Cellular clearance of circulating transthyretin decreases cell-nonautonomous proteotoxicity in Caenorhabditis elegans.

Cell-autonomous and cell-nonautonomous mechanisms of neurodegeneration appear to occur in the proteinopathies, including Alzheimer's and Parkinson's diseases. However, how neuronal toxicity is generated from misfolding-prone proteins secreted by nonneuronal tissues and whether modulating protein aggregate levels at distal locales affects the degeneration of postmitotic neurons remains unknown. We generated and characterized animal models of the transthyretin (TTR) amyloidoses that faithfully recapitulate cell-nonautonomous neuronal proteotoxicity by expressing human TTR in the Caenorhabditis elegans muscle. We identified sensory neurons with affected morphological and behavioral nociception-sensing impairments. Nonnative TTR oligomer load and neurotoxicity increased following inhibition of TTR degradation in distal macrophage-like nonaffected cells. Moreover, reducing TTR levels by RNAi or by kinetically stabilizing natively folded TTR pharmacologically decreased TTR aggregate load and attenuated neuronal dysfunction. These findings reveal a critical role for in trans modulation of aggregation-prone degradation that directly affects postmitotic tissue degeneration observed in the proteinopathies.

Psychosocial and lifestyle predictors of distress and well-being in people with mental illness during the COVID-19 pandemic.

OBJECTIVES: People with mental illness may be vulnerable to psychological distress and reduced well-being during the COVID-19 pandemic. The aim of this study was to assess psychosocial and lifestyle predictors of distress and well-being in people with mental illness during the pandemic. METHOD: People with mental illness who participated in an exercise programme prior to the pandemic were invited to complete surveys about mental health and lifestyle corresponding to before and during the pandemic. RESULTS: Social support reduced, alcohol intake increased, and sleep quality and diet worsened during the pandemic, contributing to distress. Psychological distress was associated with the two or more mental illnesses, and negatively associated with having a physical disease. Better diet appeared to protect against increases in distress; loneliness hindered improvements in well-being. CONCLUSIONS: Healthy lifestyle programmes designed to improve social connection may improve health for people with mental illnesses during and after the COVID-19 pandemic.

Preferences of people with mental illness for engaging in exercise programs under COVID-19 restrictions.

OBJECTIVES: People with mental illness may be vulnerable to decline in mental health and reduced physical activity because of the COVID-19 pandemic and associated restrictions. The aim of this study was to inform the design of physical activity interventions for implementation under these conditions to improve/maintain well-being and physical activity in this population. METHODS: People with mental illness who had participated in a physical activity program prior to the pandemic were invited to complete a survey about the impact of COVID-19 on mental health and physical activity and their preferences for engaging in a physical activity program under pandemic-related restrictions. RESULTS: More than half the 59 respondents reported worse mental health and lower physical activity during the pandemic. The preferred format for a physical activity program was one-on-one exercise instruction in-person in a park. Program components endorsed as helpful included incentivization, provision of exercise equipment and fitness devices, and daily exercise programs. About a third of the participants reported limitations in using technology for a physical activity program. CONCLUSIONS: In-person exercise support is preferred by people with mental illnesses during pandemic-related restrictions. Enablement strategies such as providing equipment and self-monitoring devices should be utilized; assistance may be needed to incorporate the use of technology in exercise programs.

A comparison study of three physical activity measurement tools examining acceptability in people with psychosis.

OBJECTIVE: To compare the acceptability of three distinct physical activity measurement tools in people with psychosis: an objective measurement tool, a self-report measure, and an exercise capacity test. METHODS: We measured the completion rate for each measurement tool. Participants rated the ease/difficulty of each measure using a 7-point Likert scale. Participants were also asked to rank the three tools in order of the ease of use. RESULTS: Sixty-six per cent (46/69) of participants completed all three assessment tools, and 60.9% (42/69) completed the acceptability questionnaire. The majority of the participants found it easy to complete all three measurement tools. The majority (52.8%) of the participants ranked the objective measurement tool as the easiest to use. CONCLUSION: All three measures were acceptable to people with psychosis, but objective measurement tools may be easier to use.

Erythroferrone contributes to hepcidin suppression and iron overload in a mouse model of ß-thalassemia.

