Effect of MDMA-assisted therapy on mood and anxiety symptoms in advanced-stage cancer (EMMAC): study protocol for a double-blind, randomised controlled trial.

BACKGROUND: Symptoms of anxiety and depression are common in patients with terminal illness and multiple challenges exist with timely and effective care in this population. Several centres have reported that one dose of the serotonergic psychedelic psilocybin, combined with therapeutic support, improves these symptoms for up to 6 months in this patient group. Drawing upon related therapeutic mechanisms, 3,4-methylenedioxymethamphetamine (MDMA)-assisted therapy may have the potential to achieve similar, positive mental health outcomes in this group. Preliminary evidence also supports the tolerability of MDMA-assisted therapy for anxiety and depression in advanced-stage cancer. METHODS: Up to 32 participants with advanced-stage cancer and associated depression and anxiety will be randomised in a 1:1 ratio into one of two blinded parallel treatment arms. The intervention group will receive 120 mg (+ 60 mg optional supplemental dose) MDMA-assisted therapy. The psychoactive control group will receive 20 mg oral (+ 10 mg optional supplemental dose) methylphenidate-assisted therapy. For each medication-assisted therapy session, participants will undergo two 90-min therapeutic support sessions in the week preceding, and one 90-min support session the day after the experimental session. A battery of measures (mood, anxiety, quality of life, mystical experience, spiritual wellbeing, attitudes towards death, personality traits, holistic health and wellbeing, connectedness, demoralisation, expectations, qualitative data and safety measures) will be assessed at baseline and through to the end of the protocol. Participants will be followed up until either 12 months post-randomisation or death, whichever occurs first. DISCUSSION: This study will examine the effect of MDMA-assisted therapy on symptoms of anxiety and depression in advanced-stage cancer. Potential therapeutic implications include establishing the safety and effectiveness of a novel treatment that may relieve mental suffering in patients with life-threatening illness. TRIAL REGISTRATION: Trial registered on Australian New Zealand Clinical Trials Registry. REGISTRATION NUMBER: ACTRN12619001334190p. Date registered: 30/09/2019. URL: https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=378153&showOriginal=true&isReview=true.

Improvements from a small-group multidisciplinary pain self-management intervention for women living with pelvic pain maintained at 12 months.

BACKGROUND: A small-group multidisciplinary pain self-management program for women living with pelvic pain, with or without endometriosis, was developed to address identified unmet treatment needs. Following completion, over 80% of participants demonstrated clinically significant improvement across a number of domains. There was no clinically significant deterioration on any measure and benefits continued at three months follow-up. AIMS: This study examines patient-reported outcomes at 12 months following program completion to ascertain maintenance of these improvements. MATERIALS AND METHODS: Self-report measures assessed quality of life across the Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials domains prior to, at completion and 12 months following participation. RESULTS: At 12 months follow-up, improvement was seen in mean group scores for all baseline measures for 57% of participants who returned valid 12-month follow-up data, with clinically significant improvement seen for within-subject scores for 50% of these participants for pain severity and also for pain-related activity interference. Improvements were also reported in key predictors of long-term outcomes, pain self-efficacy and catastrophic worry, with 92% reporting improvement in each of these two constructs. There were 83% of respondents who reported feeling both improvement in overall sense of wellbeing and improvement in their physical ability compared to before the program. CONCLUSIONS: Results suggest that a six-week multidisciplinary small-group intervention increases participants' abilities to self-manage pain and improves quality of life with lasting clinically significant improvements.

A Mixed-Methods Study to Better Measure Patient-Reported Pain and Fatigue in Soft Tissue Sarcoma.

