Development and application of an assay for uranyl complexation by fungal metabolites, including siderophores

An assay to detect UO2 2+ complexation was developed based on the chrome azurol S (CAS) assay for siderophores (B. Schwyn and J. B. Neilands, Anal. Biochem. 160:47-56, 1987) and was used to investigate the ability of fungal metabolites to complex actinides. In this assay the discoloration of two dyed agars (one containing a CAS-Fe3+ dye and the other containing a CAS-UO2 2+ dye) caused by ligands was quantified. The assay was tested by using the siderophore desferrioxamine B (DFO), and the results showed that there was a regular, reproducible relationship between discoloration and the amount of siderophore added. The ratio of the discoloration on the CAS-UO2 2+ agar to the discoloration on the CAS-Fe3+ agar was independent of the amount of siderophore added. A total of 113 fungi and yeasts were isolated from three soil samples taken from the Peak District National Park. The fungi were screened for the production of UO2 2+ chelators by using the CAS-based assay and were also tested specifically for hydroxamate siderophore production by using the hydroxamate siderophore auxotroph Aureobacterium flavescens JG-9. This organism is highly sensitive to the presence of hydroxamate siderophores. However, the CAS-based assay was found to be less sensitive than the A. flavescens JG-9 assay. No significant difference between the results for each site for the two tests was found. Three isolates were selected for further study and were identified as two Pencillium species and a Mucor species. Our results show that the new assay can be effectively used to screen fungi for the production of UO2 2+ chelating ligands. We suggest that hydroxamate siderophores can be produced by mucoraceous fungi

Cost-effectiveness of monitoring ocular hypertension based on a risk prediction tool

Background/Aims To assess the cost-effectiveness of making treatment decisions for patients with ocular hypertension (OHT) based on a risk prediction (RP) tool in the United Kingdom. Methods A discrete event simulation model was constructed to compare the cost-effectiveness of an alternative care pathway in which the treatment decision was guided by a validated RP tool in secondary care against decision-making based on the standard care (SC). Individual patient sampling was used. Patients diagnosed with OHT and with an intraocular pressure of 24 mm Hg or over entered the model with a set of predefined individual characteristics related to their risk of conversion to glaucoma. These characteristics were retrieved from electronic medical records (n=5740). Different stages of glaucoma were modelled following conversion to glaucoma. Results Almost all (99%) patients were treated using the RP strategy, and less than half (47%) of the patients were treated using the SC strategy. The RP strategy produced higher cost but also higher quality-adjusted life years (QALYs) than the SC strategy. The RP strategy was cost-effective compared with the SC strategy in the base-case analysis, with an incremental cost-effectiveness ratio value of £11 522. The RP strategy had a 96% probability of being cost-effective under a £20 000 per QALY threshold. Conclusions The use of an RP tool for the management of patients with OHT is likely to be cost-effective. However, the generalisability of the result might be limited due to the high-risk nature of this cohort and the specific RP threshold used in the study

Computerised adaptive testing across the paranoia continuum

Background: To drive improvement in clinical services, an important innovation will be to regularly assess patients’ psychotic experiences in order to guide, monitor, and, when needed, alter treatment provision. The great heterogeneity in presentations of psychosis means that a comprehensive assessment battery is impractical. A plausible solution is computerised adaptive testing (CAT), which uses real-time computation to present the most informative questions to an individual. Fewer questions are needed to reach similar precision as a full questionnaire. Objective: We tested the potential of a CAT for paranoia to halve the number of items that need to be presented. Methods: We used the established item response theory psychometric properties of the 10-item Revised Green et al Paranoid Thoughts Scale (Persecution) to run CAT simulations in four datasets in which participants had completed the full scale: a representative survey of 10,382 UK adults; a clinical trial with 319 patients with psychosis; a cohort study of 836 NHS male patients with psychosis; and a clinical trial with 89 patients with persecutory delusions. The CAT algorithm used the graded response model and the test was concluded when the standard error of estimation dropped below 0.3 or five items had been answered. Findings: On average the CAT administered 4.2, 4.0, 4.2, and 4.0 items to each person in the four datasets. The correlations between the CAT score and the full-scale paranoia score were 0.95, 0.94, 0.94, 0.87. Minimal systematic error in paranoia estimation occurred (mean bias scores = -0.01, - 0.06, -0.07, -0.10). Estimation was least precise for people at the boundary of normal and elevated levels of paranoia. Conclusions: In datasets with people across the whole paranoia continuum, accurate estimates of paranoia can be provided by a CAT with fewer than half the items of the full scale. Tailored testing may work well with people with psychosis. Clinical implications: Computerised adaptive testing may be a way to implement informative measurement-based care in psychosis services