Inherited anemias with ineffective erythropoiesis, such as ß-thalassemia, manifest inappropriately low hepcidin production and consequent excessive absorption of dietary iron, leading to iron overload. Erythroferrone (ERFE) is an erythroid regulator of hepcidin synthesis and iron homeostasis. Erfe expression was highly increased in the marrow and spleen of Hbb(Th3/+) mice (Th3/+), a mouse model of thalassemia intermedia. Ablation of Erfe in Th3/+ mice restored normal levels of circulating hepcidin at 6 weeks of age, suggesting ERFE could be a factor suppressing hepcidin production in ß-thalassemia. We examined the expression of Erfe and the consequences of its ablation in thalassemic mice from 3 to 12 weeks of age. The loss of ERFE in thalassemic mice led to full restoration of hepcidin mRNA expression at 3 and 6 weeks of age, and significant reduction in liver and spleen iron content at 6 and 12 weeks of age. Ablation of Erfe slightly ameliorated ineffective erythropoiesis, as indicated by reduced spleen index, red cell distribution width, and mean corpuscular volume, but did not improve the anemia. Thus, ERFE mediates hepcidin suppression and contributes to iron overload in a mouse model of ß-thalassemia.

Embedding exercise interventions as routine mental health care: implementation strategies in residential, inpatient and community settings.

OBJECTIVES: Evaluation of physical activity (PA) programs among populations with severe mental illness (SMI) has predominately focused on efficacy and therapeutic benefits. There is now strong evidence to support the benefits of PA in people with SMI. What remains is a gap in the implementation of pragmatic and sustainable PA interventions in mental-health settings. The current paper provides examples of interventions that have been successfully implemented in Australian settings, identifies key components of successful PA interventions and outlines practical strategies that can assist with widespread implementation of PA interventions in mental-health settings. CONCLUSIONS: There is an emergence of PA interventions being imbedded within a variety of mental-health settings. These interventions vary in terms of mode and intensity of service delivery. Yet, all aim to increase PA and reduce sedentary behaviour. Adopting the identified strategies may help facilitate successful implementation and increase access to PA interventions for mental-health service users.

Physical activity preferences, motivators, barriers and attitudes of adults with mental illness.

BACKGROUND: Adults with mental illness may have specific attitudes toward physical activity (PA). AIMS: To assess the PA attitudes of non-institutionalised adults with mental illness, and associations with psychological distress. METHOD: Participants completed questionnaires on activity preferences (type, context and sources of support), motivators, barriers and attitudes toward personal training (PT). Relationships between responses and distress were assessed using logistic regressions. RESULTS: One-hundred forty-two participants completed the questionnaires. PA context preferences included activities done close to home, outdoors, with professional instruction, with people of the same ability, as part of a healthy lifestyle program and with a social component. The most commonly endorsed source of support was an exercise instructor. Most respondents had never received PT; however, PT had high acceptability. Common barriers included poor physical and mental health, and lack of money. Distress was positively associated with barriers of poor mental health, tiredness, disorganisation, exhaustion and being shy/embarrassed (p ≤ 0.001). CONCLUSIONS: Local outdoor walking groups that include social and healthy lifestyle components, and that are led by an exercise instructor who can provide support for overcoming barriers, may best meet PA interests of this group. PT could be an acceptable method for offering individualised support.

The feasibility and acceptability of questionnaires and accelerometry for measuring physical activity and sedentary behaviour in adults with mental illness.

BACKGROUND: Adults with mental illness may have difficulties with data collection methods such as questionnaires and accelerometry. AIMS: To assess the utility of questionnaires and accelerometry for assessing physical activity (PA) and sedentary behaviour (SB) in non-institutionalised adults with mental illness. METHODS: Participants were recruited from outpatient clinics and community organisations. Participants completed PA and SB questionnaires, wore accelerometers for 7 d, and rated the ease/difficulty of completing study components. Recruitment numbers, adherence, and ease/difficulty ratings were examined. Ease/difficulty ratings were compared between study components, and between participants by distress level. RESULTS: One hundred forty-two participants completed the questionnaires; they found it easier to report PA than reclining time (p = 0.017), and reclining time than sitting time (p < 0.001). Participants with high distress found it more difficult to report sitting time and PA than participants with low distress (p < 0.017). Ninety-nine participants (70%) completed the accelerometry; the majority (88%) met the minimum wear-time criteria. They found it easier to wear the monitor during the day than while sleeping (p < 0.001), and easier to complete accelerometry than questionnaires (p < 0.001). CONCLUSIONS: Accelerometry was more feasible for assessing SB than questionnaires. Questionnaires were feasible for assessing PA, but less acceptable for people experiencing high distress.

