Mixed-methods feasibility outcomes for a novel ACT-based video game 'ACTing Minds' to support mental health.

OBJECTIVES: To determine the feasibility and acceptability of 'ACTing Minds', a novel single-player adventure video game based on acceptance and commitment therapy (ACT). DESIGN: A single-arm, mixed-methods repeated measures feasibility study. SETTING: Intervention and questionnaires were completed at home by participants. Semistructured interviews were also conducted at home via the Zoom platform. PARTICIPANTS: Thirty-six participants were recruited into the study, 29 completed all phases of the feasibility design. Eligibility criteria required participants to be over the age of 18 and self-reporting experiencing ongoing depression, anxiety or stress. INTERVENTION: Participants completed a single session of the 'ACTing Minds' video game, lasting approximately 1 hour, designed to educate users on key principles from ACT. PRIMARY OUTCOME MEASURES: Participant recruitment and retention, questionnaire completion, long-term intervention adherence and acceptability of the intervention. Reflexive thematic analysis was conducted on semistructured interviews run immediately postintervention and 3 weeks later. SECONDARY OUTCOME MEASURES: Measures of depression, anxiety, stress, psychological flexibility, social connectedness and well-being were assessed at baseline, immediately following intervention completion, and after a 3-week follow-up period. We used a standardised battery of questionnaires. PRIMARY RESULTS: Twenty-nine participants completed the study. A reflexive thematic analysis indicated that participants responded positively to the intervention and the study at all stages. Themes reflect participants' desire for an engaging therapeutic experience, use of game for exploring emotions, as well as their perspectives on how they had applied their learning to the real world. SECONDARY RESULTS: Quantitative results indicated small to large effect sizes associated with decreases in depression (ηp2 = 0.011), anxiety (ηp2 = 0.096) and stress (ηp2 = 0.108), and increases in psychological flexibility (ηp2 = 0.060), social connectedness (ηp2 = 0.021), well-being (ηp2 = 0.011) and participation in usual activities (ηp2 = .307). CONCLUSIONS: Implementation of the 'ACTing Minds' intervention is warranted, based on both qualitative and quantitative outcomes. TRIAL REGISTRATION NUMBER: NCT04566042 ClinicalTrials.gov.

Susceptibility of pediatric acute lymphoblastic leukemia to STAT3 inhibition depends on p53 induction.

Advances in the clinical management of pediatric B-cell acute lymphoblastic leukemia (B-ALL) have dramatically improved outcomes for this disease. However, relapsed and high-risk disease still contribute to significant numbers of treatment failures. Development of new, broad range therapies is urgently needed for these cases. We previously reported the susceptibility of ETV6-RUNX1+ pediatric B-ALL to inhibition of signal transducer and activator of transcription 3 (STAT3) activity. In the present study, we demonstrate that pharmacological or genetic inhibition of STAT3 results in p53 induction and that CRISPR-mediated TP53 knockout substantially reverses susceptibility to STAT3 inhibition. Furthermore, we demonstrate that sensitivity to STAT3 inhibition in patient-derived xenograft (PDX) B-ALL samples is not restricted to any particular disease subtype, but rather depends on TP53 status, the only resistant samples being TP53 mutant. Induction of p53 following STAT3 inhibition is not directly dependent on MDM2 but correlates with degradation of MDM4. As such, STAT3 inhibition exhibits synergistic in vitro and in vivo anti-leukemia activity when combined with MDM2 inhibition. Taken together with the relatively low frequency of TP53 mutations in this disease, these data support the future development of combined STAT3/ MDM2 inhibition in the therapy of refractory and relapsed pediatric B-ALL.

Structure-Guided Design and Synthesis of a Pyridazinone Series of Trypanosoma cruzi Proteasome Inhibitors.

