A revised edition of the readiness to change questionnaire (treatment version)

The UK Alcohol Treatment Trial provided an opportunity to examine the factor structure of the Readiness to Change Questionnaire-Treatment Version (RCQ[TV]) in a large sample (N = 742) of individuals in treatment for alcohol problems who were given the RCQ[TV] at baseline, 3-months and 12-months follow-up. Confirmatory factor analysis of the previously reported factor structure (5 items for each of Precontemplation, Contemplation and Action scales) resulted in a relatively poor fit to the data. Removal of one item from each of the scales resulted in a 12-item instrument for which goodness-of-fit indices were improved, without loss of internal consistency of the three scales, on all three measurement occasions. Inspection of relationships between stage allocation by the new instrument and negative alcohol outcome expectancies provided evidence of improved construct validity for the revised edition of the RCQ[TV]. There was also a strong relationship between stage allocation at 3-months follow-up and outcome of treatment at 12 months. The revised edition of the RCQ[TV] offers researchers and clinicians a shorter and improved measurement of stage of change in the alcohol treatment population

A transcriptomics-based drug repositioning approach to identify drugs with similar activities for the treatment of muscle pathologies in spinal muscular atrophy (SMA) models

© 2023 The Author(s). Published by Oxford University Press. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY), https://creativecommons.org/licenses/by/4.0/Spinal muscular atrophy (SMA) is a genetic neuromuscular disorder caused by the reduction of survival of motor neuron (SMN) protein levels. Although three SMN-augmentation therapies are clinically approved that significantly slow down disease progression, they are unfortunately not cures. Thus, complementary SMN-independent therapies that can target key SMA pathologies and that can support the clinically approved SMN-dependent drugs are the forefront of therapeutic development. We have previously demonstrated that prednisolone, a synthetic glucocorticoid (GC) improved muscle health and survival in severe Smn-/-;SMN2 and intermediate Smn2B/- SMA mice. However, long-term administration of prednisolone can promote myopathy. We thus wanted to identify genes and pathways targeted by prednisolone in skeletal muscle to discover clinically approved drugs that are predicted to emulate prednisolone's activities. Using an RNA-sequencing, bioinformatics, and drug repositioning pipeline on skeletal muscle from symptomatic prednisolone-treated and untreated Smn-/-; SMN2 SMA and Smn+/-; SMN2 healthy mice, we identified molecular targets linked to prednisolone's ameliorative effects and a list of 580 drug candidates with similar predicted activities. Two of these candidates, metformin and oxandrolone, were further investigated in SMA cellular and animal models, which highlighted that these compounds do not have the same ameliorative effects on SMA phenotypes as prednisolone; however, a number of other important drug targets remain. Overall, our work further supports the usefulness of prednisolone's potential as a second-generation therapy for SMA, identifies a list of potential SMA drug treatments and highlights improvements for future transcriptomic-based drug repositioning studies in SMA.Peer reviewe

A posteriori inclusion of parton density functions in NLO QCD final-state calculations at hadron colliders: The APPLGRID Project

A method to facilitate the consistent inclusion of cross-section measurements based on complex final-states from HERA, TEVATRON and the LHC in proton parton density function (PDF) fits has been developed. This can be used to increase the sensitivity of LHC data to deviations from Standard Model predictions. The method stores perturbative coefficients of NLO QCD calculations of final-state observables measured in hadron colliders in look-up tables. This allows the posteriori inclusion of parton density functions (PDFs), and of the strong coupling, as well as the a posteriori variation of the renormalisation and factorisation scales in cross-section calculations. The main novelties in comparison to original work on the subject are the use of higher-order interpolation, which substantially improves the trade-off between accuracy and memory use, and a CPU and computer memory optimised way to construct and store the look-up table using modern software tools. It is demonstrated that a sufficient accuracy on the cross-section calculation can be achieved with reasonably small look-up table size by using the examples of jet production and electro-weak boson (Z, W) production in proton-proton collisions at a center-of-mass energy of 14 TeV at the LHC. The use of this technique in PDF fitting is demonstrated in a PDF-fit to HERA data and simulated LHC jet cross-sections as well as in a study of the jet cross-section uncertainties at various centre-of-mass energies

Human prefrontal cortex gene regulatory dynamics from gestation to adulthood at single-cell resolution.

