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Carsten Bantel,1 Shiva S Tripathi,2 David Molony,3 Tony Heffernan,3 Susmita Oomman,4 Vivek Mehta,5 Sara Dickerson6 1Chelsea and Westminster Hospital NHS Foundation Trust, London, 2Royal Preston Hospital, Preston, UK; 3Mallow Primary Healthcare Centre, Mallow, Ireland; 4Withybush General Hospital, Haverfordwest, 5Pain & Anaesthesia Research Centre, Barts Health NHS Trust, London, 6Mundipharma International Limited, Cambridge, UK Background: Opioids are an effective treatment for moderate-to-severe pain. However, they are associated with a number of gastrointestinal side effects, most commonly constipation. Laxatives do not target the underlying mechanism of opioid-induced constipation (OIC), so many patients do not have their symptoms resolved. Fixed-dose prolonged-release (PR) oxycodone/naloxone (OXN) tablets contain the opioid agonist oxycodone and the opioid antagonist naloxone. Naloxone blocks the action of oxycodone in the gut without compromising its analgesic effects.Aim: To evaluate the effectiveness of PR OXN in patients with severe pain who had laxative-refractory OIC with their previous opioid.Methods: The study was carried out in 13 centers across the UK and Ireland, using a bespoke online tool to capture patients’ data. Patients were reviewed according to normal clinical practice of each center and rated any changes in their constipation and quality of life (QoL) since starting PR OXN. Any change in patients’ laxative use was also recorded.Results: One hundred and seven patients were entered into the database, and 81 went on to attend at least one review. Of these, 54 (66.7%) reported an improvement in constipation and 50 (61.7%) reported an improvement in QoL since starting PR OXN. Fifty-seven patients (70.4%) said they had reduced laxative intake; 48 (59.3%) only needed laxatives as required.Conclusion: PR OXN reduced symptoms of constipation, improved QoL and reduced laxative intake in patients with OIC. It has a potential place early in any treatment strategy for severe pain in patients using opioids, particularly in patients who may be predisposed to constipation. Keywords: laxatives, opioid, opioid-induced constipation, oxycodone/naloxone, PR OXN, real-world data, severe pain

Leisure, risk and safety are for most leisure practitioners across the globe, thoughts that arise in quick succession to determine the viability of a leisure intervention. However, in a risk aware world so focused on safety, is Leisure too safely structured to be truly beneficial to the individual?, Rarely are leisure seekers given the opportunity to fail and to learn from that experience. Lack of opportunity to face adversity in a supported way hinders the individual’s ability to learn and grow, and to develop personal resilience as a result. This paper will discuss Recovery Camp, a Therapeutic Recreation initiative developed in Australia which utilizes experiential leisure to facilitate resilience in individuals with a mental illness. This paper aims to discuss Leisure Boredom data obtained from volunteer consumers attending recovery camp in 2014 and its relationship to an individual’s personal resilience in the context of living in recovery from mental illness. Importantly Theraputic Recreation interventions such as Recovery Camp should be seen as a valuable experiential alternative to assist in the personal growth and development of those from a vulnerable population. [ABSTRACT FROM PUBLISHER]

AIMS: To examine whether 'binge drinking' (BD) in young adults adversely affects prospective memory (PM). BD was defined as males drinking 8/more units and females 6/more units on at least one session per-week. BDs and non-binge drinkers (NBDs) were compared on self-reported and objective PM. DESIGN: An existing-groups design compared BDs with NBDs as the independent factor. Scores on the PM and retrospective memory (RM) subscales of the Prospective and Retrospective Memory Questionnaire (PRMQ) and scores on the Cambridge Prospective Memory Task (CAMPROMPT) were the dependent factors. Age, total years spent drinking, time since last drink consumed (hours), mood, strategy-use and pre-morbid IQ were measured as covariates. SETTING: Each participant was tested in a laboratory setting. PARTICIPANTS: An opportunity sample of 28 BDs and 28 NBDs were compared. MEASUREMENTS: Self-reported PM and RM lapses were measured using the PRMQ and the CAMPROMPT measured objective PM. Drug use was assessed using a Recreational Drug Use Questionnaire. The Hospital Anxiety and Depression Scale measured mood. The strategy-scale from the Prospective Memory Questionnaire measured strategy use. The National Adult Reading Test measured pre-morbid IQ. FINDINGS: BDs and NBDs did not differ in terms of gender makeup and a series of ANCOVAs (controlling for the covariates) revealed no significant between-groups differences on self-reported PM/RM lapses; but BDs exhibited reduced function on time-based PM, but not event-based PM, when compared with NBDs. CONCLUSIONS: BDs exhibit selective impairments on time-based PM; this deficit is a new finding in terms of the neuropsychological sequelae associated with BD. [ABSTRACT FROM AUTHOR]

Abstract: Aims: To examine whether teenage binge drinking has an adverse effect upon everyday prospective memory (PM). Design: The study utilised an existing-groups design, with alcohol group: binge drinkers vs non-binge drinkers as the independent factor, and scores on the two PM memory subscales of the Prospective and Retrospective Memory Questionnaire (PRMQ) and the score on the Prospective Remembering Video Procedure (PRVP) as the dependent factors. Age, anxiety and depression scores, last alcohol use (in hours) and how many years spent drinking, were measured and analysed between the groups. Setting: Each participant was tested in a laboratory setting. Participants: An opportunity sample of 21 ‘binge drinkers’ (those drinking above 6 units for females and 8 units for males on 2 or more occasions per week) and 29 non-bingers were compared. Measurements: Self-reported everyday PM lapses were measured using the PRMQ. The PRVP was used as an objective measure of PM. Alcohol and other drug use were assessed by the University of East London Recreational Drug Use Questionnaire. The Hospital Anxiety and Depression Scale gauged self-reported levels of anxiety and depression. Findings: After controlling for age, anxiety and depression scores, last alcohol use and how many years spent drinking, there were no significant between-group differences on either the self-reported long-term or short-term PM lapses. However, binge drinkers recalled significantly fewer location-action combinations on the PRVP than non-binge drinkers. Conclusions: The results of the present study suggest that binge drinking in the teenage years leads to impairments in everyday PM. [Copyright &y& Elsevier]