There is an urgent need for new treatments for Chagas disease, a parasitic infection which mostly impacts South and Central America. We previously reported on the discovery of GSK3494245/DDD01305143, a preclinical candidate for visceral leishmaniasis which acted through inhibition of the Leishmania proteasome. A related analogue, active against Trypanosoma cruzi, showed suboptimal efficacy in an animal model of Chagas disease, so alternative proteasome inhibitors were investigated. Screening a library of phenotypically active analogues against the T. cruzi proteasome identified an active, selective pyridazinone, the development of which is described herein. We obtained a cryo-EM co-structure of proteasome and a key inhibitor and used this to drive optimization of the compounds. Alongside this, optimization of the absorption, distribution, metabolism, and excretion (ADME) properties afforded a suitable compound for mouse efficacy studies. The outcome of these studies is discussed, alongside future plans to further understand the series and its potential to deliver a new treatment for Chagas disease.

Applying an osteopathic intervention to improve mild to moderate mental health symptoms: a mixed-methods feasibility study protocol.

INTRODUCTION: Mental health services are stretched in the UK and are in need of support. One approach that could improve mental health symptoms is osteopathy. Research suggests that osteopathy influences psychophysiological factors, which could lead to improvements in mental health. The first objective of this protocol is to investigate the feasibility and acceptability of four osteopathic interventions. A secondary aim is to evaluate the interventions' effectiveness for improving psychophysiological and mental health outcomes. METHODS AND ANALYSIS: This study will be an explanatory mixed-methods design. Participants will be 30 adults who have mild to moderate mental health symptoms and not experiencing any issues with pain. The feasibility and acceptability of the interventions will be the primary outcomes. Secondary outcomes will be physiological measures including heart rate variability, interoceptive accuracy and blood pressure. Psychological outcomes, collected preintervention and postintervention, will also be measured by five standardised questionnaires, which include: (1) the Depression, Anxiety and Stress Scale (DASS); (2) the International Positive and Negative Affect Schedule-Short-Form; (3) Acceptance and Action Questionnaire-II; (4) the Self as Context Scale and (5) and the Multidimensional Assessment of Interoceptive Awareness Version 2. Participants will be randomised to one of four intervention groups and receive a single intervention treatment session. These intervention groups are: (1) high-velocity and articulation techniques, (2) soft-tissue massage, (3) craniosacral techniques, and (4) a combination of these three approaches. Mixed design two (preintervention and postintervention) by the four interventions analysis of covariance models will be used to analyse the quantitative data for each quantitative measure. Participants will also be interviewed about their experiences of the study and interventions and a thematic analysis will be used to analyse this qualitative data. This will aid the assessment of the feasibility and acceptability of the study design. ETHICS AND DISSEMINATION: The protocol for this feasibility study has received ethical approval from the Department of Psychology Ethics Committee at Swansea University, ethical review reference number: 2022-5603-4810. Feasibility results from this protocol will be published in a peer review journal and presented at both national and international conferences. DISCUSSION: This study will assess the feasibility and acceptability of conducting osteopathic interventions for improving mental health outcomes. The results from this will help to inform the development of a future randomised controlled trial. The study will also produce original data which could provide preliminary evidence of whether osteopathic approaches are of benefit to individual's mental health in the form of effect sizes, even if they are pain-free. TRIAL REGISTRATION NUMBER: NCT05674071.

Functional contextual implementation of an evolutionary, entropy-based, and embodied free energy framework: Utilizing Lagrangian mechanics and evolutionary game theory's truth vs. fitness test of the veridicality of phenomenological experience.

