were not accounted for by either severity of voice-hearing or paranoia. Whilst perceptions of in-group empathy were associated with VH social identification, perceptions of outgroup empathy were important for identity integration. Conclusions Integrating a VH social identity with other important identities into a coherent sense of self is important for wellbeing in voice hearers; perceived in-group and outgroup empathy are important in this process

Anti-parasitic benzoxaboroles are ineffective against Theileria parva in vitro

East Coast Fever (ECF) is a disease affecting cattle in sub-Saharan Africa, caused by the tick-borne Apicomplexan pathogen Theileria parva. The disease is a major problem for cattle farmers in affected regions and there are few methods of control, including a complex infection and treatment vaccine, expensive chemotherapy, and the more widespread tick control through acaricides. New intervention strategies are, therefore, sorely needed. Benzoxaboroles are a versatile class of boron-heterocyclic compounds with demonstrable pharmacological activity against a diverse group of pathogens, including those related to T. parva. In this study, the in vitro efficacy of three benzoxaboroles against the intracellular schizont stage of T. parva was investigated using a flow cytometry approach. Of the benzoxaboroles tested, only one showed any potency, albeit only at high concentrations, even though there is high protein sequence similarity in the CPSF3 protein target compared to other protozoan pathogen species. This finding suggests that benzoxaboroles currently of interest for the treatment of African animal trypanosomiasis, toxoplasmosis, cryptosporidiosis and malaria may not be suitable for the treatment of ECF. We conclude that testing of further benzoxaborole compounds is needed to fully determine whether any lead compounds can be identified to target T. parva

Diminazene resistance in Trypanosoma congolense is not caused by reduced transport capacity but associated with reduced mitochondrial membrane potential

Trypanosoma congolense is a principal agent causing livestock trypanosomiasis in Africa, costing developing economies billions of dollars and undermining food security. Only the diamidine diminazene and the phenanthridine isometamidium are regularly used, and resistance is widespread but poorly understood. We induced stable diminazene resistance in T. congolense strain IL3000 in vitro. There was no cross‐resistance with the phenanthridine drugs, melaminophenyl arsenicals, oxaborole trypanocides, or with diamidine trypanocides, except the close analogues DB829 and DB75. Fluorescence microscopy showed that accumulation of DB75 was inhibited by folate. Uptake of [3H]‐diminazene was slow, low affinity and partly but reciprocally inhibited by folate and by competing diamidines. Expression of T. congolense folate transporters in diminazene‐resistant T. b. brucei significantly sensitized the cells to diminazene and DB829, but not to oxaborole AN7973. However, [3H]‐diminazene transport studies, whole genome sequencing and RNA‐seq found no major changes in diminazene uptake, folate transporter sequence or expression. Instead, all resistant clones displayed a moderate reduction in the mitochondrial membrane potential. We conclude that diminazene uptake in T. congolense proceed via multiple low affinity mechanisms including folate transporters; while resistance is associated with a reduction in Ψm it is unclear whether this is the primary cause of the resistance

Targeting dissociation using cognitive behavioural therapy in voice hearers with psychosis and a history of interpersonal trauma: A case series

From Wiley via Jisc Publications RouterHistory: received 2020-01-23, rev-recd 2020-07-27, pub-electronic 2020-09-10, pub-print 2021-06Article version: VoRPublication status: PublishedAbstract: Objectives: Previous studies have suggested that dissociation might represent an important mechanism in the maintenance of auditory verbal hallucinations (i.e., voices) in people who have a history of traumatic life experiences. This study investigated whether a cognitive behavioural therapy (CBT) intervention for psychosis augmented with techniques specifically targeting dissociative symptoms could improve both dissociation and auditory hallucination severity in a sample of voice hearers with psychosis and a history of interpersonal trauma (e.g., exposure to sexual, physical, and/or emotional abuse). Design: Case series. Methods: A total of 19 service users with psychosis were offered up to 24 therapy sessions over a 6‐month intervention window. Participants were assessed four times over a 12‐month period using measures of dissociation, psychotic symptoms severity, and additional secondary mental‐health and recovery measures. Results: Sixteen participants engaged in the intervention and were included in last‐observation‐carried‐forward analyses. Dropout rates were in line with those of other CBT for psychosis trials (26.3%). Repeated measures ANOVAs revealed large and significant improvements in dissociation (drm = 1.23) and hallucination severity (drm = 1.09) by the end of treatment; treatment gains were maintained 6 months following the end of therapy. Large and statistically significant gains were also observed on measures of post‐traumatic symptoms, delusion severity, emotional distress, and perceived recovery from psychosis. Conclusions: The findings of this case series suggest that the reduction of dissociation represents a valuable and acceptable treatment target for clients with auditory verbal hallucinations and a trauma history. Future clinical trials might benefit from considering targeting dissociative experiences as part of psychological interventions for distressing voices. Practitioner points: Practitioners should consider the role of dissociation when assessing and formulating the difficulties of voice hearers with a history of trauma. Techniques to reduce dissociation can be feasibly integrated within psychological interventions for voices. Voice hearers with histories of trauma can benefit from psychological interventions aimed at reducing dissociation