Human brain development is underpinned by cellular and molecular reconfigurations continuing into the third decade of life. To reveal cell dynamics orchestrating neural maturation, we profiled human prefrontal cortex gene expression and chromatin accessibility at single-cell resolution from gestation to adulthood. Integrative analyses define the dynamic trajectories of each cell type, revealing major gene expression reconfiguration at the prenatal-to-postnatal transition in all cell types followed by continuous reconfiguration into adulthood and identifying regulatory networks guiding cellular developmental programs, states, and functions. We uncover links between expression dynamics and developmental milestones, characterize the diverse timing of when cells acquire adult-like states, and identify molecular convergence from distinct developmental origins. We further reveal cellular dynamics and their regulators implicated in neurological disorders. Finally, using this reference, we benchmark cell identities and maturation states in organoid models. Together, this captures the dynamic regulatory landscape of human cortical development.This work was supported by the following grants: R.L.—National Health and Medical Research Council (NHMRC) Project Grant 1130168, NHMRC Investigator Grant 1178460, Silvia and Charles Viertel Senior Medical Research Fellowship, Howard Hughes Medical Institute International Research Scholarship, and Australian Research Council (ARC) LE170100225; S.F.—NHMRC Ideas Grant 1184421; I.V.—ARC Future Fellowship FT170100359, UNSW Scientia Fellowship, and NHMRC Project Grant RG170137; S.B.—NHMRC-ARC Dementia Research Development Fellowship 1111206; C.P.—Raine Foundation Priming Grant RPG66-21; J.M.P.—Silvia and Charles Viertel Senior Medical Research Fellowship, ARC Future Fellowship FT180100674. This work was supported by a Cancer Research Trust grant ‘‘Enabling advanced single cell cancer genomics in WA’’ and Cancer Council WA enabling grant. Genomic data were generated at the ACRF Centre for Advanced Cancer Genomics and Genomics WA. Human brain tissue was received from the UMB Brain and Tissue Bank at the University of Maryland, part of the NIH NeuroBioBank. The glioblastoma sample was procured and provided by the AGOG biobank, funded by CINSW grant SRP-08-10. L.M. was a fellow of The Lorenzo and Pamela Galli Medical Research Trust. We thank Ankur Sharma and Greg Neely for valuable feedback. The graphical abstract and elements of Figure 1A were created with BioRender.S

Peddling a semiotics of fear: a critical examination of scare tactics and commercial strategies in public health promotion

This study critically examines the ways in which the nationwide Diabetes UK/Tesco public health promotion campaign (2013-2014) sought to raise awareness of Type 2 diabetes. Conducting a multimodal critical discourse analysis of six campaign images, we identify the presence of fear-inducing, stigmatising and commercial strategies, through which the campaign emphasises the dangers of diabetes and advocates personal responsibility for assessing both individual and others’ risk of the disease. Specifically, three discursive techniques are deployed in this campaign to achieve these ends: (1) the depiction of grief and amplification of diabetes-related danger, (2) the promotion of diabetes risk and responsibilization of individuals for their health, and (3) the commercial branding and framing of the Diabetes UK/Tesco partnership as providing tools for diabetes prevention and management. Our findings raise concerns about the moral legitimacy of using fear-inducing and commercial strategies in public health campaigns, strategies which do little to address the environmental factors which are associated with increasing rates of the disease

Modern microwave methods in solid state inorganic materials chemistry: from fundamentals to manufacturing

No abstract available

Attribution of multi-annual to decadal changes in the climate system: The Large Ensemble Single Forcing Model Intercomparison Project (LESFMIP)