Research indicates that the use of recreational drugs, including MDMA ('ecstasy') can result in impairments in cognitive functioning. Recent evidence, based on accounts of 'on drug' effects and cortical binding ratios suggests that women may be more susceptible to the effects of MDMA; however, no research has explored whether there are differences in the long-term behavioural sequelae of the drug between men and women. In addition, little is known about the profile of functioning of the 'typical' user. The present investigation accessed a large sample of recreational drug users, using the Internet, to obtain self-reports of memory functioning with a view to exploring any differences in self-reported ability amongst male and female users, and the level of difficulty reported by the 'typical' ecstasy user. A web site (www.drugresearch.org.uk) was developed and used for data collection. Prospective memory ability was assessed using the Prospective Memory Questionnaire. Self-report of day-to-day memory performance was investigated using the Everyday Memory Questionnaire. The UEL Drug Questionnaire assessed the use of other substances. The number of mistakes made while completing the questionnaires was also taken as an objective measure of performance errors. Findings, based on datasets submitted from 763 respondents, indicate no differences in self-reports of functioning between male and female participants. An overall dissociation between the effects of cannabis and ecstasy on self-reported memory functioning and on the likelihood of making an error during the completion of the questionnaire was found. Typical ecstasy users were found to report significantly more difficulties in long-term prospective memory and to make more completion errors than users of other substances and drug naive controls. Whilst taking into account the fact that participants were recruited via the World Wide Web and that a number of stringent exclusion criteria were applied to the data, a number of conclusions can be drawn. Recreational drug users perceive their memory ability to be impaired compared to non-users. The type of memory difficulties reported varies depending upon the drug of choice. These difficulties are exacerbated in ecstasy users. Individuals reporting average levels of use of ecstasy are more likely to report memory problems than non-ecstasy drug users or drug free individuals. The deleterious effects of ecstasy are therefore not restricted to heavy or chronic users. No gender differences were detected, suggesting that there may be a dissociation between cognitive impairment and cortical binding worthy of further exploration. [ABSTRACT FROM AUTHOR]

Rationale The recreational use of MDMA/Ecstasy (3,4-methylenedioxymethamphetamine) is associated with many psychobiological problems, but there is a paucity of data on how these relate to the level of past use. Objectives: to assess the incidence of Ecstasy-attributed problems as reported by novice, moderate and heavy users. Methods: 763 unpaid volunteers took part in a WWW study of recreational drug use. This report is based on the 282 Ecstasy users from that sample, who comprised 109 novice users (1–9 occasions), 136 moderate users (10–99 occasions), and 36 heavy users (+100 occasions). Yes/no responses were automatically recorded to a series of questions covering psychobiological problems experienced when drug-free, which were attributed by the respondents to their Ecstasy use. Results: Depression, memory problems, anxiety, mood fluctuation, poor concentration, infections, tremors/twitches and weight loss, were all significantly associated with the extent of Ecstasy use. Thus memory problems attributed to Ecstasy were reported by 19% of novice users, 52% of heavy users and 73% of heavy users (chi-square 42.74, df=2, p <0.001); many of the other variables showed similar trends. Conclusions The incidence of problems attributed to Ecstasy use, is directly related to the number of occasions it has been used. Copyright © 2002 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Chronic use of MDMA (3,4-methylenedioxymethamphetamine), or Ecstasy, is believed to lead to impaired psychological performance, including well-documented decrements in laboratory and field tests of retrospective memory. Less is known about the impact of Ecstasy on aspects of ‘everyday’ memory, despite obvious concerns about such effects. The three studies reported here focused on the impact of chronic Ecstasy use on prospective memory (PM), associated central executive function and other aspects of day-to-day cognition. In study 1 46 regular Ecstasy users were compared with 46 Ecstasy-free controls using the Prospective Memory Questionnaire (PMQ). Ecstasy users reported significantly more errors in PM (remembering to do something in the future); these findings persisted after controlling for other drug use and the number of strategies used to aid memory. No difference was found between representative subgroups on the Lies Scale of the Eysenck Personality Questionnaire. In study 2 a different group of 30 regular Ecstasy users and 37 Ecstasy-free controls was assessed on the PMQ and on a central executive task comprising verbal fluency measures. The results confirmed the significant impairments in long- and short-term PM and revealed corresponding impairments in verbal fluency. In study 3 15 Ecstasy users, 15 cannabis users and 15 non-drug users were assessed using the Cognitive Failures Questionnaire, which requires participants to provide ratings of the frequency of various day-to-day cognitive slips. The results indicate that the Ecstasy users did not perceive their general cognitive performance to be worse than that of controls. Taken together, these results suggest that Ecstasy users have impaired PM that cannot be explained by an increased propensity to exaggerate cognitive failures. These may be attributable, in part, to central executive deficits that are due to frontal lobe damage associated with Ecstasy use. Copyright © 2001 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Introduction The Alcohol Hangover State (AHS) is characterized by range of symptoms (e.g., drowsiness, fatigue, gastro-intestinal problems, dry mouth, nausea, sweating) that remain after ones blood-alcohol level returns to zero following a recent bout of excessive drinking. A recent study found deficits in everyday prospective memory (PM: memory for future plans/actions; such as remembering to meet with friends or to perform a task at a specific time) associated with the AHS. Objectives Given the importance of PM to everyday living, it is important to attempt to verify these findings. Aims The present study aimed to provide converging evidence on the impact AHS has upon PM and extend this focus to explore whether any sex differences relating to AHS and PM exist. Methods Twenty-six AHS participants (13 males/13 females) were compared with 27 non-AHS controls (12 males/15 females) using a between-groups design. All completed a Virtual Reality Prospective Memory Test (VRPMT) was used as an objective test of time-based and event-based PM. Results The AHS group recalled significantly fewer time-based and event-based PM tasks on VRPMT compared with the non-AHS control group. There was a sex and hangover interaction on time based PM, with the male AHS group recalling significantly fewer items than the female AHS group. Conclusions These results confirm the deleterious impact of AHS upon PM and further reveal that males who are in an AHS are significantly more impaired in their time-based PM than females in an AHS, a novel addition to the literature. [ABSTRACT FROM AUTHOR]