The Bayesian approach of cognitive science largely takes the position that evolution drives perception to produce precepts that are veridical. However, some efforts utilizing evolutionary game theory simulations have shown that perception is more likely based on a fitness function, which promotes survival rather than promoting perceptual truth about the environment. Although these findings do not correspond well with the standard Bayesian approach to cognition, they may correspond with a behavioral functional contextual approach that is ontologically neutral (a-ontological). This approach, formalized through a post-Skinnerian account of behaviorism called relational frame theory (RFT), can, in fact, be shown to correspond well with an evolutionary fitness function, whereby contextual functions form that corresponds to a fitness function interface of the world. This fitness interface approach therefore may help provide a mathematical description for a functional contextual interface of phenomenological experience. Furthermore, this more broadly fits with a neurological active inference approach based on the free-energy principle (FEP) and more broadly with Lagrangian mechanics. These assumptions of how fitness beats truth (FBT) and FEP correspond to RFT are then discussed within a broader multidimensional and evolutionary framework called the extended evolutionary meta-model (EEMM) that has emerged out of the functional contextual behavioral science literature to incorporate principles of cognition, neurobiology, behaviorism, and evolution and are discussed in the context of a novel RFT framework called "Neurobiological and Natural Selection Relational Frame Theory" (N-frame). This framework mathematically connects RFT to FBT, FEP, and EEMM within a single framework that expands into dynamic graph networking. This is then discussed for its implications of empirical work at the non-ergodic process-based idiographic level as applied to individual and societal level dynamic modeling and clinical work. This discussion is framed within the context of individuals that are described as evolutionary adaptive and conscious (observer-self) agents that minimize entropy and can promote a prosocial society through group-level values and psychological flexibility.

Going beyond the DSM in predicting, diagnosing, and treating autism spectrum disorder with covarying alexithymia and OCD: A structural equation model and process-based predictive coding account.

Background: There is much overlap among the symptomology of autistic spectrum disorders (ASDs), obsessive compulsive disorders (OCDs), and alexithymia, which all typically involve impaired social interactions, repetitive impulsive behaviors, problems with communication, and mental health. Aim: This study aimed to identify direct and indirect associations among alexithymia, OCD, cardiac interoception, psychological inflexibility, and self-as-context, with the DV ASD and depression, while controlling for vagal related aging. Methodology: The data involved electrocardiogram (ECG) heart rate variability (HRV) and questionnaire data. In total, 1,089 participant's data of ECG recordings of healthy resting state HRV were recorded and grouped into age categories. In addition to this, another 224 participants completed an online survey that included the following questionnaires: Yale-Brown Obsessive Compulsive Scale (Y-BOCS); Toronto Alexithymia Scale 20 (TAS-20); Acceptance and Action Questionnaire (AAQII); Depression, Anxiety, and Stress Scale 21 (DAS21); Multi-dimensional Assessment of Interoceptive Awareness Scale (MAIA); and the Self-as-Context Scale (SAC). Results: Heart rate variability was shown to decrease with age when controlling for BMI and gender. In the two SEMs produced, it was found that OCD and alexithymia were causally associated with autism and depression indirectly through psychological inflexibility, SAC, and ISen interoception. Conclusion: The results are discussed in relation to the limitations of the DSM with its categorical focus of protocols for syndromes and provide support for more flexible ideographic approaches in diagnosing and treating mental health and autism within the Extended Evolutionary Meta-Model (EEMM). Graph theory approaches are discussed in their capacity to depict the processes of change potentially even at the level of the relational frame.

High-Throughput Screening Platform To Identify Inhibitors of Protein Synthesis with Potential for the Treatment of Malaria.

Artemisinin-based combination therapies have been crucial in driving down the global burden of malaria, the world's largest parasitic killer. However, their efficacy is now threatened by the emergence of resistance in Southeast Asia and sub-Saharan Africa. Thus, there is a pressing need to develop new antimalarials with diverse mechanisms of action. One area of Plasmodium metabolism that has recently proven rich in exploitable antimalarial targets is protein synthesis, with a compound targeting elongation factor 2 now in clinical development and inhibitors of several aminoacyl-tRNA synthetases in lead optimization. Given the promise of these components of translation as viable drug targets, we rationalized that an assay containing all functional components of translation would be a valuable tool for antimalarial screening and drug discovery. Here, we report the development and validation of an assay platform that enables specific inhibitors of Plasmodium falciparum translation (PfIVT) to be identified. The primary assay in this platform monitors the translation of a luciferase reporter in a P. falciparum lysate-based expression system. Hits identified in this primary assay are assessed in a counterscreen assay that enables false positives that directly interfere with the luciferase to be triaged. The remaining hit compounds are then assessed in an equivalent human IVT assay. This platform of assays was used to screen MMV's Pandemic and Pathogen Box libraries, identifying several selective inhibitors of protein synthesis. We believe this new high-throughput screening platform has the potential to greatly expedite the discovery of antimalarials that act via this highly desirable mechanism of action.