Multi-annual to decadal changes in climate are accompanied by changes in extreme events that cause major impacts on society and severe challenges for adaptation. Early warnings of such changes are now potentially possible through operational decadal predictions. However, improved understanding of the causes of regional changes in climate on these timescales is needed both to attribute recent events and to gain further confidence in forecasts. Here we document the Large Ensemble Single Forcing Model Intercomparison Project that will address this need through coordinated model experiments enabling the impacts of different external drivers to be isolated. We highlight the need to account for model errors and propose an attribution approach that exploits differences between models to diagnose the real-world situation and overcomes potential errors in atmospheric circulation changes. The experiments and analysis proposed here will provide substantial improvements to our ability to understand near-term changes in climate and will support the World Climate Research Program Lighthouse Activity on Explaining and Predicting Earth System Change.publishedVersio

Rationale and design of the Multidisciplinary Approach to Novel Therapies in Cardiology Oncology Research Trial (MANTICORE 101 - Breast): a randomized, placebo-controlled trial to determine if conventional heart failure pharmacotherapy can prevent trastuzumab-mediated left ventricular remodeling among patients with HER2+ early breast cancer using cardiac MRI

<p>Abstract</p> <p>Background</p> <p>MANTICORE 101 - Breast (Multidisciplinary Approach to Novel Therapies in Cardiology Oncology Research) is a randomized trial to determine if conventional heart failure pharmacotherapy (angiotensin converting enzyme inhibitor or beta-blocker) can prevent trastuzumab-mediated left ventricular remodeling, measured with cardiac MRI, among patients with HER2+ early breast cancer.</p> <p>Methods/Design</p> <p>One hundred and fifty-nine patients with histologically confirmed HER2+ breast cancer will be enrolled in a parallel 3-arm, randomized, placebo controlled, double-blind design. After baseline assessments, participants will be randomized in a 1:1:1 ratio to an angiotensin-converting enzyme inhibitor (perindopril), beta-blocker (bisoprolol), or placebo. Participants will receive drug or placebo for 1 year beginning 7 days before trastuzumab therapy. Dosages for all groups will be systematically up-titrated, as tolerated, at 1 week intervals for a total of 3 weeks. The primary objective of this randomized clinical trial is to determine if conventional heart failure pharmacotherapy can prevent trastuzumab-mediated left ventricular remodeling among patients with HER2+ early breast cancer, as measured by 12 month change in left ventricular end-diastolic volume using cardiac MRI. Secondary objectives include 1) determine the evolution of left ventricular remodeling on cardiac MRI in patients with HER2+ early breast cancer, 2) understand the mechanism of trastuzumab mediated cardiac toxicity by assessing for the presence of myocardial injury and apoptosis on serum biomarkers and cardiac MRI, and 3) correlate cardiac biomarkers of myocyte injury and extra-cellular matrix remodeling with left ventricular remodeling on cardiac MRI in patients with HER2+ early breast cancer.</p> <p>Discussion</p> <p>Cardiac toxicity as a result of cancer therapies is now recognized as a significant health problem of increasing prevalence. To our knowledge, MANTICORE will be the first randomized trial testing proven heart failure pharmacotherapy in the prevention of trastuzumab-mediated cardiotoxicity. We expect the findings of this trial to provide important evidence in the development of guidelines for preventive therapy.</p> <p>Trial Registration</p> <p>ClinicalTrials.gov: <a href="http://www.clinicaltrials.gov/ct2/show/NCT01016886">NCT01016886</a></p

Adjunctive rifampicin to reduce early mortality from Staphylococcus aureus bacteraemia: the ARREST RCT.