Introduction Anabolic Androgenic Steroids (AAS) are typically used by athletes, sports coaches and recreational sports users in an attempt to improve muscle mass and enhance sporting regimes. Despite a myriad of health problems associated with using AAS, no research to date has considered whether AAS use has a detrimental impact upon cognition. Objectives This study considered putative links between regular AAS use in gym users and prospective memory (PM: remembering future intentions and activities) and executive function (EF: memory organization and attentional control). Aims To compare a group of regular AAS gym users with a group of regular gym users who do not use AAS on measures of PM and EF. Methods 35 young adult regular gym users who use AAS to enhance muscle/training (the AAS group) were compared with a group of 35 young adult gym users who do not use AAS (the Non-AAS group). The Prospective and Retrospective Memory Questionnaire was used to measure self-reported PM and the Executive Function Scale measured self-reported EF. Other drug use and mood were also measured since these can impact upon memory independent of AAS use. Results After observing no between-group differences on other drug use and mood, the AAS group reported significantly more PM lapses and EF deficits when compared with the Non-AAS group. Conclusions These findings suggest that the use of AAS in sporting contexts may compromise everyday memory in the form of PM and EF. The findings and their implications will be considered at conference. [ABSTRACT FROM AUTHOR]

The in vitro solubility of airborne uranium dusts collected at a former uranium processing facility now undergoing safe shutdown, decontamination, and dismantling was evaluated by immersing air filters fromhigh volume samplers in simulated lung fluid and measuring the 238U in sequential dissolution fractions using specific radiochemical analysis for uranium. X rays and photons from the decay of uranium and thorium remaining on the filter after each dissolution period were also directly measured using a planar germanium detector as a means for rapidly evaluating the solubility of the uranium-bearing dusts. Results of these analyses demonstrate that two distinct types ofuranium-bearing dusts were collected on the filters depending upon the location of the air samplers. The first material exhibited a dissolution half-time much less than 1 d and was most likely UO3. The dissolution rate of the second material, which was most likelyU3O8, exhibited two components. Approximately one-third of this material dissolved with a half time much less than 1 d. The remaining two-thirds of the material dissolved with half times between 230 +/- 16 d and 1,350 +/- 202 d. The dissolution rates for uranium determined by radiochemical analysis and by gamma spectrometry were similar. However, gamma spectrometry analysis suggested a difference between the half times of 238U and its initial decay product 234Th, which may have important implications for in vivo monitoring of uranium. [ABSTRACT FROM AUTHOR]

It is unclear how cells counteract the potentially harmful effects of uncoordinated DNA replication in the context of oncogenic stress. Here, we identify the WRAD (WDR5/RBBP5/ASH2L/DPY30) core as a modulator of DNA replication in pancreatic ductal adenocarcinoma (PDAC) models. Molecular analyses demonstrated that the WRAD core interacts with the replisome complex, with disruption of DPY30 resulting in DNA re-replication, DNA damage, and chromosomal instability (CIN) without affecting cancer cell proliferation. Consequently, in immunocompetent models, DPY30 loss induced T cell infiltration and immune-mediated clearance of highly proliferating cancer cells with complex karyotypes, thus improving anti-tumor efficacy upon anti-PD-1 treatment. In PDAC patients, DPY30 expression was associated with high tumor grade, worse prognosis, and limited response to immune checkpoint blockade. Together, our findings indicate that the WRAD core sustains genome stability and suggest that low intratumor DPY30 levels may identify PDAC patients who will benefit from immune checkpoint inhibitors.

Background: Occipitocervical arthrodesis has a variety of indications to treat craniocervical and atlantoaxial pathologies for which a selective cervical fusion would not provide sufficient stability. Over time, the indications for occipitocervical fusions (OCFs) have evolved, as new technologies and surgical techniques were developed. In this bibliometric analysis, we aim to explore the progression of OCF literature over time, analyzing the trends in publications and citations, publishing countries and authors, keywords, and topics., Methods: The Web of Science database was used for data retrieval on July 3, 2024, with the search "occipitocervical fusion" OR "occipito-cervical fusion" OR "occipitocervical arthrodesis" OR "occipital cervical fusion" OR "occipital cervical arthrodesis" OR ("OCF" AND "spine surgery"). Excel was used to create the citation analysis and publication trend figures, along with the publishing countries and author analysis. The bibliometric software VosViewer was used to generate the keyword co-occurrence network visualizations., Results: Overall, 762 articles were extracted. The number of pertinent publications and citations increased until 2020 before beginning to decrease. We found that Ehlers Danlos syndrome has become a more prevalent topic, as the association between Ehlers Danlos syndrome and craniocervical instability has received further scrutiny. "Dysphagia" continues to be a commonly cited topic, while, conversely, rheumatoid arthritis has decreased in publication frequency, possibly related to advances in medical management and surgical techniques. Overall, the United States, China, and Japan are the top publishing countries., Conclusions: This analysis of OCF literature provides a helpful overview of emerging trends and clinician concerns, especially as seen through the perspective of time., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

