Older Adults' Experiences of a Physical Activity and Sedentary Behaviour Intervention: A Nested Qualitative Study in the SITLESS Multi-Country Randomised Clinical Trial.

BACKGROUND: The SITLESS programme comprises exercise referral schemes and self-management strategies and has been evaluated in a trial in Denmark, Spain, Germany and Northern Ireland. The aim of this qualitative study was to understand the implementation and contextual aspects of the intervention in relation to the mechanisms of impact and to explore the perceived effects. METHODS: Qualitative methodologies were nested in the SITLESS trial including 71 individual interviews and 12 focus groups targeting intervention and control group participants from postintervention to 18-month follow-up in all intervention sites based on a semi-structured topic guide. RESULTS: Overarching themes were identified under the framework categories of context, implementation, mechanisms of impact and perceived effects. The findings highlight the perceived barriers and facilitators to older adults' engagement in exercise referral schemes. Social interaction and enjoyment through the group-based programmes are key components to promote adherence and encourage the maintenance of targeted behaviours through peer support and connectedness. Exit strategies and signposting to relevant classes and facilities enabled the maintenance of positive lifestyle behaviours. CONCLUSIONS: When designing and implementing interventions, key components enhancing social interaction, enjoyment and continuity should be in place in order to successfully promote sustained behaviour change.

The effectiveness and complexity of interventions targeting sedentary behaviour across the lifespan: a systematic review and meta-analysis.

BACKGROUND: Evidence suggests that sedentary behaviour (SB) is associated with poor health outcomes. SB at any age may have significant consequences for health and well-being and interventions targeting SB are accumulating. Therefore, the need to review the effects of multicomponent, complex interventions that incorporate effective strategies to reduce SB are essential. METHODS: A systematic review and meta-analysis were conducted investigating the impact of interventions targeting SB across the lifespan. Six databases were searched and two review authors independently screened studies for eligibility, completed data extraction and assessed the risk of bias and complexity of each of the included studies. RESULTS: A total of 77 adult studies (n=62, RCTs) and 84 studies (n=62, RCTs) in children were included. The findings demonstrated that interventions in adults when compared to active controls resulted in non-significant reductions in SB, although when compared to inactive controls significant reductions were found in both the short (MD -56.86; 95%CI -74.10, -39.63; n=4632; I2 83%) and medium-to-long term (MD -20.14; 95%CI -34.13, -6.16; n=4537; I2 65%). The findings demonstrated that interventions in children when compared to active controls may lead to relevant reductions in daily sedentary time in the short-term (MD -59.90; 95%CI -102.16, -17.65; n=267; I2 86%), while interventions in children when compared to inactive controls may lead to relevant reductions in the short-term (MD -25.86; 95%CI -40.77, -10.96; n=9480; I2 98%) and medium-to-long term (MD -14.02; 95%CI -19.49, -8.55; n=41,138; I2 98%). The assessment of complexity suggested that interventions may need to be suitably complex to address the challenges of a complex behaviour such as SB, but demonstrated that a higher complexity score is not necessarily associated with better outcomes in terms of sustained long-term changes. CONCLUSIONS: Interventions targeting reductions in SB have been shown to be successful, especially environmental interventions in both children and adults. More needs to be known about how best to optimise intervention effects. Future intervention studies should apply more rigorous methods to improve research quality, considering larger sample sizes, randomised controlled designs and valid and reliable measures of SB.

Correction: Excess hepsin proteolytic activity limits oncogenic signaling and induces ER stress and autophagy in prostate cancer cells.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Excess hepsin proteolytic activity limits oncogenic signaling and induces ER stress and autophagy in prostate cancer cells.