A Functional Contextual Account of Background Knowledge in Categorization: Implications for Artificial General Intelligence and Cognitive Accounts of General Knowledge.

Psychology has benefited from an enormous wealth of knowledge about processes of cognition in relation to how the brain organizes information. Within the categorization literature, this behavior is often explained through theories of memory construction called exemplar theory and prototype theory which are typically based on similarity or rule functions as explanations of how categories emerge. Although these theories work well at modeling highly controlled stimuli in laboratory settings, they often perform less well outside of these settings, such as explaining the emergence of background knowledge processes. In order to explain background knowledge, we present a non-similarity-based post-Skinnerian theory of human language called Relational Frame Theory (RFT) which is rooted in a philosophical world view called functional contextualism (FC). This theory offers a very different interpretation of how categories emerge through the functions of behavior and through contextual cues, which may be of some benefit to existing categorization theories. Specifically, RFT may be able to offer a novel explanation of how background knowledge arises, and we provide some mathematical considerations in order to identify a formal model. Finally, we discuss much of this work within the broader context of general semantic knowledge and artificial intelligence research.

The metabolism of the synthetic cannabinoids ADB-BUTINACA and ADB-4en-PINACA and their detection in forensic toxicology casework and infused papers seized in prisons.

Early warning systems detect new psychoactive substances (NPS), while dedicated monitoring programs and routine drug and toxicology testing identify fluctuations in prevalence. We report the increasing prevalence of the synthetic cannabinoid receptor agonist (SCRA) ADB-BUTINACA (N-[1-amino-3,3-dimethyl-1-oxobutan-2-yl]-1-butyl-1H-indazole-3-carbox-amide). ADB-BUTINACA was first detected in a seizure in Sweden in 2019, and we report its detection in 13 routine Swedish forensic toxicology cases soon after. In January 2021, ADB-BUTINACA was detected in SCRA-infused papers seized in Scottish prisons and has rapidly increased in prevalence, being detected in 60.4% of the SCRA-infused papers tested between January and July 2021. In this work, ADB-BUTINACA was incubated with human hepatocytes (HHeps), and 21 metabolites were identified in vitro, 14 being detected in authentic case samples. The parent drug and metabolites B9 (mono-hydroxylation on the n-butyl tail) and B16 (mono-hydroxylation on the indazole ring) are recommended biomarkers in blood, while metabolites B4 (dihydrodiol formation on the indazole core), B9, and B16 are suitable biomarkers in urine. ADB-4en-PINACA (N-[1-amino-3,3-dimethyl-1-oxobutan-2-yl]-1-[pent-4-en-1-yl]-1H-indazole-3-carboxamide) was detected in Scottish prisons in December 2020, but, unlike ADB-BUTINACA, prevalence has remained low. ADB-4en-PINACA was incubated with HHeps, and 11 metabolites were identified. Metabolites E3 (dihydrodiol formed in the tail moiety) and E7 (hydroxylation on the linked/head group) are the most abundant metabolites in vitro and are suggested as urinary biomarkers. The in vitro potencies of ADB-BUTINACA (EC50 , 11.5 nM and ADB-4en-PINACA (EC50 , 11.6 nM) are similar to that of MDMB-4en-PINACA (EC50 , 4.3 nM). A third tert-leucinamide SCRA, ADB-HEXINACA was also detected in prison samples and warrants further investigation.

High-throughput sequencing of peripheral blood for minimal residual disease monitoring in childhood precursor B-cell acute lymphoblastic leukemia: A prospective feasibility study.