This paper challenges current approaches to undertaking community-centred disaster recovery. Community-centred approaches are widely recognised as 'the gold standard' for effective recovery from disasters. Yet, they are rarely applied well enough in practice. Challenges include the 'authority' culture of command-and-control agencies, the emphasis on discrete recovery time frames, and the reluctance to relinquish centralised control. The paper focuses on people's experiences of community-centred recovery in New South Wales, Australia, which has experienced severe fires and floods since 2019. We undertook key informant interviews and an online survey to inquire into how community-centred recovery is enacted. Our work uncovered widespread dissatisfaction with current practices. The paper discusses key themes emerging from the research and ends with a call to change how community-centred recovery is framed and conducted by responding organisations, to include the underlying causes of vulnerability in recovery, to measure success differently, and to alter the narrative of who 'owns' disasters., (© 2024 The Author(s). Disasters published by John Wiley & Sons Ltd on behalf of ODI.)

One of the hallmarks of cancer is high levels of DNA replication stress and defects in the DNA damage response (DDR) pathways, which are critical for maintaining genomic integrity. Ataxia telangiectasia and Rad3-related protein (ATR) is a key regulator of the DDR machinery and an attractive therapeutic target, with multiple ATR inhibitors holding significant promise in ongoing clinical studies. Herein, we describe the discovery and characterization of ART0380 ( 6 ), a potent and selective ATR inhibitor with a compelling in vitro and in vivo pharmacological profile currently undergoing Phase 2 clinical studies in patients with advanced or metastatic solid tumors as monotherapy and in combination with DNA-damaging agents (NCT04657068 and NCT05798611). ART0380 ( 6 ) has a favorable human PK profile suitable for both intermittent and continuous once-daily (QD) dosing, characterized by a dose-proportional increase in exposure and low variability.

Aim: This paper presents a case study review of an Australian research partnership between an independent mental health lived experience-led research network and an academic organisation established for the research and treatment of disorders of the brain and mind. The aim of the study was to explore the principles and practical requirements needed for a successful partnership that promotes inclusive research practices and power sharing and provide a framework to improve the operationalization of future similar partnerships., Methods: This study was led and conducted by lived experience researchers. We used a mixed-method approach to data collection for data triangulation. An environmental scan of peer-reviewed and grey literature on mental health research partnerships was conducted, followed by a three-part data collection with members of both organisations. Data collection comprised an online survey, in-depth interviews, and a roundtable discussion to integrate findings and formulate recommendations., Results and Conclusion: This case study explores and describes a missed opportunity of a consumer led mental health research organisation to work successfully with an established mental health research organisation. Poor communication and unclear processes led to unmet expectations on both sides. Findings suggest the use of reflective practice by team members of both partner organisations may have been helpful in identifying further improvements to inclusive research practice, empowering consumers in inclusive mental health research., (© 2024. The Author(s).)

Background: Childhood obesity is a significant global public health challenge, with significant adverse effects on both mental and physical health outcomes. During the period from birth to one-year, modifiable caregiver behaviours, such as what, how and when infants are fed, can influence obesity development and prevention. The Choosing Healthy Eating for Infant Health (CHErIsH) intervention was developed to support healthy infant feeding practices to prevent childhood obesity in the first year. A feasibility study examined acceptability and feasibility of the CHErIsH intervention in primary care and identified key challenges and possible areas for refinement of the intervention and trial processes. The current project aims to refine delivery of the CHErIsH intervention and trial processes to maximise the likelihood of successful future implementation and evaluation., Methods: This study will utilise a mixed-methods approach and will be conducted in three phases. In Phase 1 potential refinements to the CHErIsH intervention delivery and trial processes will be developed from a review of the feasibility study findings and input from the multidisciplinary team. An online mixed-methods survey will be conducted in Phase 2 to evaluate caregiver attitudes about the proposed refinements from Phase 1. Participants will be pregnant women, their partners, and/or parents/primary caregivers of infants up to 2-years of age, based in Ireland. Participants will be recruited using convenience and snowball sampling. In Phase 3 a stakeholder consensus meeting, using the nominal group technique, will be conducted to agree the refined intervention and trial processes. Stakeholders will include healthcare professionals, researchers, policymakers, and parents/caregivers, who will discuss and rate refinements in terms of preference., Conclusions: Findings from this study will address uncertainties in the intervention delivery and trial processes of the CHErIsH intervention, with the potential to maximise the likelihood of successful future implementation and evaluation of a primary-care based obesity prevention intervention., Competing Interests: No competing interests were disclosed., (Copyright: © 2024 Looney E et al.)