The effect of exercise on global, social, daily living and occupational functioning in people living with schizophrenia: A systematic review and meta-analysis.

BACKGROUND: Schizophrenia is associated with high rates of global, social and occupational functional impairments. While prior meta-analyses have extensively examined the impact of exercise on physical and mental health, the impact on functioning in schizophrenia have yet to be fully established. This review aimed to update the evidence base regarding the impact of exercise on functioning in schizophrenia, and explore moderators of effect. METHODS: A systematic search was conducted to identify randomized controlled trials (RCTs) of exercise evaluating global functioning versus any comparator in people with schizophrenia; between group meta-analyses of global functioning (and secondary - social, living skills, occupational, adverse events) were computed using a random effects model. Subgroup analyses based on diagnosis and aspects of the intervention were conducted. RESULTS: 18 full text articles were included, involving 734 participants. A moderate impact of exercise on global functioning was found (g = 0.40, 95 % C·I. = 0.12 to 0.69, p = 0.006), with a moderate impact of exercise on social (N = 5, g = 0.54 95 % C.I = 0.16 to 0.9 p = 0.005), and daily living functioning (N = 3, g = 0.65, 95 % C.I. = 0.07 to 1.22, p = 0.005). CONCLUSIONS: There is good evidence that exercise can improve the global functioning of people with schizophrenia, with preliminary evidence for social and daily living skills; exercise should be considered an important adjunct to usual care. Higher impacts on global functioning were seen in aerobic interventions and of at least moderate to vigorous intensity. More research is required into resistance training, in early psychosis cohorts and to evaluate the comparison of exercise with other established psychosocial therapies.

Changes in self-determined motivation for exercise in people with mental illness participating in a community-based exercise service in Australia.

Exercise has diverse benefits for physical and mental health in people with mental illness; however, it is unclear how to effectively promote exercise motivation in this group. The aim of this study is to evaluate the effectiveness of interventions utilising exercise instruction or behavioural counselling with people with mental illness to improve self-determined motivation for exercise, and physical and mental health. Participants were adults (aged 18+ years) receiving mental health services. Participants could choose from two 8-week programs comprising weekly group-based sessions delivered by an exercise physiologist: (a) exercise instruction in a gym (GYM) or (b) behavioural counselling (MOT). Self-determined motivation was measured using the Behaviour Regulations for Exercise Questionnaire (BREQ3). Physical health indicators included waist circumference, blood pressure, leg strength (sit-to-stand test), physical capacity (six-minute walk test) and self-reported exercise. Mental health was assessed using the Kessler-6 scale of psychological distress. Most of the 95 participants chose exercise instruction (GYM = 60; MOT = 35). At baseline, participants who chose MOT had higher external motivation, body mass index, waist circumference and psychological distress, and a higher proportion had multiple physical comorbidities than those who chose GYM. More self-determined motivation was associated with meeting physical activity guidelines. Post-intervention, GYM participants had significant improvements in self-determined motivation, psychological distress and sit-to-stand test; MOT participants had significant improvements in integrated regulation, self-reported exercise and physical functioning. In conclusion, exercise instruction can improve self-determined motivation; however, more intensive behavioural counselling support may be needed to improve self-determined motivation. Counselling programs can increase exercise behaviour and may appeal more to people with poorer health and more external motivation. Findings have high ecological validity and applicability to real-world implementation of exercise interventions. To accommodate people with diverse conditions and motivations, motivational counselling should be combined with practical exercise support, and participants afforded the autonomy to decide their level of involvement.

Biopsychology of Physical Activity in People with Schizophrenia: An Integrative Perspective on Barriers and Intervention Strategies.