BACKGROUND: Staphylococcus aureus bacteraemia is a common and frequently fatal infection. Adjunctive rifampicin may enhance early S. aureus killing, sterilise infected foci and blood faster, and thereby reduce the risk of dissemination, metastatic infection and death. OBJECTIVES: To determine whether or not adjunctive rifampicin reduces bacteriological (microbiologically confirmed) failure/recurrence or death through 12 weeks from randomisation. Secondary objectives included evaluating the impact of rifampicin on all-cause mortality, clinically defined failure/recurrence or death, toxicity, resistance emergence, and duration of bacteraemia; and assessing the cost-effectiveness of rifampicin. DESIGN: Parallel-group, randomised (1 : 1), blinded, placebo-controlled multicentre trial. SETTING: UK NHS trust hospitals. PARTICIPANTS: Adult inpatients (≥ 18 years) with meticillin-resistant or susceptible S. aureus grown from one or more blood cultures, who had received < 96 hours of antibiotic therapy for the current infection, and without contraindications to rifampicin. INTERVENTIONS: Adjunctive rifampicin (600-900 mg/day, oral or intravenous) or placebo for 14 days in addition to standard antibiotic therapy. Investigators and patients were blinded to trial treatment. Follow-up was for 12 weeks (assessments at 3, 7, 10 and 14 days, weekly until discharge and final assessment at 12 weeks post randomisation). MAIN OUTCOME MEASURES: The primary outcome was all-cause bacteriological (microbiologically confirmed) failure/recurrence or death through 12 weeks from randomisation. RESULTS: Between December 2012 and October 2016, 758 eligible participants from 29 UK hospitals were randomised: 370 to rifampicin and 388 to placebo. The median age was 65 years [interquartile range (IQR) 50-76 years]. A total of 485 (64.0%) infections were community acquired and 132 (17.4%) were nosocomial; 47 (6.2%) were caused by meticillin-resistant S. aureus. A total of 301 (39.7%) participants had an initial deep infection focus. Standard antibiotics were given for a median of 29 days (IQR 18-45 days) and 619 (81.7%) participants received flucloxacillin. By 12 weeks, 62 out of 370 (16.8%) patients taking rifampicin versus 71 out of 388 (18.3%) participants taking the placebo experienced bacteriological (microbiologically confirmed) failure/recurrence or died [absolute risk difference -1.4%, 95% confidence interval (CI) -7.0% to 4.3%; hazard ratio 0.96, 95% CI 0.68 to 1.35; p = 0.81]. There were 4 (1.1%) and 5 (1.3%) bacteriological failures (p = 0.82) in the rifampicin and placebo groups, respectively. There were 3 (0.8%) versus 16 (4.1%) bacteriological recurrences (p = 0.01), and 55 (14.9%) versus 50 (12.9%) deaths without bacteriological failure/recurrence (p = 0.30) in the rifampicin and placebo groups, respectively. Over 12 weeks, there was no evidence of differences in clinically defined failure/recurrence/death (p = 0.84), all-cause mortality (p = 0.60), serious (p = 0.17) or grade 3/4 (p = 0.36) adverse events (AEs). However, 63 (17.0%) participants in the rifampicin group versus 39 (10.1%) participants in the placebo group experienced antibiotic or trial drug-modifying AEs (p = 0.004), and 24 (6.5%) participants in the rifampicin group versus 6 (1.5%) participants in the placebo group experienced drug-interactions (p = 0.0005). Evaluation of the costs and health-related quality-of-life impacts revealed that an episode of S. aureus bacteraemia costs an average of £12,197 over 12 weeks. Rifampicin was estimated to save 10% of episode costs (p = 0.14). After adjustment, the effect of rifampicin on total quality-adjusted life-years (QALYs) was positive (0.004 QALYs), but not statistically significant (standard error 0.004 QALYs). CONCLUSIONS: Adjunctive rifampicin provided no overall benefit over standard antibiotic therapy in adults with S. aureus bacteraemia. FUTURE WORK: Given the substantial mortality, other antibiotic combinations or improved source management should be investigated. TRIAL REGISTRATIONS: Current Controlled Trials ISRCTN37666216, EudraCT 2012-000344-10 and Clinical Trials Authorisation 00316/0243/001. FUNDING: This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 22, No. 59. See the NIHR Journals Library website for further project information.NIHR HTA Programm