Purpose: As environmental disasters become more common and severe due to climate change, there is a growing need for strategies to bolster recovery that are proactive, cost-effective, and which mobilise community resources., Aims: We propose that building social group connections is a particularly promising strategy for supporting mental health in communities affected by environmental disasters., Methods: We tested the social identity model of identity change in a disaster context among 627 people substantially affected by the 2019-2020 Australian fires., Results: We found high levels of post-traumatic stress, strongly related to severity of disaster exposure, but also evidence of psychological resilience. Distress and resilience were weakly positively correlated. Having stronger social group connections pre-disaster was associated with less distress and more resilience 12-18 months after the disaster, via three pathways: greater social identification with the disaster-affected community, greater continuity of social group ties, and greater formation of new social group ties. New group ties were a mixed blessing, positively predicting both resilience and distress., Conclusions: We conclude that investment in social resources is key to supporting mental health outcomes, not just reactively in the aftermath of disasters, but also proactively in communities most at risk., (© 2023. The Author(s).)

"Compulsive Shopping" is characterized by poorly controlled preoccupations/urges/behaviors focused on shopping and spending, causing significant distress/impairment. This study looked at what roles executive and related memory problems might exist in compulsive shopping. 205 adults completed on-line questionnaires measuring compulsive shopping, mood, as well as working memory and inhibition components of executive function. The Bergen Shopping Addiction Scale was used to assign participants to either a High Compulsive Shopping (HCS) group or Low Compulsive Shopping (LCS) group. Working memory (WM) and inhibition control (IC) were measured as two components of executive function (EF) using the Adult Executive Functioning Inventory (ADEXI), the Dysexecutive Questionnaire Revised ( DEX-R) measured general EF. The Hospital Anxiety and Depression Scale measured anxiety and depression. MANCOVA and mediation analyses were carried out controlling for age, gender, anxiety, depression. The HCS group scored significantly higher on all three EF measures, indicating greater executive difficulties. Subsequent mediation analyses with the ADEXI-IC as the mediator removed the significance of the relationship between Group and both the DEX-R and ADEXI-WM outcome variables. Thus, observed Group difference in DEX-R and ADEXI-WM could be fully accounted for by group differences in inhibitory control. The results highlight the role inhibitory control plays in compulsive shopping.

Tumors represent ecosystems where subclones compete during tumor growth. While extensively investigated, a comprehensive picture of the interplay of clonal lineages during dissemination is still lacking. Using patient-derived pancreatic cancer cells, we created orthotopically implanted clonal replica tumors to trace clonal dynamics of unperturbed tumor expansion and dissemination. This model revealed the multifaceted nature of tumor growth, with rapid changes in clonal fitness leading to continuous reshuffling of tumor architecture and alternating clonal dominance as a distinct feature of cancer growth. Regarding dissemination, a large fraction of tumor lineages could be found at secondary sites each having distinctive organ growth patterns as well as numerous undescribed behaviors such as abortive colonization. Paired analysis of primary and secondary sites revealed fitness as major contributor to dissemination. From the analysis of pro- and nonmetastatic isogenic subclones, we identified a transcriptomic signature able to identify metastatic cells in human tumors and predict patients' survival.

Witnessing degradation and loss to one's home environment can cause the negative emotional experience of solastalgia. We review the psychometric properties of the 9-item Solastalgia subscale from the Environmental Distress Scale (Higginbotham et al. (EcoHealth 3:245-254, 2006)). Using data collected from three large, independent, adult samples (N = 4229), who were surveyed soon after the 2019/20 Australian bushfires, factor analyses confirmed the scale's unidimensionality, while analyses derived from Item Response Theory highlighted the poor psychometric performance and redundant content of specific items. Consequently, we recommend a short-form scale consisting of five items. This Brief Solastalgia Scale (BSS) yielded excellent model fit and internal consistency in both the initial and cross-validation samples. The BSS and its parent version provide very similar patterns of associations with demographic, health, life satisfaction, climate emotion, and nature connectedness variables. Finally, multi-group confirmatory factor analysis demonstrated comparable construct architecture (i.e. configural, metric, and scalar invariance) across validation samples, gender categories, and age. As individuals and communities increasingly confront and cope with climate change and its consequences, understanding related emotional impacts is crucial. The BSS promises to aid researchers, decision makers, and practitioners to understand and support those affected by negative environmental change., (© 2024. The Author(s).)

Aims: We assessed the mental health effects of Australia's 2019-2020 bushfires 12-18 months later, predicting psychological distress and positive psychological outcomes from bushfire exposure and a range of demographic variables, and seeking insights to enhance disaster preparedness and resilience planning for different profiles of people., Methods: We surveyed 3083 bushfire-affected and non-affected Australian residents about their experiences of bushfire, COVID-19, psychological distress (depression, anxiety, stress, post-traumatic stress disorder) and positive psychological outcomes (resilient coping, wellbeing)., Results: We found high rates of distress across all participants, exacerbated by severity of bushfire exposure. For people who were bushfire-affected, being older, having less financial stress, and having no or fewer pre-existing mental disorders predicted both lower distress and higher positive outcomes. Being male or having less income loss also predicted positive outcomes. Severity of exposure, higher education and higher COVID-19-related stressors predicted both higher distress and higher positive outcomes. Pre-existing physical health diagnosis and previous bushfire experience did not significantly predict distress or positive outcomes., Recommendations: To promote disaster resilience, we recommend investment in mental health, particularly for younger adults and for those in rural and remote areas. We also recommend investment in mechanisms to protect against financial distress and the development of a broader definition of bushfire-related impacts than is currently used to capture brushfires' far-reaching effects., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship and/or publication of this article.