People with severe mental illness such as schizophrenia experience high physical comorbidity, leading to a 15-20-year mortality gap compared with the general population. Lifestyle behaviours such as physical activity (PA) play important roles in the quest to bridge this gap. Interventions to increase PA engagement in this population have potential to be efficacious; however, their effectiveness can be hindered by low participant engagement, including low adherence and high drop-out, and by implementation of interventions that are not designed to compensate for the cognitive and motivational impairments characteristic for this group. Moreover, and importantly, the negative symptoms of schizophrenia are associated with neurobiological changes in the brain, which-based on principles of biopsychology-can contribute to poor motivation and impaired decision-making processes and behavioural maintenance. To increase PA levels in people with schizophrenia, better understanding of these neurological changes that impact PA engagement is needed. This has the potential to inform the design of interventions that, through enhancement of motivation, could effectively increase PA levels in this specific population. Incorporating strategies that address the dopamine dysregulation associated with schizophrenia, such as boosting the role of reward and self-determined motivation, may improve long-term PA maintenance, leading to habitual PA. Consideration of motivation and behavioural maintenance is also needed to impart health benefits such as prevention of chronic disease, which is associated with currently low PA levels in this high metabolic risk population. Taking a biopsychological perspective, we outline the neural pathways involved in motivation that are impacted by schizophrenia and propose strategies for promoting motivation for and PA engagement from adoption to habit formation.

Functional heterogeneity of CD11c-positive adipose tissue macrophages in diet-induced obese mice.

Obesity represents a state of chronic, low grade inflammation and is associated with infiltration of increased numbers of adipose tissue macrophages (ATMs). Diet-induced obesity leads to an increase in non-inflammatory M1-like ATMs displaying the CD11c surface marker. We assessed the function of CD11c-positive ATMs when insulin resistant high fat diet (HFD) mice become insulin-sensitive after switching from HFD to normal chow (NC). HFD mice rapidly become insulin-sensitive in all major insulin-target tissues, including muscle, liver, and adipose tissue, after the diet switch. In adipose tissue the CD11c-positive macrophages remain constant in number despite the presence of insulin sensitivity, but these macrophages now assume a new phenotype in which they no longer exhibit increased inflammatory pathway markers. Adipose tissue markers of apoptosis and necrosis were elevated on HFD and remain high after the HFD --> NC diet switch. Furthermore, ATM accumulation preceded detectable adipocyte necrosis at the early phase of HFD. Together, these results indicate that 1) CD11c-positive M1-like ATMs can exhibit phenotypic plasticity and that the polarization of these cells between inflammatory and non-inflammatory states is well correlated to the presence of absence of insulin resistance, and 2) adipocyte necrosis and apoptosis can be dissociated from ATM accumulation.

Multi-tissue, selective PPARγ modulation of insulin sensitivity and metabolic pathways in obese rats.

Peroxisome proliferator-activated receptor-γ (PPARγ) ligands, including the insulin-sensitizing thiazolidinedione drugs, transcriptionally regulate hundreds of genes. Little is known about the relationship between PPARγ ligand-specific modulation of cellular mechanisms and insulin sensitization. We characterized the insulin sensitivity and multitissue gene expression profiles of lean and insulin-resistant, obese Zucker rats untreated or treated with one of four PPARγ ligands (pioglitazone, rosiglitazone, troglitazone, and AG-035029). We analyzed the transcriptional profiles of adipose tissue, skeletal muscle, and liver from the rats and determined whether ligand treatment insulin-sensitizing potency was related to ligand treatment-induced alteration of functional pathways. Ligand treatments improved insulin sensitivity in obese rats to varying degrees. Adipose tissue profiles revealed ligand treatment-selective modulation of inflammatory and branched-chain amino acid (BCAA) metabolic pathways, which correlated with ligand treatment-specific insulin-sensitizing potency. Skeletal muscle profiles showed that obese rats exhibited elevated expression of adipocyte and slow-twitch fiber markers, which further increased after ligand treatment, but the magnitude of the treatment-induced changes was not correlated with insulin sensitization. Although PPARγ ligand treatments heterogeneously improved dysregulated expression of cholesterol and fatty acid biosynthetic pathways in obese rat liver, these alterations were not correlated with ligand insulin-sensitizing potency. PPARγ ligand treatment-specific insulin-sensitizing potency correlated with modulation of adipose tissue inflammatory and BCAA metabolic pathways, suggesting a functional relationship between these pathways and whole body insulin sensitivity. Other PPARγ ligand treatment-induced functional pathway changes were detected in adipose tissue, skeletal muscle, and liver profiles but were not related to degree of insulin sensitization.

Characterization of PF-4708671, a novel and highly specific inhibitor of p70 ribosomal S6 kinase (S6K1).