BACKGROUND: Minimal residual disease (MRD) measured on end-of-induction bone marrow (BM) is the most important biomarker for guiding therapy in pediatric acute lymphoblastic leukemia (ALL). Due to limited sensitivity of current approaches, peripheral blood (PB) is not a reliable source for identifying patients needing treatment changes. We sought to determine if high-throughput sequencing (HTS) (next-generation sequencing) of rearranged immunoglobulin and T-cell receptor genes can overcome this and be used to measure MRD in PB. PROCEDURE: We employed a quantitative HTS approach to accurately measure MRD from one million cell equivalents of DNA from 17 PB samples collected at day 29 after induction therapy in patients with precursor B-cell ALL. We compared these results to the gold-standard real-time PCR result obtained from their paired BM samples, median follow-up 49 months. RESULTS: With the increased sensitivity, detecting up to one abnormal cell in a million normal cells, we were able to detect MRD in the PB by HTS in all those patients requiring treatment intensification (MRD ≥ 0.005% in BM). CONCLUSION: This is proof of principle that using the increased sensitivity of HTS, PB can be used to measure MRD and stratify children with ALL. The method is cost effective, rapid, accurate, and reproducible, with inherent advantages in children. Importantly, increasing the frequency testing by PB as opposed to intermittent BM sampling may allow extension of the dynamic range of MRD, giving a more complete picture of the kinetics of disease remission while improving relapse prediction and speed of detection.

Ensuring Effective Public Health Communication: Insights and Modeling Efforts From Theories of Behavioral Economics, Heuristics, and Behavioral Analysis for Decision Making Under Risk.

Public health (PH) messaging can have an enormous impact on shaping how individuals within society behave, and can ensure it is in a safe and responsible way, consistent with up-to-date evidence-based PH guidelines. If done effectively, messaging can save lives and improve the health of those within society. However, unfortunately, those within Government PH bodies typically have little training about how to effectively represent PH messages in a way that is consistent with psychological theories of cognitive bias, in order to avoid cognitively biasing the public through their messages. As a result of this, inadequate representation of PH messages can result, which can often lead to cognitive bias in those from the public who read or listen to the message information. This can lead to poor decision making of the pubic as a whole, which can then further lead to harm and even death of public members as a result of these poor decisions. One way to minimize the problem of bias in decision making is to explore psychology theories that model how bias can occur from PH messaging, and identify ways in which PH agencies can utilize such approaches to improve the effectiveness of their messages. Previous focus has been largely on behavioral economic theories, however, here, other accounts are offered in addition to these. These include theories of heuristics and theories from the behavior analysis domain, which may increase the predictive power of modeling bias, and have applications for how best to represent PH message information which minimize bias.

Associations Between Mental Health, Interoception, Psychological Flexibility, and Self-as-Context, as Predictors for Alexithymia: A Deep Artificial Neural Network Approach.

Background: Alexithymia is a personality trait which is characterized by an inability to identify and describe conscious emotions of oneself and others. Aim: The present study aimed to determine whether various measures of mental health, interoception, psychological flexibility, and self-as-context, predicted through linear associations alexithymia as an outcome. This also included relevant mediators and non-linear predictors identified for particular sub-groups of participants through cluster analyses of an Artificial Neural Network (ANN) output. Methodology: Two hundred and thirty participants completed an online survey which included the following questionnaires: Toronto alexithymia scale; Acceptance and Action Questionnaire 2 (AQQII); Positive and Negative Affect Scale (PANAS-SF), Depression, Anxiety, and Stress Scale 21 (DAS21); Multidimensional Assessment of Interoceptive Awareness (MAIA); and the Self-as-Context (SAC) scale. A stepwise backwards linear regression and mediation analysis were performed, as well as a cluster analysis of the non-linear ANN upper hidden layer output. Results: Higher levels of alexithymia were associated with increased psychological inflexibility, lower positive affect scores, and lower interoception for the subscales of "not distracting" and "attention regulation." SAC mediated the relation between emotional regulation and total alexithymia. The ANNs accounted for more of the variance than the linear regressions, and were able to identify complex and varied patterns within the participant subgroupings. Conclusion: The findings were discussed within the context of developing a SAC processed-based therapeutic model for alexithymia, where it is suggested that alexithymia is a complex and multi-faceted condition, which requires a similarly complex, and process-based approach to accurately diagnose and treat this condition.