Patients harboring CRLF2-rearranged B-lineage acute lymphocytic leukemia (B-ALL) face a 5-year survival rate as low as 20%. While significant gains have been made to position targeted therapies for B-ALL treatment, continued efforts are needed to develop therapeutic options with improved duration of response. Here, first we have demonstrated that patients with CRLF2-rearranged Ph-like ALL harbor elevated thymic stromal lymphopoietin receptor (TSLPR) expression, which is comparable with CD19. Then we present and evaluate the anti-tumor characteristics of 1B7/CD3, a novel CD3-redirecting bispecific antibody (BsAb) that co-targets TSLPR. In vitro, 1B7/CD3 exhibits optimal binding to both human and cynomolgus CD3 and TSLPR. Further, 1B7/CD3 was shown to induce potent T cell activation and tumor lytic activity in both cell lines and primary B-ALL patient samples. Using humanized cell- or patient-derived xenograft models, 1B7/CD3 treatment was shown to trigger dose-dependent tumor remission or growth inhibition across donors as well as induce T cell activation and expansion. Pharmacokinetic studies in murine models revealed 1B7/CD3 to exhibit a prolonged half-life. Finally, toxicology studies using cynomolgus monkeys found that the maximum tolerated dose of 1B7/CD3 was ≤1 mg/kg. Overall, our preclinical data provide the framework for the clinical evaluation of 1B7/CD3 in patients with CRLF2-rearranged B-ALL., (© 2023. The Author(s).)

Monotherapy with Menin inhibitor (MI), e.g., SNDX-5613, induces clinical remissions in patients with relapsed/refractory AML harboring MLL1-r or mtNPM1, but most patients either fail to respond or eventually relapse. Utilizing single-cell RNA-Seq, ChiP-Seq, ATAC-Seq, RNA-Seq, RPPA, and mass cytometry (CyTOF) analyses, present pre-clinical studies elucidate gene-expression correlates of MI efficacy in AML cells harboring MLL1-r or mtNPM1. Notably, MI-mediated genome-wide, concordant, log2 fold-perturbations in ATAC-Seq and RNA-Seq peaks were observed at the loci of MLL-FP target genes, with upregulation of mRNAs associated with AML differentiation. MI treatment also reduced the number of AML cells expressing the stem/progenitor cell signature. A protein domain-focused CRISPR-Cas9 screen in MLL1-r AML cells identified targetable co-dependencies with MI treatment, including BRD4, EP300, MOZ and KDM1A. Consistent with this, in vitro co-treatment with MI and BET, MOZ, LSD1 or CBP/p300 inhibitor induced synergistic loss of viability of AML cells with MLL1-r or mtNPM1. Co-treatment with MI and BET or CBP/p300 inhibitor also exerted significantly superior in vivo efficacy in xenograft models of AML with MLL1-r. These findings highlight novel, MI-based combinations that could prevent escape of AML stem/progenitor cells following MI monotherapy, which is responsible for therapy-refractory AML relapse., (© 2023. The Author(s).)

Purpose: Cisplatin (CDDP)-based chemotherapy is a first-line treatment for patients with advanced head and neck squamous cell carcinomas (HNSCC), despite a high rate of treatment failures, acquired resistance, and subsequent aggressive behavior. The purpose of this study was to study the mechanism of CDDP resistance and metastasis in HNSCC. We investigated the role of NRF2 pathway activation as a driven event for tumor progression and metastasis of HNSCC., Experimental Design: Human HNSCC cell lines that are highly resistant to CDDP were generated. Clonogenic survival assays and a mouse model of oral cancer were used to examine the impact of NRF2 activation in vitro and in vivo on CDDP sensitivity and development of metastasis. Western blotting, immunostaining, whole-exome sequencing, single-cell transcriptomic and epigenomic profiling platforms were performed to dissect clonal evolution and molecular mechanisms., Results: Implantation of CDDP-resistant HNSCC cells into the tongues of nude mice resulted in a very high rate of distant metastases. The CDDP-resistant cells had significantly higher expression of NRF2 pathway genes in the presence of newly acquired KEAP1 mutations, or via epigenomic activation of target genes. Knockdown of NRF2 or restoration of the wild-type KEAP1 genes resensitized resistant cells to CDDP and decreased distant metastasis (DM). Finally, treatment with inhibitor of glutaminase-1, a NRF2 target gene, alleviated CDDP resistance., Conclusions: CDDP resistance and development of DM are associated with dysregulated and epigenetically reprogrammed KEAP1-NRF2 signaling pathway. A strategy targeting KEAP1/NRF2 pathway or glutamine metabolism deserves further clinical investigation in patients with CDDP-resistant head and neck tumors., (©2023 The Authors; Published by the American Association for Cancer Research.)

Hoarding is the excessive acquisition of, and failure to discard of, large numbers of items, leading to personal distress. Impairments on memory and executive functions have been systematically associated with hoarding behavior, predominantly focusing upon clinical (mainly middle-aged-elderly) patients with hoarding and/or PTSD. We were interested in hoarding-related memory and executive problems in younger non-clinical hoarders or non-hoarders, based on their Saving Inventory-Revised scores. In total, 113 young adults (aged 18-35 years) were assigned to either a hoarder group ( N  = 40) or non-hoarder group ( N  = 73) determined by their scores on the Saving Inventory-Revised (SI-R). Working memory (WM) and inhibition control (IC) were measured using the Adult Executive Functioning Inventory (ADEXI) and the Dysexecutive Questionnaire Revised ( DEX-R) measured general executive function (EF). The Hospital Anxiety and Depression Scale measured anxiety and depression. After controlling for gender and anxiety, the analysis revealed that the hoarders reported significantly more problems than the non-hoarders on both the IC and general EF. There was no significant between-group difference on the WM sub-scale ADEXI. Self-reported deficits in IC and EF are associated with hoarding behavior. The IC deficits cold explain hoarders' inability to resist urges to buy, and general EF deficits suggest other domains are involved.