S6K1 (p70 ribosomal S6 kinase 1) is activated by insulin and growth factors via the PI3K (phosphoinositide 3-kinase) and mTOR (mammalian target of rapamycin) signalling pathways. S6K1 regulates numerous processes, such as protein synthesis, growth, proliferation and longevity, and its inhibition has been proposed as a strategy for the treatment of cancer and insulin resistance. In the present paper we describe a novel cell-permeable inhibitor of S6K1, PF-4708671, which specifically inhibits the S6K1 isoform with a Ki of 20 nM and IC50 of 160 nM. PF-4708671 prevents the S6K1-mediated phosphorylation of S6 protein in response to IGF-1 (insulin-like growth factor 1), while having no effect upon the PMA-induced phosphorylation of substrates of the highly related RSK (p90 ribosomal S6 kinase) and MSK (mitogen- and stress-activated kinase) kinases. PF-4708671 was also found to induce phosphorylation of the T-loop and hydrophobic motif of S6K1, an effect that is dependent upon mTORC1 (mTOR complex 1). PF-4708671 is the first S6K1-specific inhibitor to be reported and will be a useful tool for delineating S6K1-specific roles downstream of mTOR.

Association Between COVID-19 Relief Funds and Hospital Characteristics in the US.

Importance: In response to financial stress created by the reduction in care during the COVID-19 pandemic, hospitals received financial assistance through the Coronavirus Aid, Relief, and Economic Security (CARES) Act program. To date, the allocation of CARES Act funding is not well understood. Objective: To examine the disbursement of the High-Impact Distribution CARES Act funds and the association between financial assistance and hospital-level financial resources prior to the COVID-19 pandemic. Design Setting and Participants: This cross-sectional analysis of US-based hospitals and health systems assesses the hospital characteristics associated with CARES Act funding with linear regression models using linked hospital and health system-level information on CARES Act funding with hospital characteristics from Hospital Cost Report data. Exposures: Hospital and health system CARES Act financial assistance. Main Outcomes and Measures: Hospital and health system affiliation, status, and financial health prior to the COVID-19 pandemic. Data analysis took place from December 2020 through June 2021. Results: The analysis included 952 hospital-level entities with an average payment of $33.6 million, most of which was received during the first payment round. Wide ranges existed in CARES Act funding, with 24% of matched hospitals receiving less than $5 million in funding and 8% receiving more than $50 million. Academic-affiliated hospitals, hospitals with higher pre-COVID-19 assets and hospitals with higher COVID-19 cases received higher levels of funding, while critical access hospitals received lower levels of financial assistance. A 10% increase in hospital assets, endowment size, and COVID-19 cases was associated with 1.4% (95% CI, 0.8% to 2.0%; P = .003), 0.2% (95% CI, 0.1% to 0.3%; P < .001), and 3.5% (95% CI, 2.8% to 4.2%; P < .001) increases in CARES Act funding, respectively. Conclusions and Relevance: In this cross-sectional study of US hospitals and health systems, findings suggest that High-Impact Distribution CARES Act funds may have disproportionately gone to hospitals that were in a stronger financial situation prior to the pandemic compared with those that were not, but funds also went disproportionately to those that eventually had the most cases.

Effect of orchiectomy on renal function in control and diabetic rats with chronic inhibition of nitric oxide.

1. Male gender is associated with higher blood pressure (BP) and more rapid loss of renal function in a spectrum of clinical and experimental renal diseases, including diabetic nephropathy. Consequently, modulation of testosterone levels could exert beneficial effects in the diabetic kidney. 2. The aim of the present study was to determine whether testosterone deficiency (orchiectomy) could influence BP and renal function in streptozotocin-diabetic rats, with or without accelerated endothelial dysfunction achieved by chronic inhibition of nitric oxide (NO) synthesis using N(G)-nitro-L-arginine methyl ester (l-NAME; 40-100 mg/L in the drinking water for 2 weeks), as well as in age-matched non-diabetic rats subjected to the same interventions. 3. Orchiectomy did not affect L-NAME-induced increases in BP in non-diabetic or diabetic rats. In non-diabetic rats, orchiectomy prevented L-NAME-induced increases in proteinuria. These effects on proteinuria were not observed in diabetic rats. In non-diabetic rats, orchiectomy had no effect on renal haemodynamics in animals receiving vehicle and did not affect L-NAME-induced changes in renal haemodynamics, characterized by reductions in renal plasma flow (RPF) and higher filtration fractions (FF). In intact diabetic rats, L-NAME treatment resulted in lower RPF. This difference was not observed in diabetic rats subjected to orchiectomy, although L-NAME-treated diabetic orchiectomized rats had lower RPF and higher FF compared with vehicle-treated intact diabetic rats. 4. In conclusion, we report modest beneficial effects of orchiectomy on proteinuria in normal, but not in diabetic, rats with inhibition of NO production. This suggests that testosterone reduction does not attenuate the deleterious impact of the diabetic metabolic milieu in the kidney.