INTRODUCTION: Pain and fatigue are commonly reported by patients with soft tissue sarcoma (STS) as distressing symptoms, yet no patient-reported outcome (PRO) measures have been validated or developed specifically for STS. This study aimed to develop novel PRO scales using existing item banks to measure pain and fatigue in STS. METHODS: A three-stage mixed-methods approach was used. Stage 1: a literature review examined the development and validation of the European Organization for Research and Treatment of Cancer (EORTC) library, Patient-Reported Outcomes Measurement Information System (PROMIS) pain/fatigue item banks, Functional Assessment of Cancer Therapy-General, and FACIT-Fatigue. Conceptual models were developed for pain and fatigue. Stage 2: semi-structured interviews were conducted with clinical experts (n = 3) and STS patients (n = 28) to ensure conceptual coverage and cognitively debrief the selected PRO items. Stage 3: exploratory Rasch measurement theory (RMT) analyses were performed to examine the measurement properties of the proposed scales. RESULTS: Stage 1: The conceptual model for fatigue was organized into two overarching domains: fatigability and fatigue, further split into two subdomains: symptoms and impact. The conceptual model for pain had one overarching domain split into two subdomains: descriptors and impact. Pain (n = 56) and fatigue (n = 40) items were selected from the EORTC item library. Stage 2: qualitative findings ensured conceptual coverage, provided insight into the relevance and comprehension of the items, and informed subsequent item reduction. Stage 3: The total item number was reduced to 43 (pain n = 18, fatigue n = 25). Exploratory RMT analyses supported the final scales' psychometric properties. CONCLUSIONS: This mixed-methods research generated important information on the experience of pain and fatigue in specific subtypes of STS. Five novel PRO scales have been developed through careful item selection in consultation with experts and supported by qualitative and quantitative evidence. These scales may be of value to future clinical trials for STS.

Creating psychological safety in interprofessional simulation for health professional learners: a scoping review of the barriers and enablers.

Interprofessional simulation-based education (IP-SBE) supports the acquisition of interprofessional collaborative competencies. Psychologically safe environments are necessary to address socio-historical hierarchies and coercive practices that may occur in IP-SBE, facilitating fuller student participation. A scoping review was conducted to understand the barriers and enablers of psychological safety within IP-SBE. Research papers were eligible if they included two or more undergraduate and/or post-graduate students in health/social care qualifications/degrees and discussed barriers and/or enablers of psychological safety within simulation-based education. Sources of evidence included experimental, quasi-experimental, analytical observational, descriptive observational, qualitative, and mixed-methodological peer-reviewed studies. English or English-translated articles, published after January 1, 1990, were included. Data were extracted by two members of the research team. Extraction conflicts were resolved by the principal investigators. In total, 1,653 studies were screened; 1,527 did not meet inclusion criteria. After a full-text review, 99 additional articles were excluded; 27 studies were analyzed. Psychological safety enablers include prebriefing-debriefing by trained facilitators, no-blame culture, and structured evidenced-based simulation designs. Hierarchy among/between professions, fear of making mistakes, and uncertainty were considered barriers. Recognition of barriers and enablers of psychological safety in IP-SBE is an important first step towards creating strategies that support the full participation of students in their acquisition of IPC competencies.

Modulating Macrophage Clearance of Nanoparticles: Comparison of Small-Molecule and Biologic Drugs as Pharmacokinetic Modifiers of Soft Nanomaterials.

Nanomedicines show benefits in overcoming the limitations of conventional drug delivery systems by reducing side effects, toxicity, and exhibiting enhanced pharmacokinetic (PK) profiles to improve the therapeutic window of small-molecule drugs. However, upon administration, many nanoparticles (NPs) prompt induction of host innate immune responses, which in combination with other clearance pathways such as renal and hepatic, eliminate up to 99% of the administered dose. Here, we explore a drug predosing strategy to transiently suppress the mononuclear phagocyte system (MPS), subsequently improving the PK profile and biological behaviors exhibited by a model NP system [hyperbranched polymers (HBPs)] in an immunocompetent mouse model. In vitro assays allowed the identification of five drug candidates that attenuated cellular association. Predosing of lead compounds chloroquine (CQ) and zoledronic acid (ZA) further showed increased HBP retention within the circulatory system of mice, as shown by both fluorescence imaging and positron emission tomography-computed tomography. Flow cytometric evaluation of spleen and liver tissue cells following intravenous administration further demonstrated that CQ and ZA significantly reduced HBP association with myeloid cells by 23 and 16%, respectively. The results of this study support the use of CQ to pharmacologically suppress the MPS to improve NP PKs.

Steroid-induced fibroblast growth factors drive an epithelial-mesenchymal inflammatory axis in severe asthma.