The serine protease hepsin is frequently overexpressed in human prostate cancer (PCa) and is associated with matrix degradation and PCa progression in mice. Curiously, low expression of hepsin is associated with poor survival in different cancer types, and transgenic overexpression of hepsin leads to loss of viability in various cancer cell lines. Here, by comparing isogenic transfectants of the PCa cell line PC-3 providing inducible overexpression of wild-type hepsin (HPN) vs. the protease-deficient mutant HPNS353A, we were able to attribute hepsin-mediated tumor-adverse effects to its excess proteolytic activity. A stem-like expression signature of surface markers and adhesion molecules, Notch intracellular domain release, and increased pericellular protease activity were associated with low expression levels of wild-type hepsin, but were partially lost in response to overexpression. Instead, overexpression of wild-type hepsin, but not of HPNS353A, induced relocalization of the protein to the cytoplasm, and increased autophagic flux in vitro as well as LC3B punctae frequency in tumor xenografts. Confocal microscopy revealed colocalization of wild-type hepsin with both LC3B punctae as well as with the autophagy cargo receptor p62/SQSTM1. Overexpression of wild type, but not protease-deficient hepsin induced expression and nuclear presence of CHOP, indicating activation of the unfolded protein response and ER-associated protein degradation (ERAD). Whereas inhibitors of ER stress and secretory protein trafficking slightly increased viability, combined inhibition of the ubiquitin-proteasome degradation pathway (by bortezomib) with either ER stress (by salubrinal) or autophagy (by bafilomycin A1) revealed a significant decrease of viability during overexpression of wild-type hepsin in PC-3 cells. Our results demonstrate that a precise control of Hepsin proteolytic activity is critical for PCa cell fate and suggest, that the interference with ERAD could be a promising therapeutic option, leading to induction of proteotoxicity in hepsin-overexpressing tumors.

Exercise referral schemes enhanced by self-management strategies to reduce sedentary behaviour and increase physical activity among community-dwelling older adults from four European countries: protocol for the process evaluation of the SITLESS randomised controlled trial.

INTRODUCTION: SITLESS is a randomised controlled trial determining whether exercise referral schemes can be enhanced by self-management strategies to reduce sedentary behaviour and increase physical activity in the long term, in community-dwelling older citizens. The intervention is complex and requires a process evaluation to understand how implementation, causal mechanisms and context shape outcomes. The specific aims are to assess fidelity and reach of the implementation, understand the contextual aspects of each intervention site, evaluate the mechanisms of impact, and explore perceived effects. METHODS AND ANALYSIS: Following the Medical Research Council guidance on complex interventions, a combination of qualitative and quantitative procedures is applied, including observational checklists and attendance registries, standardised scales (ie, Marcus's Self-Efficacy Questionnaire, Physical Activity Self-Regulation Scale and the Lubben Social Network Scale) at baseline, postintervention and follow-up assessments, semistructured questionnaires gathering contextual characteristics, and participant observations of the sessions. Semistructured interviews and focus groups with the participants and trainers are conducted at postintervention and during the follow-up to explore their experiences. Outcomes from the standardised scales are analysed as moderators within the impact evaluation. Descriptive results on context and perceived effects complement results on impact. The qualitative and quantitative findings will help to refine the logic model to finally support the interpretation of the results on the effectiveness of the intervention. ETHICS AND DISSEMINATION: The study design was approved by the respective Ethical Committee of Ramon Llull University, Southern Denmark, Northern Ireland and Ulm University. Participation is voluntary, and all participants are asked to sign informed consent before starting the study. A dissemination plan operationalises how to achieve a social impact by reaching academic and non-academic stakeholders. A data management plan describes the specific data sets and regulates its deposition and curation. All publications will be open access. TRIAL REGISTRATION NUMBER: NCT02629666; Pre-results.

Examining the effect of Early Life Stress on autonomic and endocrine indicators of individual stress reactivity.

Early life stress (ELS) is associated with altered stress reactivity and an increased risk for the development of psychopathological conditions in later life. However, depending on whether autonomic or endocrine measures were used as indicators of stress reactivity, previous studies reported conflicting findings of either increased or decreased stress reactivity after ELS experience. In the present study we therefore aimed to investigate the effect of ELS on both autonomic and endocrine indicators (heart rate and salivary cortisol) of individual stress reactivity and applied a psychosocial stress task in a sample of healthy participants with and without exposure to mild to moderate ELS. Results showed no significant effects of ELS on autonomic and endocrine indicators of individual stress reactivity. Importantly though, heart rate proved as more sensitive than salivary cortisol with regard to differentiating between stress and control conditions and thereby as a more feasible indicator of an individual's stress reactivity. Accordingly, our data suggest that sole reliance on salivary cortisol as an indicator of stress reactivity might lead to an oversight of more subtle effects of psychosocial stress.

["The Diagnosis is not me - But it is a Part of me" - An In-Depth Interview Study on Perspectives of Mentally Ill People]. / "Ich bin nicht die Diagnose ­ aber sie ist auch ein Teil von mir" ­ Eine qualitative Interviewstudie zu Sichtweisen von psychisch erkrankten Menschen.