Veterinary trypanocidal benzoxaboroles are peptidase-activated prodrugs.

Livestock diseases caused by Trypanosoma congolense, T. vivax and T. brucei, collectively known as nagana, are responsible for billions of dollars in lost food production annually. There is an urgent need for novel therapeutics. Encouragingly, promising antitrypanosomal benzoxaboroles are under veterinary development. Here, we show that the most efficacious subclass of these compounds are prodrugs activated by trypanosome serine carboxypeptidases (CBPs). Drug-resistance to a development candidate, AN11736, emerged readily in T. brucei, due to partial deletion within the locus containing three tandem copies of the CBP genes. T. congolense parasites, which possess a larger array of related CBPs, also developed resistance to AN11736 through deletion within the locus. A genome-scale screen in T. brucei confirmed CBP loss-of-function as the primary mechanism of resistance and CRISPR-Cas9 editing proved that partial deletion within the locus was sufficient to confer resistance. CBP re-expression in either T. brucei or T. congolense AN11736-resistant lines restored drug-susceptibility. CBPs act by cleaving the benzoxaborole AN11736 to a carboxylic acid derivative, revealing a prodrug activation mechanism. Loss of CBP activity results in massive reduction in net uptake of AN11736, indicating that entry is facilitated by the concentration gradient created by prodrug metabolism.

A novel ACT-based video game to support mental health through embedded learning: a mixed-methods feasibility study protocol.

INTRODUCTION: In recent years, serious video games have been used to promote emotional regulation in individuals with mental health issues. Although these therapeutic strategies are innovative, they are limited with respect to scope of treatment, often focusing on specific cognitive skills, to help remediate a specific mental health disorder. OBJECTIVE: Here, we propose a protocol for assessing the feasibility of a novel acceptance and commitment therapy (ACT)-based video game for young adults. METHODS AND ANALYSIS: The Medical Research Council (MRC) framework will be used for developing a complex intervention to design and test the feasibility of an ACT-based video game intervention using a mixed-methods approach involving qualitative and quantitative data. The primary outcomes will include feasibility testing of recruitment processes and the acceptability of the intervention through qualitative interviews, attendance and rates of attrition. Secondary outcomes will involve a series of quantitative questionnaires to obtain effect sizes for power analysis, allowing for the ideal sample size for an appropriately powered, randomised controlled trial to be determined. ETHICS AND DISSEMINATION: This study has been approved by the Psychology Department Research Ethics Committee (2020-4929-3923) at Swansea University in the UK. Dissemination activities will involve publications in peer-reviewed journals, presentations at local and national conferences and promotion through social media. TRIAL REGISTRATION NUMBER: NCT04566042.

A Systematic Review of Associations Between Interoception, Vagal Tone, and Emotional Regulation: Potential Applications for Mental Health, Wellbeing, Psychological Flexibility, and Chronic Conditions.

Background: Interoception and heart rate variability have been found to predict outcomes of mental health and well-being. However, these have usually been investigated independently of one another. Objectives: This systematic review aimed to explore a key gap in the current literature, that being, identifying whether HRV and interoception predict emotional regulation outcomes and strategies. Methods: The process of article retrieval and selection followed the PRISMA guidelines. Databases PsychINFO, Web of Science, PubMed, CINAHL, and MEDLINE were scanned for papers published. Preliminary inclusion and exclusion criteria were specified following the PICO framework, whilst the CHARMS framework was used to help formulate the research question, and critically assess for bias. Results: Two hundred and thirty-seven studies were identified after initial database searches. Of these, eight studies were included in the final selection. Six studies explored the associations between HRV and ER, whilst three investigated the associations between interoception and ER (one study included both). Results show that greater HRV and interoception are associated with better ER. Specifically, high parasympathetic activity largely predicted the use of adaptive ER strategies such as reappraisal, and better acceptance of emotions. High interoception, instead, was predictive of effective downregulation of negative emotions and handling of social uncertainty, there was no association with any specific ER strategy. Conclusions: Awareness of one's own bodily feelings and vagal activation seem to be of central importance for the effective regulation of emotional responses. However, one limitation is the small sample of studies found, thus more studies in this area are needed in the future.