Asthma and inflammatory airway diseases restrict airflow in the lung, compromising gas exchange and lung function. Inhaled corticosteroids (ICSs) can reduce inflammation, control symptoms, and improve lung function; however, a growing number of patients with severe asthma do not benefit from ICS. Using bronchial airway epithelial brushings from patients with severe asthma or primary human cells, we delineated a corticosteroid-driven fibroblast growth factor (FGF)-dependent inflammatory axis, with FGF-responsive fibroblasts promoting downstream granulocyte colony-stimulating factor (G-CSF) production, hyaluronan secretion, and neutrophilic inflammation. Allergen challenge studies in mice demonstrate that the ICS, fluticasone propionate, inhibited type 2-driven eosinophilia but induced a concomitant increase in FGFs, G-CSF, hyaluronan, and neutrophil infiltration. We developed a model of steroid-induced neutrophilic inflammation mediated, in part, by induction of an FGF-dependent epithelial-mesenchymal axis, which may explain why some individuals do not benefit from ICS. In further proof-of-concept experiments, we found that combination therapy with pan-FGF receptor inhibitors and corticosteroids prevented both eosinophilic and steroid-induced neutrophilic inflammation. Together, these results establish FGFs as therapeutic targets for severe asthma patients who do not benefit from ICS.

Nanoparticle based medicines: approaches for evading and manipulating the mononuclear phagocyte system and potential for clinical translation.

For decades, nanomedicines have been reported as a potential means to overcome the limitations of conventional drug delivery systems by reducing side effects, toxicity and the non-ideal pharmacokinetic behaviour typically exhibited by small molecule drugs. However, upon administration many nanoparticles prompt induction of host inflammatory responses due to recognition and uptake by macrophages, eliminating up to 95% of the administered dose. While significant advances in nanoparticle engineering and consequent therapeutic efficacy have been made, it is becoming clear that nanoparticle recognition by the mononuclear phagocyte system (MPS) poses an impassable junction in the current framework of nanoparticle development. Hence, this has negative consequences on the clinical translation of nanotechnology with respect to therapeutic efficacy, systemic toxicity and economic benefit. In order to improve the translation of nanomedicines from bench-to-bedside, there is a requirement to either modify nanomedicines in terms of how they interact with intrinsic processes in the body, or modulate the body to be more accommodating for nanomedicine treatments. Here we provide an overview of the current standard for design elements of nanoparticles, as well as factors to consider when producing nanomedicines that have minimal MPS-nanoparticle interactions; we explore this landscape across the cellular to tissue and organ levels. Further, rather than designing materials to suit the body, a growing research niche involves modulating biological responses to administered nanomaterials. We here discuss how developing strategic methods of MPS 'pre-conditioning' with small molecule or biological drugs, as well as implementing strategic dosing regimens, such as 'decoy' nanoparticles, is essential to increasing nanoparticle therapeutic efficacy. By adopting such a perspective, we hope to highlight the increasing trends in research dedicated to improving nanomedicine translation, and subsequently making a positive clinical impact.

Oncostatin M expression induced by bacterial triggers drives airway inflammatory and mucus secretion in severe asthma.

Exacerbations of symptoms represent an unmet need for people with asthma. Bacterial dysbiosis and opportunistic bacterial infections have been observed in, and may contribute to, more severe asthma. However, the molecular mechanisms driving these exacerbations remain unclear. We show here that bacterial lipopolysaccharide (LPS) induces oncostatin M (OSM) and that airway biopsies from patients with severe asthma present with an OSM-driven transcriptional profile. This profile correlates with activation of inflammatory and mucus-producing pathways. Using primary human lung tissue or human epithelial and mesenchymal cells, we demonstrate that OSM is necessary and sufficient to drive pathophysiological features observed in severe asthma after exposure to LPS or Klebsiella pneumoniae. These findings were further supported through blockade of OSM with an OSM-specific antibody. Single-cell RNA sequencing from human lung biopsies identified macrophages as a source of OSM. Additional studies using Osm-deficient murine macrophages demonstrated that macrophage-derived OSM translates LPS signals into asthma-associated pathologies. Together, these data provide rationale for inhibiting OSM to prevent bacterial-associated progression and exacerbation of severe asthma.

Over the counter low-dose cannabidiol: A viewpoint from the ACRE Capacity Building Group.