High Intensity Interval training (HIIT) for people with severe mental illness: A systematic review & meta-analysis of intervention studies- considering diverse approaches for mental and physical recovery.

There is a mortality gap of 15 to 20 years for people with severe mental illness (SMI - psychotic spectrum, bipolar, major depressive disorders). Modifiable risk factors include inactivity and low cardiorespiratory fitness (CRF). Exercise can improve mental and physical outcomes; optimal type and intensity of exercise for people with SMI has yet to be determined. High Intensity Interval training (HIIT) is an exercise with distinct cardio-metabolic advantages in other disease populations compared to traditional moderate intensity continuous training (MCT). We investigated the feasibility and efficacy of HIIT for people with SMI. Major electronic databases were searched, identifying HIIT studies for adults experiencing SMI.Data on feasibility, safety, study design, sample characteristics, and physical and psychological outcomes were extracted and systematically reviewed. Meta-analyses were conducted within group, pre and post HIIT interventions, and between group, to compare HIIT with control conditions. Nine articles were identified including three pre/post studies, one non randomised and five randomised trials, (366 participants, 45.1% female). HIIT appears as feasible as MCT, with few safety concerns. Following HIIT, there was a moderate improvement in CRF and depression. There was no difference between HIIT and MCT for adherence or CRF.HIIT improved depression more than MCT.

Feasibility and Acceptability of a Student-Led Lifestyle (Diet and Exercise) Intervention Within a Residential Rehabilitation Setting for People With Severe Mental Illness, GO HEART (Group Occupation, Health, Exercise And Rehabilitation Treatment).

PURPOSE: People with severe mental illness (SMI) experience poor physical health and premature mortality, contributed significantly by modifiable lifestyle risk factors such as poor nutrition, low cardiorespiratory fitness, and physical inactivity. Lifestyle interventions can reduce cardiometabolic risk and confer a range of other positive mental and physical health benefits. We assessed the feasibility, acceptability, safety, and preliminary effectiveness of a lifestyle (combined dietary and exercise) intervention lead by senior exercise and dietetics students in a residential mental health rehabilitation setting. DESIGN: Single arm, prospective study evaluating outcomes pre and post a 10-week dietary and exercise intervention. METHOD: People with SMI from three residential rehabilitation units participated in a mixed aerobic and resistance training exercise intervention three times per week that was combined with a dietary intervention (six individual and group sessions). Primary outcome considerations were feasibility (recruitment, retention, and participation rates), acceptability, and adverse events. Secondary outcomes were preliminary effectiveness; (functional exercise capacity, volume of exercise, and metabolic markers), psychiatric symptoms, quality of life, and attitudes to exercise. RESULTS: Forty-two participants were recruited (92% primary diagnosis of schizophrenia). Intervention feasibility was supported by high levels of recruitment (68%), retention (77%), and participation (70% exercise, 65% diet sessions); and the absence of serious adverse events. Significant improvements in functional exercise capacity, volume of exercise, general psychiatric symptoms, and negative psychotic symptoms occurred. Anthropometric and metabolic blood markers did not change. While the intervention was acceptable to participants, motivation for and perceived value of exercise reduced over 10 weeks. CONCLUSIONS: A brief pragmatic student-led lifestyle intervention integrated into usual mental health care was feasible, acceptable, safe, and scalable across two additional mental health residential rehabilitation sites, and resulted in physical and mental health improvements. Increased frequency of dietary sessions and length of dietary intervention may improve metabolic outcomes in the future. People with SMI living in residential rehabilitation units should have access to lifestyle programs to address modifiable lifestyle risk factors. While this brief intervention was feasible and acceptable, this study highlights some of the challenges associated with maintaining motivation for healthy lifestyles for people with SMI. Longer term investigation of real-world lifestyle interventions is warranted, together with additional interventions that may support people with SMI to sustain motivation to address lifestyle factors. CLINICAL TRIAL REGISTRATION: The trial was registered with the Australian New Zealand Clinical Trials Registry (ANZCTR), Unique Identifier: ACTRN 12618000478213, http://www.anzctr.org.au Universal trial number (UTN)-U1111-1211-4009.