For clinicians working in mental health services, 'aggression management' training is generally prioritised, and often mandated. Traditional 'aggression management' training has the potential to reinforce the perception that violence and aggression are inevitable, and thus defensive and coercive practices are needed. This paper outlines the principles and processes that underpinned the development of two training programs designed as recovery-oriented and trauma-informed alternatives to traditional 'aggression management' training. The focus of the paper is on exploring how 'aggression management' training can be aligned with best practice principles. The programs were developed in a metropolitan and rural mental health service and aimed to reduce the need for defensive and coercive practices by promoting therapeutic engagement. A key feature of both programs is an orientation towards safety rather than risk. By embedding the principles of recovery and trauma-informed care in their development and orienting training towards enhancing safety, clinicians are provided with a new way of conceptualising and responding to 'aggression'. Experiential methods in the delivery of the training, and the co-design and co-delivery with peer (consumer) educators were important in supporting attitudinal change. To promote safety, the language and content of training programs must reflect contemporary principles and approaches such as trauma-informed care and recovery. This paper illustrates that to be effective, these principles and approaches must not just be described, but modelled in the development, design, and delivery of the training.

Despite radiation forming the curative backbone of over 50% of malignancies, there are no genomically-driven radiosensitizers for clinical use. Herein we perform in vivo shRNA screening to identify targets generally associated with radiation response as well as those exhibiting a genomic dependency. This identifies the histone acetyltransferases CREBBP/EP300 as a target for radiosensitization in combination with radiation in cognate mutant tumors. Further in vitro and in vivo studies confirm this phenomenon to be due to repression of homologous recombination following DNA damage and reproducible using chemical inhibition of histone acetyltransferase (HAT), but not bromodomain function. Selected mutations in CREBBP lead to a hyperacetylated state that increases CBP and BRCA1 acetylation, representing a gain of function targeted by HAT inhibition. Additionally, mutations in CREBBP/EP300 are associated with recurrence following radiation in squamous cell carcinoma cohorts. These findings provide both a mechanism of resistance and the potential for genomically-driven treatment., (© 2021. The Author(s).)

Src homology 2 (SH2) domain-containing phosphatase 2 (SHP2) plays a role in receptor tyrosine kinase (RTK), neurofibromin-1 (NF-1), and Kirsten rat sarcoma virus (KRAS) mutant-driven cancers, as well as in RTK-mediated resistance, making the identification of small-molecule therapeutics that interfere with its function of high interest. Our quest to identify potent, orally bioavailable, and safe SHP2 inhibitors led to the discovery of a promising series of pyrazolopyrimidinones that displayed excellent potency but had a suboptimal in vivo pharmacokinetic (PK) profile. Hypothesis-driven scaffold optimization led us to a series of pyrazolopyrazines with excellent PK properties across species but a narrow human Ether-à-go-go-Related Gene (hERG) window. Subsequent optimization of properties led to the discovery of the pyrimidinone series, in which multiple members possessed excellent potency, optimal in vivo PK across species, and no off-target activities including no hERG liability up to 100 μM. Importantly, compound 30 (IACS-15414) potently suppressed the mitogen-activated protein kinase (MAPK) pathway signaling and tumor growth in RTK-activated and KRAS mut xenograft models in vivo.

Objective: Early-life nutrition plays a key role in establishing healthy lifestyles and preventing chronic disease. This study aimed to (1) explore healthcare professionals' (HCP) opinions on the acceptability of and factors influencing the delivery of interventions to promote healthy infant feeding behaviours within primary care and (2) identify proposed barriers/enablers to delivering such interventions during vaccination visits, to inform the development of a childhood obesity prevention intervention., Design: A qualitative study design was employed using semi-structured telephone interviews. Data were analysed using qualitative content analysis; findings were also mapped to the Theoretical Framework of Acceptability (TFA)., Setting: Primary care in Ireland., Participants: Twenty-one primary care-based HCP: five practice nurses, seven general practitioners, three public health nurses, three community dietitians and three community medical officers., Results: The acceptability of delivering interventions to promote healthy infant feeding within primary care is influenced by the availability of resources, HCP's roles and priorities, and factors relating to communication and relationships between HCP and parents. Proposed barriers and enablers to delivering interventions within vaccination visits include time constraints v. opportunistic access, existing relationships and trust between parents and practice nurses, and potential communication issues. Barriers/enablers mapped to TFA constructs of Affective Attitude, Perceived Effectiveness and Self-Efficacy., Conclusions: This study provides a valuable insight into HCP perspectives of delivering prevention-focused infant feeding interventions within primary care settings. While promising, factors such as coordination and clarity of HCP roles and resource allocation need to be addressed to ensure acceptability of interventions to HCP involved in delivery.

The sage ( Salvia ) plant contains a host of terpenes and phenolics which interact with mechanisms pertinent to brain function and improve aspects of cognitive performance. However, previous studies in humans have looked at these phytochemicals in isolation and following acute consumption only. A preclinical in vivo study in rodents, however, has demonstrated improved cognitive outcomes following 2-week consumption of Cognivia TM , a proprietary extract of both Salvia officinalis polyphenols and Salvia lavandulaefolia terpenoids, suggesting that a combination of phytochemicals from sage might be more efficacious over a longer period of time. The current study investigated the impact of this sage combination on cognitive functions in humans with acute and chronic outcomes. Participants ( n = 94, 25 M, 69 F, 30-60 years old) took part in this randomised, double-blind, placebo-controlled, parallel groups design where a comprehensive array of cognitions were assessed 120- and 240-min post-dose acutely and following 29-day supplementation with either 600 mg of the sage combination or placebo. A consistent, significant benefit of the sage combination was observed throughout working memory and accuracy task outcome measures (specifically on the Corsi Blocks, Numeric Working Memory, and Name to Face Recall tasks) both acutely (i.e., changes within day 1 and day 29) and chronically (i.e., changes between day 1 to day 29). These results fall slightly outside of those reported previously with single Salvia administration, and therefore, a follow-up study with the single and combined extracts is required to confirm how these effects differ within the same cohort.