Amidst growing global acceptance of medicinal cannabinoids as a potential therapeutic interest in cannabidiol (CBD) is increasing. In Australia in 2020, a government inquiry examined the barriers that the public are experiencing in accessing medicinal cannabis. A number of recommendations to improve access were made. In response to these recommendations, the Australian therapeutics regulatory authority down-scheduled CBD from Prescription Only (Schedule 4) to Pharmacist Only (Schedule 3). As a group of early to mid-career researchers of the Australian Centre for Cannabinoid Clinical and Research Excellence (ACRE), we propose some considerations in relation to over-the-counter availability of CBD and opportunities to improve knowledge about its potential therapeutic benefits alongside its increased uptake.

Inhibition of miR-99a-5p prevents allergen-driven airway exacerbations without compromising type-2 memory responses in the intestine following helminth infection.

Acute exacerbations (AE) of asthma, remain one of the biggest concerns for patients living with asthma. As such, identifying the causes, the molecular mechanisms involved and new therapeutic interventions to prevent AE is a high priority. Immunity to intestinal helminths involves the reactivation of type-2 immune responses leading to smooth muscle contraction and mucus hypersecretion-physiological processes very similar to acute exacerbations in the airways following allergen exposure. In this study, we employed a murine model of intestinal helminth infection, using Heligmosomoides polygyrus, to identify miRNAs during active expulsion, as a system for the identification of miRNAs that may contribute to AE in the airways. Concomitant with type-2 immunity and expulsion of H. polygyrus, we identified miR-99a-5p, miR-148a-3p and miR-155-5p that were differentially regulated. Systemic inhibition of these miRNAs, alone or in combination, had minimal impact on expulsion of H. polygyrus, but inhibition of miR-99a-5p or miR-155-5p significantly reduced house dust mite (HDM)-driven acute inflammation, modelling human acute exacerbations. Immunological, pathological and transcriptional analysis identified that miR-155-5p or miR-99a-5p contribute significantly to HDM-driven AE and that transient inhibition of these miRNAs may provide relief from allergen-driven AE, without compromising anti-helminth immunity in the gut.

Clinical and cost-effectiveness of an online-delivered group-based pain management programme in improving pain-related disability for people with persistent pain-protocol for a non-inferiority randomised controlled trial (iSelf-help trial).

INTRODUCTION: Persistent non-cancer pain affects one in five adults and is more common in Maori-the Indigenous population of New Zealand (NZ), adults over 65 years, and people living in areas of high deprivation. Despite the evidence supporting multidisciplinary pain management programmes (PMPs), access to PMPs is poor due to long waiting lists. Although online-delivered PMPs enhance access, none have been codesigned with patients or compared with group-based, in-person PMPs. This non-inferiority trial aims to evaluate the clinical and cost-effectiveness of a cocreated, culturally appropriate, online-delivered PMP (iSelf-help) compared with in-person PMP in reducing pain-related disability. METHODS AND ANALYSIS: Mixed-methods, using a modified participatory action research (PAR) framework, involving three phases. Phase I involved cocreation and cultural appropriateness of iSelf-help by PAR team members. Phase II: The proposed iSelf-help trial is a pragmatic, multicentred, assessor-blinded, two-arm, parallel group, non-inferiority randomised controlled trial. Adults (n=180, age ≥18 years) with persistent non-cancer pain eligible for a PMP will be recruited and block randomised (with equal probabilities) to intervention (iSelf-help) and control groups (in-person PMP). The iSelf-help participants will participate in two 60-minute video-conferencing sessions weekly for 12 weeks with access to cocreated resources via smartphone application and a password-protected website. The control participants will receive group-based, in-person delivered PMP. Primary outcome is pain-related disability assessed via modified Roland Morris Disability Questionnaire at 6 months post intervention. Secondary outcomes include anxiety, depression, stress, pain severity, quality of life, acceptance, self-efficacy, catastrophising and fear avoidance. Data will be collected at baseline, after the 12-week intervention, and at 3 and 6 months post intervention. We will conduct economic analyses and mixed-method process evaluations (Phase IIA). ETHICS AND DISSEMINATION: The Health and Disability Ethics Committee approved the study protocol (HDEC18/CEN/162). Phase III involves dissemination of findings guided by the PAR team as outcomes become apparent. TRIAL REGISTRATION NUMBER: ACTRN 12619000771156.