Hydroxychloroquine and short-course radiotherapy in elderly patients with newly diagnosed high-grade glioma: a randomized phase II trial.

BACKGROUND: Effective treatment for patients at least 70 years with newly diagnosed glioblastoma remains challenging and alternatives to conventional cytotoxics are appealing. Autophagy inhibition has shown promising efficacy and safety in small studies of glioblastoma and other cancers. METHODS: We conducted a randomized phase II trial to compare radiotherapy with or without hydroxychloroquine (2:1 allocation). Patients aged at least 70 years with newly diagnosed high-grade glioma deemed suitable for short-course radiotherapy with an ECOG performance status of 0-1 were included. Radiotherapy treatment consisted of 30 Gy, delivered as 6 fractions given over 2 weeks (5 Gy per fraction). Hydroxychloroquine was given as 200 mg orally b.d. from 7 days prior to radiotherapy until disease progression. The primary endpoint was 1-year overall survival (OS). Secondary endpoints included progression-free survival (PFS), quality of life, and toxicity. RESULTS: Fifty-four patients with a median age of 75 were randomized between May 2013 and October 2016. The trial was stopped early in 2016. One-year OS was 20.3% (95% confidence interval [CI] 8.2-36.0) hydroxychloroquine group, and 41.2% (95% CI 18.6-62.6) radiotherapy alone, with a median survival of 7.9 and 11.5 months, respectively. The corresponding 6-month PFS was 35.3% (95% CI 19.3-51.7) and 29.4% (95% CI 10.7-51.1). The outcome in the control arm was better than expected and the excess of deaths in the hydroxychloroquine group appeared unrelated to cancer. There were more grade 3-5 events in the hydroxychloroquine group (60.0%) versus radiotherapy alone (38.9%) without any clear common causation. CONCLUSIONS: Hydroxychloroquine with short-course radiotherapy did not improve survival compared to radiotherapy alone in elderly patients with glioblastoma.

Corrigendum: The Immediate Effect of Therapeutic Touch and Deep Touch Pressure on Range of Motion, Interoceptive Accuracy and Heart Rate Variability: A Randomized Controlled Trial With Moderation Analysis.

[This corrects the article DOI: 10.3389/fnint.2018.00041.].

Discovery of an Allosteric Binding Site in Kinetoplastid Methionyl-tRNA Synthetase.

Methionyl-tRNA synthetase (MetRS) is a chemically validated drug target in kinetoplastid parasites Trypanosoma brucei and Leishmania donovani. To date, all kinetoplastid MetRS inhibitors described bind in a similar way to an expanded methionine pocket and an adjacent, auxiliary pocket. In the current study, we have identified a structurally novel class of inhibitors containing a 4,6-diamino-substituted pyrazolopyrimidine core (the MetRS02 series). Crystallographic studies revealed that MetRS02 compounds bind to an allosteric pocket in L. major MetRS not previously described, and enzymatic studies demonstrated a noncompetitive mode of inhibition. Homology modeling of the Trypanosoma cruzi MetRS enzyme revealed key differences in the allosteric pocket between the T. cruzi and Leishmania enzymes. These provide a likely explanation for the lower MetRS02 potencies that we observed for the T. cruzi enzyme compared to the Leishmania enzyme. The identification of a new series of MetRS inhibitors and the discovery of a new binding site in kinetoplastid MetRS enzymes provide a novel strategy in the search for new therapeutics for kinetoplastid diseases.