Rabies Encephalitis in Malaria-Endemic Area, Malawi, Africa

In a malaria-endemic area of Africa, rabies was an important cause of fatal central nervous system infection, responsible for 14 (10.5%) of 133 cases. Four patients had unusual clinical manifestations, and rabies was only diagnosed postmortem. Three (11.5%) of 26 fatal cases were originally attributed to cerebral malaria

Multisite randomised controlled trial of a novel dialogical therapy in comparison to treatment as usual in adults with distressing and persistent auditory hallucinations: study protocol for the Talking With Voices (TWV-II) trial

Background: Hearing voices (“auditory hallucinations”) is associated with numerous negative outcomes, including hospitalisation, suicidality, and impaired functioning. Currently, the main treatment approaches are antipsychotic medication and cognitive behavioural therapy (CBT), yet both have variable effectiveness and are often unavailable to those without a schizophrenia diagnosis. Furthermore, CBT does not consistently address the role of trauma in voice onset and maintenance. In response to these unmet needs, a feasibility/acceptability trial of a new intervention, Talking With Voices (TWV), was conducted. TWV involves a therapist speaking to the voice(s) while the client repeats its response verbatim, with the aim of promoting recovery and reducing voice-related distress. This prior pilot study (N = 50) found excellent feasibility/acceptability data amongst participants with schizophrenia, and signals of positive change in measures of personal recovery and voice relating. The next step is to evaluate treatment mechanisms and clinical efficacy of TWV in a transdiagnostic population. Methods: We aim to establish TWV’s clinical efficacy in a multisite RCT for adults with serious mental health problems (SMHP) who hear persistent, distressing voices, and to assess whether improved measures of personal recovery and negative voice impact are mediated via key psychological mechanisms (improved relating to, and beliefs about, voices; and reductions in dissociation and negative self-beliefs). We aim to recruit 296 participants from psychiatric services across 4 UK sites (Manchester, London, Newcastle, and Oxford) who will be randomised to either treatment (TWV + treatment as usual [TAU]) or control (TAU only). The primary outcome is total score on the Questionnaire About the Process of Recovery. Secondary outcomes include overall voice severity and other relevant dimensions of voices and trauma sequalae, with mediational and outcome variables collected at baseline, 8 months (post-treatment), and 14 months. Discussion: The study will investigate the clinical efficacy of a novel intervention deliverable within healthcare services, including hypothesised mechanisms of change to identify key psychological targets for ameliorating distressing voices in a transdiagnostic population. Potential benefits include improving the effectiveness and accessibility of evidence-based psychosocial interventions for SMHP. Trial registration: ISRCTN, ISRCTN15897915. Registered 13 July 2023

Pathogenicity and immunogenicity of attenuated, nef-deleted HIV-1 strains in vivo