Cortisol in relation to problematic eating behaviours, adiposity and symptom profiles in Major Depressive Disorder.

Aims: Major Depressive Disorder (MDD) is associated with an increased risk of chronic disease related to weight gain, problematic eating behaviours and neuroendocrine changes. MDD is frequently associated with altered hypothalamic-pituitary-adrenal axis activity and cortisol secretion, where cortisol has been implicated in regulating energy balance, food intake and depressogenic weight changes. However, little research has examined the relationships between cortisol, adiposity and depressogenic problematic eating behaviours. Method: Plasma cortisol concentrations were compared between 37 participants with MDD reporting appetite/weight loss, 43 participants with MDD reporting appetite/weight gain, and 60 healthy controls, by sex. Associations between cortisol, indices of adiposity and problematic eating behaviours were then assessed after accounting for demographic variables and depressive symptoms. Depressive symptoms were assessed using the Depression subscale of the Depression, Anxiety and Stress Scale, and eating behaviours with the Dutch Eating Behaviours Questionnaire and Yale Food Addiction Scale. Results: Participants with MDD reporting appetite/weight loss had higher cortisol compared to controls, and marginally higher cortisol than those with MDD reporting appetite/weight gain. Cortisol negatively and significantly accounted for unique variance in body mass index and waist circumference after accounting for variance associated with age, sex and depressive symptoms, however it was not a significant predictor of problematic eating behaviours, such as emotional eating or food addiction. Cortisol concentrations did not differ between sexes. Conclusion: The results indicate that cortisol is related to lower indices of adiposity and depressogenic symptoms of appetite/weight loss but is not related to problematic eating behaviours and appetite increases in MDD. These findings provide further evidence that the melancholic and atypical subtypes of MDD are associated with differential neuroendocrine and anthropometric indices, as well as behavioural and symptom profiles. Further research investigating the temporal nature of the identified relationships may assist in facilitating the development of improved interventions for individuals affected by weight changes in MDD.

Plasma prolactin is higher in major depressive disorder and females, and associated with anxiety, hostility, somatization, psychotic symptoms and heart rate.

Background: Major Depressive Disorder (MDD) is linked to poor physical health including an increased risk of developing cardiometabolic disease (CMD), yet the underlying physiology of this relationship is not clear. One pathophysiological mechanism that may underlie this relationship is neuroendocrine dysregulation, including that of the hormone prolactin. Prolactin has a role in the regulation of stress, and it is linked to anxiety, hostility, and weight gain, which are all implicated in MDD and increased CMD risk. However, little research has examined plasma prolactin in association with psychological symptoms of MDD or biometric indices of CMD risk. Method: Plasma samples of 120 participants (n â€‹= â€‹60 meeting DSM-5 criteria for MDD and n â€‹= â€‹60 control; age and sex matched) were analysed to assess prolactin concentration. Biometric data (BMI, waist circumference, blood pressure and heart rate) were collected, and participants completed the Brief Symptom Inventory (BSI) and Depression Anxiety Stress Scale (DASS). Results: Plasma prolactin was higher in participants with MDD versus controls (8.79 â€‹± â€‹5.16 â€‹ng/mL and 7.03 â€‹± â€‹4.78 â€‹ng/mL, respectively; F â€‹= â€‹4.528, p â€‹= â€‹0.035) and among females versus males (9.14 â€‹± â€‹5.57 â€‹ng/mL and 6.31 â€‹± â€‹3.70 â€‹ng/mL, respectively; F â€‹= â€‹9.157, p â€‹= â€‹0.003). Prolactin was correlated with several psychological symptoms including anxiety, hostility and somatization, and with heart rate, but not with any other biometric measures. Conclusions: The results of this study indicate that neuroendocrine dysregulation in MDD may extend to the hormone prolactin, with prolactin being specifically associated with a subset of related psychometric and cardiovascular measures.

Psychopathy and substance use in relation to prostitution and pimping among women offenders.