LSST: from Science Drivers to Reference Design and Anticipated Data Products

(Abridged) We describe here the most ambitious survey currently planned in the optical, the Large Synoptic Survey Telescope (LSST). A vast array of science will be enabled by a single wide-deep-fast sky survey, and LSST will have unique survey capability in the faint time domain. The LSST design is driven by four main science themes: probing dark energy and dark matter, taking an inventory of the Solar System, exploring the transient optical sky, and mapping the Milky Way. LSST will be a wide-field ground-based system sited at Cerro Pach\'{o}n in northern Chile. The telescope will have an 8.4 m (6.5 m effective) primary mirror, a 9.6 deg$^2$ field of view, and a 3.2 Gigapixel camera. The standard observing sequence will consist of pairs of 15-second exposures in a given field, with two such visits in each pointing in a given night. With these repeats, the LSST system is capable of imaging about 10,000 square degrees of sky in a single filter in three nights. The typical 5$\sigma$ point-source depth in a single visit in $r$ will be $\sim 24.5$ (AB). The project is in the construction phase and will begin regular survey operations by 2022. The survey area will be contained within 30,000 deg$^2$ with $\delta<+34.5^\circ$, and will be imaged multiple times in six bands, $ugrizy$, covering the wavelength range 320--1050 nm. About 90\% of the observing time will be devoted to a deep-wide-fast survey mode which will uniformly observe a 18,000 deg$^2$ region about 800 times (summed over all six bands) during the anticipated 10 years of operations, and yield a coadded map to $r\sim27.5$. The remaining 10\% of the observing time will be allocated to projects such as a Very Deep and Fast time domain survey. The goal is to make LSST data products, including a relational database of about 32 trillion observations of 40 billion objects, available to the public and scientists around the world.Comment: 57 pages, 32 color figures, version with high-resolution figures available from https://www.lsst.org/overvie

Divergent metabolism between Trypanosoma congolense and Trypanosoma brucei results in differential sensitivity to metabolic inhibition

Animal African Trypanosomiasis (AAT) is a debilitating livestock disease prevalent across sub-Saharan Africa, a main cause of which is the protozoan parasite Trypanosoma congolense. In comparison to the well-studied T. brucei, there is a major paucity of knowledge regarding the biology of T. congolense. Here, we use a combination of omics technologies and novel genetic tools to characterise core metabolism in T. congolense mammalian-infective bloodstream-form parasites, and test whether metabolic differences compared to T. brucei impact upon sensitivity to metabolic inhibition. Like the bloodstream stage of T. brucei, glycolysis plays a major part in T. congolense energy metabolism. However, the rate of glucose uptake is significantly lower in bloodstream stage T. congolense, with cells remaining viable when cultured in concentrations as low as 2 mM. Instead of pyruvate, the primary glycolytic endpoints are succinate, malate and acetate. Transcriptomics analysis showed higher levels of transcripts associated with the mitochondrial pyruvate dehydrogenase complex, acetate generation, and the glycosomal succinate shunt in T. congolense, compared to T. brucei. Stable-isotope labelling of glucose enabled the comparison of carbon usage between T. brucei and T. congolense, highlighting differences in nucleotide and saturated fatty acid metabolism. To validate the metabolic similarities and differences, both species were treated with metabolic inhibitors, confirming that electron transport chain activity is not essential in T. congolense. However, the parasite exhibits increased sensitivity to inhibition of mitochondrial pyruvate import, compared to T. brucei. Strikingly, T. congolense exhibited significant resistance to inhibitors of fatty acid synthesis, including a 780-fold higher EC50 for the lipase and fatty acid synthase inhibitor Orlistat, compared to T. brucei. These data highlight that bloodstream form T. congolense diverges from T. brucei in key areas of metabolism, with several features that are intermediate between bloodstream- and insect-stage T. brucei. These results have implications for drug development, mechanisms of drug resistance and host-pathogen interactions

The ATP-Binding Cassette Proteins of the Deep-Branching Protozoan Parasite Trichomonas vaginalis

The ATP binding cassette (ABC) proteins are a family of membrane transporters and regulatory proteins responsible for diverse and critical cellular process in all organisms. To date, there has been no attempt to investigate this class of proteins in the infectious parasite Trichomonas vaginalis. We have utilized a combination of bioinformatics, gene sequence analysis, gene expression and confocal microscopy to investigate the ABC proteins of T. vaginalis. We demonstrate that, uniquely among eukaryotes, T. vaginalis possesses no intact full-length ABC transporters and has undergone a dramatic expansion of some ABC protein sub-families. Furthermore, we provide preliminary evidence that T. vaginalis is able to read through in-frame stop codons to express ABC transporter components from gene pairs in a head-to-tail orientation. Finally, with confocal microscopy we demonstrate the expression and endoplasmic reticulum localization of a number of T. vaginalis ABC transporters

The state of the Martian climate

60°N was +2.0°C, relative to the 1981–2010 average value (Fig. 5.1). This marks a new high for the record. The average annual surface air temperature (SAT) anomaly for 2016 for land stations north of starting in 1900, and is a significant increase over the previous highest value of +1.2°C, which was observed in 2007, 2011, and 2015. Average global annual temperatures also showed record values in 2015 and 2016. Currently, the Arctic is warming at more than twice the rate of lower latitudes