In efforts to develop an effective vaccine, sterilizing immunity to primate lentiviruses has only been achieved by the use of live attenuated viruses carrying major deletions in nef and other accessory genes. Although live attenuated HIV vaccines are unlikely to be developed due to a myriad of safety concerns, opportunities exist to better understand the correlates of immune protection against HIV infection by studying rare cohorts of long-term survivors infected with attenuated, nef-deleted HIV strains such as the Sydney blood bank cohort (SBBC). Here, we review studies of viral evolution, pathogenicity, and immune responses to HIV infection in SBBC members. The studies show that potent, broadly neutralizing anti-HIV antibodies and robust CD8+ T-cell responses to HIV infection were not necessary for long-term control of HIV infection in a subset of SBBC members, and were not sufficient to prevent HIV sequence evolution, augmentation of pathogenicity and eventual progression of HIV infection in another subset. However, a persistent T-helper proliferative response to HIV p24 antigen was associated with long-term control of infection. Together, these results underscore the importance of the host in the eventual outcome of infection. Thus, whilst generating an effective antibody and CD8+ T-cell response are an essential component of vaccines aimed at preventing primary HIV infection, T-helper responses may be important in the generation of an effective therapeutic vaccine aimed at blunting chronic HIV infection

Prednisolone or tetracosactide depot for infantile epileptic spasms syndrome? A prospective analysis of data embedded within two randomised controlled trials

OBJECTIVE: To report a prospectively planned analysis of two randomised controlled trials with embedded comparisons of prednisolone versus tetracosactide depot for the treatment of infantile epileptic spasms syndrome (IESS). METHODS: Individual patient data from patients randomly allocated to prednisolone or tetracosactide depot were analysed from two trials (UKISS, ICISS). The comparison was embedded within trials in which some patients also received vigabatrin but only patients receiving monotherapy with randomly allocated hormonal treatments are included in this analysis. The main outcome was cessation of spasms (Days 13-14 after randomisation). Lead time to treatment and underlying aetiology were taken into account. Cessation of spasms on Days 14-42 inclusive, electroclinical response (EEG Day 14), plus developmental and epilepsy outcomes (at 14 months in UKISS and 18 months in ICISS) are also reported. Minimum treatment was prednisolone 40 mg per day for two weeks or tetracosactide depot 0·5 mg IM on alternate days for two weeks, all followed by a reducing dose of prednisolone over two weeks. RESULTS: 126 infants were included in this study. On tetracosactide depot, 47 of 62 (76%) were free of spasms on Days 13-14 compared to 43 of 64 (67%) on prednisolone (difference 9%, 95% CI -7·2% to +25·2%, chi square 1·15, p = 0·28). For Day 14-42 cessation of spasms, on tetracosactide depot, 41 of 61 (67%) were free of spasms compared to 35 of 62 (56%) on prednisolone (difference 11%, 95% CI -6·4% to +28·4%, chi square 1·51, p = 0·22). There was no significant difference in mean VABS score between infants who received prednisolone compared with those who received tetracosactide depot (74·8 (SD 18·3) versus 78·0 (SD 20·2) t = -0·91 p = 0·36). The proportion with ongoing epilepsy at the time of developmental assessment was 20 of 61 (33%) in the tetracosactide group compared with 26 out of 63 (41%) in the prednisolone group (difference 8%, 95% CI -9·2% to +25·2%, Chi [2] 0·95, p = 0·33). SIGNIFICANCE: With hormone monotherapy, either prednisolone or tetracosactide depot may be recommended for infantile epileptic spasms syndrome

Assignment of epidemiological lineages in an emerging pandemic using the pangolin tool.

Funder: Oxford Martin School, University of OxfordThe response of the global virus genomics community to the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic has been unprecedented, with significant advances made towards the 'real-time' generation and sharing of SARS-CoV-2 genomic data. The rapid growth in virus genome data production has necessitated the development of new analytical methods that can deal with orders of magnitude of more genomes than previously available. Here, we present and describe Phylogenetic Assignment of Named Global Outbreak Lineages (pangolin), a computational tool that has been developed to assign the most likely lineage to a given SARS-CoV-2 genome sequence according to the Pango dynamic lineage nomenclature scheme. To date, nearly two million virus genomes have been submitted to the web-application implementation of pangolin, which has facilitated the SARS-CoV-2 genomic epidemiology and provided researchers with access to actionable information about the pandemic's transmission lineages