Much research exists examining sex work in relation to substance use and other physical health risks. However, there is a paucity of research exploring person-level characteristics, such as pathological personality traits, in relation to sex work. This study used a large sample of incarcerated women (n = 310) to address 2 aims involving prostitution and pimping. The first aim was an attempt to replicate and generalize previous findings from Edwards and Verona (2016) on associations among psychopathic traits, substance use, and prostitution. The second aim explored relationships among substance use, psychopathic traits, and pimping. Psychopathy and substance use were measured using the Psychopathy Checklist-Revised and a modified version of the Addiction Severity Index, respectively. Prostitution and pimping were coded through institutional file review and self-report. Results replicated those of the study by Edwards and Verona (2016), such that psychopathy, and impulsive-antisocial traits specifically, positively related to prostitution above substance use. Results for the second aim showed that PCL-R total and impulsive-antisocial traits were also related to pimping, above the influence of substance use. Substance use was also higher in women who engaged in pimping versus those who did not. Results indicate that substance use and impulsive-antisocial traits of psychopathy are independently related to engagement in distinct roles across sex work contexts among incarcerated women. (PsycInfo Database Record (c) 2021 APA, all rights reserved).

Overeating and food addiction in Major Depressive Disorder: Links to peripheral dopamine.

The concept of food addiction refers to addiction-like behaviours that develop in association with the intake of highly palatable foods. Previous research indicates that a high proportion of individuals with Major Depressive Disorder (MDD) meet the criteria for food addiction, and are also at an increased risk of weight gain and chronic disease. In the central nervous system, dopamine is a neurotransmitter associated with reward salience and food intake, whereas peripheral dopamine is involved in sympathetic stress regulation, digestion and gastrointestinal motility. However, little research has examined relationships between peripheral dopamine, depressive symptoms and problematic eating behaviours in MDD. Biometrics, psychopathology and plasma dopamine levels were compared between participants with MDD (n = 80) and controls (n = 60). Participants were sub-categorised into those meeting or not meeting Yale Food Addiction Scale (YFAS) criteria. Psychometric measures of mood and appetite were used to assess MDD symptoms, problematic eating behaviours and food-addiction related symptoms. Twenty-three (23; 29%) MDD participants met the Yale criteria for food addiction. Depressed individuals meeting YFAS criteria had significantly greater psychopathology scores for both mood and eating compared to depressed individuals not meeting YFAS criteria and controls. A significant interaction between food addiction status and sex was also observed for plasma dopamine levels. Plasma dopamine levels correlated positively with disordered eating behaviours in females, and negatively in males. The results provide evidence that depressogenic excess eating and weight gain are associated with peripheral dopamine levels. Longitudinal research is warranted investigating endocrine dysregulation and excess eating in MDD, which may inform interventions and reduce chronic disease risk in affected individuals.

Unmet treatment needs in patients with chronic pelvic pain in a New Zealand gynaecology service.

BACKGROUND: Chronic pelvic pain, which carries a high burden of disability and distress, is a common presentation to gynaecology clinics. While there is increasing acknowledgment of the complexity of chronic pelvic pain, and the benefits of providing management from a multidisciplinary team within a sociopsychobiomedical framework, the mainstay of management in gynaecology outpatient clinics remains within a single clinician biomedical-focused model. This model of care is only sufficient for women who present with minimal psychosocial complexity to their pain. AIMS: To estimate the proportion of women attending the gynaecology outpatient clinic at a public women's hospital in New Zealand referred with chronic pelvic pain who have needs unmet by the current biomedical model of care. Informed by international research, pain catastrophising was used as a psychosocial correlate of this complexity. METHODS: An audit was undertaken of 100 consecutive pre-appointment questionnaires of women, referred to a gynaecology outpatient clinic for review of pelvic pain of duration over six months, with no red flags in their referral history. RESULTS: An unexpectedly high level of catastrophic thoughts about pain was reported. Seventy-seven percent of the women scored in the high or severe range, with 55% endorsing clinically significant scores for helpless catastrophising. CONCLUSIONS: The Pain Catastrophising Scores in this cohort were found to be higher than those in similar groups in the published international literature and also than in patients referred to the local tertiary level pain management centre, further reinforcing the need for investment into appropriate services for women with chronic pelvic pain.