Demonstration of proof of mechanism and pharmacokinetics and pharmacodynamic relationship with 4'-cyano-biphenyl-4-sulfonic acid (6-amino-pyridin-2-yl)-amide (PF-915275), an inhibitor of 11 -hydroxysteroid dehydrogenase type 1, in cynomolgus monkeys.

Glucocorticoids, through activation of the glucocorticoid receptor (GR), regulate hepatic gluconeogenesis. Elevated hepatic expression and activity of 11beta-hydroxysteroid dehydrogenase type 1 (11betaHSD1) play a key role in ligand-induced activation of the GR through the production of cortisol. Evidence from genetically modified mice suggests that inhibition of 11betaHSD1 might be a therapeutic approach to treat the metabolic syndrome. We have identified a potent 11betaHSD1 inhibitor, 4'-cyano-biphenyl-4-sulfonic acid (6-amino-pyridin-2-yl)-amide (PF-915275), that is selective for the primate and human enzymes. The objective of this study was to demonstrate target inhibition with PF-915275 and to quantify the relationship between target inhibition and drug exposure in monkeys. We characterized the ability of PF-915275 to inhibit the conversion of prednisone, a synthetic cortisone analog that can be distinguished from the endogenous substrate cortisone, enabling a direct measure of substrate to product conversion without the complication of feedback. Adult cynomolgus monkeys were administered either vehicle or various doses of PF-915275 followed by a 10-mg/kg dose of prednisone. Prednisone conversion to prednisolone and the concentrations of PF-915275 were measured by liquid chromatography/tandem mass spectrometry. PF-915275 dose-dependently inhibited 11betaHSD1-mediated conversion of prednisone to prednisolone, with a maximum of 87% inhibition at a 3-mg/kg dose. An exposure-response relationship was demonstrated, with an estimated EC(50) of 391 nM (total) and 17 nM (free). Insulin levels were also reduced in a dose-related manner. These results should enable the development of a biomarker for evaluating target modulation in humans that will aid in identifying 11betaHSD1 inhibitors to treat diabetes and other related metabolic diseases.

Protocol for a randomised controlled trial of interventions to promote adoption and maintenance of physical activity in adults with mental illness.

INTRODUCTION: Physical activity (PA) has diverse benefits for physical and mental health and can reduce symptoms of mental illness. Adults with mental illness face practical, psychosocial and socioeconomic barriers to adopting and maintaining PA, and it is unclear how to effectively promote PA in this group. Supervised exercise interventions provide high support but may not promote autonomous motivation, which is important for PA maintenance. The aim of this study is to compare the effectiveness of two interventions to promote PA in adults with mental illness. METHODS AND ANALYSIS: This is a randomised controlled trial of two interventions to promote PA: (1) supervised exercise and gym membership and (2) motivational discussions and self-monitoring of PA using fitness trackers. The intervention duration is 16 weeks, including 8 weeks of weekly supervised group sessions, and 8 weeks of access to the gym or fitness tracker unsupervised. Participants are community-dwelling adults recruited from outpatient clinics of public mental health services. The primary outcome is PA adoption assessed using GENEActiv accelerometers worn continuously over 8 weeks. Secondary outcomes measured at baseline, postintervention (8 weeks) and follow-up (16 weeks), include exercise motivation, psychological distress and self-reported PA assessed using self-administered questionnaires and indicators of physical health measured by a researcher blinded to allocation (blood pressure, weight, waist circumference, 6 min walk test). Participant experiences will be assessed using qualitative focus groups with analysis informed by a theoretical model of behaviour (COM-B). ETHICS AND DISSEMINATION: Ethics approval has been obtained from the Royal Brisbane and Women's Hospital (HREC/17/QRBW/302). We plan to submit a manuscript on protocol development from pilot work, and a manuscript of the results to a peer-reviewed journal. Results will be presented at conferences, community and consumer forums and hospital grand rounds. TRIAL REGISTRATION NUMBER: ACTRN12617001017314; Pre-results.