Background: Consumer peer workers are individuals with lived experience of mental health issues and recovery who are employed to use their lived experience to support others. The consumer peer workforce has expanded substantially in recent years. While some research has explored the workplace experiences of peer workers, no previous studies have explored job satisfaction, burnout or turnover intention for this workforce., Methods: Consumer peer workers in New South Wales, Australia were invited to complete a survey designed to explore their workplace experiences. The survey included measures of job satisfaction, burnout, turnover intention, job demands and job resources, and satisfaction with supervision, professional development and opportunities for career progression. Questions also explored positive and negative aspects of positions. Analyses included exploration of the relationships between of job satisfaction, burnout, turnover intention, job demands and job resources as well as tabulation of common positive and negative aspects of positions. Results were also compared with findings from a previous study exploring workplace experiences of other mental health workers., Results: A total of 67 peer workers participated in the study. Overall job satisfaction, burnout (disengagement and exhaustion) and turnover intention for peer workers was not significantly different to other mental health workers. Job satisfaction, disengagement, exhaustion and turnover intention were all significantly inter-related. Job resources of social support, job control, feedback, and rewards and recognition were associated with positive workplace experiences and the job demand of "physical environment" was most substantially associated with poorer workplace experiences. The most common positive aspect of positions was "connecting with consumers" and the most common negative aspect of positions was "attitudes of clinicians / workplace culture". Access to supervision from a senior peer worker was associated with more positive workplace experiences., Conclusions: This research demonstrates that while consumer peer workers do not appear to experience poorer job satisfaction or higher levels of burnout or turnover intention than other mental health workers, a range of challenges do exist. Efforts to further expand the peer workforce (especially senior peer worker roles) and to promote more positive attitudes and workplace cultures are likely to promote better workplace experiences for peer workers.

Objectives and Design: There is growing recognition of the need for effective behaviour change interventions to prevent chronic diseases that are feasible and sustainable and can be implemented within routine health care systems. Focusing on implementation from the outset of intervention development, and incorporating multiple stakeholder perspectives to achieve this, is therefore essential. This study explores the development of the Choosing Healthy Eating for Infant Health (CHErIsH) childhood obesity prevention intervention and implementation strategy to improve infant feeding behaviours., Methods: Five qualitative and quantitative evidence syntheses, two primary qualitative studies, and formal/informal consultations were conducted with practice, policy, research, and parent stakeholders. The Behaviour Change Wheel was used to guide the integration of findings., Results: The CHErIsH intervention targets parent-level behaviour change and comprises (1) brief verbal messages and (2) trustworthy resources, to be delivered by health care professionals (HCPs) during routine infant vaccination visits. The implementation strategy targets HCP-level behaviour change and comprises (1) a local opinion leader, (2) incentivized training, (3) HCP resources and educational materials, (4) electronic delivery prompts, (5) awareness-raising across all primary care HCPs, and (6) local technical support., Conclusions: This study provides a rigorous example of the development of an evidence-based intervention aimed at improving parental infant feeding behaviours, alongside an evidence-based behaviour change strategy to facilitate implementation and sustainability in primary care. This approach demonstrates how to systematically incorporate multiple stakeholder perspectives with existing literature and move from multiple evidence sources to clearly specified intervention components for both the intervention and implementation strategy. Statement of Contribution What is already known? Incorporating insights from practice, policy, and public/patient stakeholders plays a key role in developing behaviour change interventions that are feasible and sustainable and can be implemented within routine health care systems. However, there are limited examples that provide in-depth guidance of how to do this using a systematic approach. What this study adds? This study describes an innovative use of the Behaviour Change Wheel to integrate multiple sources of evidence collected from practice, policy, research, and parent stakeholders to concurrently develop an evidence-based intervention to improve parental infant feeding behaviours and an implementation strategy to facilitate sustainable delivery by health care professionals in routine primary care., (© 2020 The British Psychological Society.)

The 2010 Alcohol Hangover Research Group consensus paper defined a cutoff blood alcohol concentration (BAC) of 0.11% as a toxicological threshold indicating that sufficient alcohol had been consumed to develop a hangover. The cutoff was based on previous research and applied mostly in studies comprising student samples. Previously, we showed that sensitivity to hangovers depends on (estimated) BAC during acute intoxication, with a greater percentage of drinkers reporting hangovers at higher BAC levels. However, a substantial number of participants also reported hangovers at comparatively lower BAC levels. This calls the suitability of the 0.11% threshold into question. Recent research has shown that subjective intoxication, i.e., the level of severity of reported drunkenness, and not BAC, is the most important determinant of hangover severity. Non-student samples often have a much lower alcohol intake compared to student samples, and overall BACs often remain below 0.11%. Despite these lower BACs, many non-student participants report having a hangover, especially when their subjective intoxication levels are high. This may be the case when alcohol consumption on the drinking occasion that results in a hangover significantly exceeds their "normal" drinking level, irrespective of whether they meet the 0.11% threshold in any of these conditions. Whereas consumers may have relative tolerance to the adverse effects at their "regular" drinking level, considerably higher alcohol intake-irrespective of the absolute amount-may consequentially result in a next-day hangover. Taken together, these findings suggest that the 0.11% threshold value as a criterion for having a hangover should be abandoned.