Cholinesterase Inhibitory Arisugacins L-Q from a Penicillium sp. Isolate Obtained through a Citizen Science Initiative and Their Activities in a Phenotype-Based Zebrafish Assay.

Phenotype-based screening of a fungal extract library yielded an active sample from a Penicillium sp. isolate that impaired zebrafish motility. Bioassay-guided purification led to the identification of 14 meroterpenoids including six new metabolites, arisugacins L-Q (4, 5, 8, and 12-14), seven known arisugacins (1-3, 6, 7, 9, and 10), and one known terreulactone (11). Their structures were determined using a combination of NMR and HRESIMS data, evidence secured from theoretical and experimental ECD spectra, and the modified Mosher's method. The purified compounds were tested in zebrafish embryos, as well as in vitro for cholinesterase inhibition activities. Compound 12 produced defects in myotome structure (metameric muscle, which is critical for locomotion) in vivo and showed the most potent and selective acetylcholinesterase inhibitory activity with an IC50 of 191 nM in vitro. The phenotype assay was also used to reveal bioactivities for several previously reported arisugacins, which had failed to show activity in prior cell-based and in vitro testing. This study demonstrates that utilization of the zebrafish phenotype assay is an effective approach for the identification of bioactive extracts, is compatible with the bioassay-guided compound purification strategies, and offers a valuable tool for probing complex natural product sources to detect bioactive small molecules with potential therapeutic or other commercial applications.

Weight gain in Major Depressive Disorder: Linking appetite and disordered eating to leptin and ghrelin.

Major Depressive Disorder (MDD) involves changes in appetite and weight, with a subset of individuals at an increased risk of weight gain. Pathways to weight gain may include appetite disturbances, excess eating, and dysregulation of appetite hormones. However, little research has simultaneously examined relationships between hormones, eating behaviours and MDD symptoms. Plasma ghrelin and leptin, biometrics, eating behaviours and psychopathology were compared between depressed (n = 60) and control (n = 60) participants. Depressed participants were subcategorised into those with increased or decreased appetite/weight for comparison by subtype. The Dutch Eating Behaviours Questionnaire and Yale Food Addiction Scale measured eating behaviours. Disordered eating was higher in MDD than controls, in females than males, and in depressed individuals with increased, compared to decreased, appetite/weight. Leptin levels were higher in females only. Leptin levels correlated positively, and ghrelin negatively, with disordered eating. The results provide further evidence for high levels of disordered eating in MDD, particularly in females. The correlations suggest that excessive eating in MDD is significantly linked to appetite hormones, indicating that it involves physiological, rather than purely psychological, factors. Further, longitudinal, research is needed to better understand whether hormonal factors play a causal role in excessive eating in MDD.

Barriers and Enablers to Implementing the Children's Hospital Early Warning Score: A Pre- and Post-Implementation Qualitative Descriptive Study.

PURPOSE: The purpose of this study was to identify and compare barriers and enablers to the implementation of the Children's Hospital Early Warning Score (CHEWS) on a pediatric inpatient unit pre- and post-implementation. DESIGN AND METHODS: A qualitative descriptive design, guided by the Theoretical Domains Framework, was used to conduct semi-structured focus groups and individual interviews with nurses on a pediatric inpatient unit to identify barriers and enablers in the pre- and post- CHEWS implementation phases. Data were analyzed using a directed content analysis approach followed by inductive thematic analysis. RESULTS: Two pre-implementation focus groups (N = 15) and 8 post-implementation individual interviews with nurses were conducted. We identified pre- and post- CHEWS implementation barriers related to clinical decision making, interprofessional relationships, the unit context, and negative emotions, and enablers related to quality of care and patient safety. The identified barriers and enablers to implementation were categorized within 13 TDF domains. CONCLUSIONS: Our findings illustrate a range of barriers and enablers to CHEWS implementation during the pre- and post-implementation phases. Tailored strategies are needed to overcome barriers related to nurses' perceptions of CHEWS impeding clinical decision-making and interprofessional collaboration. By addressing the identified barriers, we can leverage nurses' motivations for using CHEWS to improve the quality of patient care and enhance patient safety. PRACTICE IMPLICATIONS: The barriers and enablers identified in this study can be used to select implementation strategies to support the use of early warning systems in pediatric nursing practice.