OBJECTIVE: This study aimed at investigating how mentally ill people experience and evaluate their diagnosis. METHODS: 16 in-depth interviews with patients with different mental health diagnosis were carried out. The interviews were transcribed and analyzed using content analysis methods. RESULTS: The study participants reported rejection and stigma experiences in many areas of their life. On the other hand, they consider the diagnosis as necessary guidance and important starting-point for changes. Dealing with the diagnosis is often described as a long-term process which changes the perception of the illness and the person's own self-concept lastingly. CONCLUSIONS: The "adoption" of a mental health diagnosis is a protracted, complex and often painful identity-related process for the people affected. This process should be supported by suitable counselling services.

Cost-effectiveness of exercise referral schemes enhanced by self-management strategies to battle sedentary behaviour in older adults: protocol for an economic evaluation alongside the SITLESS three-armed pragmatic randomised controlled trial.

INTRODUCTION: Promoting physical activity (PA) and reducing sedentary behaviour (SB) may exert beneficial effects on the older adult population, improving behavioural, functional, health and psychosocial outcomes in addition to reducing health, social care and personal costs. This paper describes the planned economic evaluation of SITLESS, a multicountry three-armed pragmatic randomised controlled trial (RCT) which aims to assess the short-term and long-term effectiveness and cost-effectiveness of a complex intervention on SB and PA in community-dwelling older adults, based on exercise referral schemes enhanced by a group intervention providing self-management strategies to encourage lifestyle change. METHODS AND ANALYSIS: A within-trial economic evaluation and long-term model from both a National Health Service/personal social services perspective and a broader societal perspective will be undertaken alongside the SITLESS multinational RCT. Healthcare costs (hospitalisations, accident and emergency visits, appointment with health professionals) and social care costs (eg, community care) will be included in the economic evaluation. For the cost-utility analysis, quality-adjusted life-years will be measured using the EQ-5D-5L and capability well-being measured using the ICEpop CAPability measure for Older people (ICECAP-O) questionnaire. Other effectiveness outcomes (health related, behavioural, functional) will be incorporated into a cost-effectiveness analysis and cost-consequence analysis.The multinational nature of this RCT implies a hierarchical structure of the data and unobserved heterogeneity between clusters that needs to be adequately modelled with appropriate statistical and econometric techniques. In addition, a long-term population health economic model will be developed and will synthesise and extrapolate within-trial data with additional data extracted from the literature linking PA and SB outcomes with longer term health states.Methods guidance for population health economic evaluation will be adopted including the use of a long-time horizon, 1.5% discount rate for costs and benefits, cost consequence analysis framework and a multisector perspective. ETHICS AND DISSEMINATION: The study design was approved by the ethics and research committee of each intervention site: the Ethics and Research Committee of Ramon Llull University (reference number: 1314001P) (Fundació Blanquerna, Spain), the Regional Committees on Health Research Ethics for Southern Denmark (reference number: S-20150186) (University of Southern Denmark, Denmark), Office for Research Ethics Committees in Northern Ireland (ORECNI reference number: 16/NI/0185) (Queen's University of Belfast) and the Ethical Review Board of Ulm University (reference number: 354/15) (Ulm, Germany). Participation is voluntary and all participants will be asked to sign informed consent before the start of the study.This project has received funding from the European Union's Horizon 2020 research and innovation programme under grant agreement number 634 270. This article reflects only the authors' view and the Commission is not responsible for any use that may be made of the information it contains.The findings of the study will be disseminated to different target groups (academia, policymakers, end users) through different means following the national ethical guidelines and the dissemination regulation of the Horizon 2020 funding agency.Use of the EuroQol was registered with the EuroQol Group in 2016.Use of the ICECAP-O was registered with the University of Birmingham in March 2017. TRIAL REGISTRATION NUMBER: NCT02629666; Pre-results.

Early-Life stress modulates neural networks associated with habitual use of reappraisal.

Recent evidence shows that early life stress (ELS) is associated with altered resting-state functional connectivity (RSFC) between amygdala and the prefrontal cortex, as well as with maladaptive emotion regulation strategies and negative mood. However, the relation between ELS and maladaptive emotion regulation is not deterministic. Adaptive emotion regulation strategies such as reappraisal can also ensue from experience and learning in adulthood and can prevent negative mood. The present study aims to investigate the joint influence of ELS, in particular early-life emotional abuse (EA), and habitual use of reappraisal on amygdala-centered RSFC and mood. We examined amygdala-centered RSFC using functional magnetic resonance imaging (fMRI) in 28 healthy adults with varied exposure to early-life emotional abuse. We found that in subjects with high early-life emotional abuse, reappraisal was predominantly associated with RSFC between left centromedial amygdala (CMA) and the ventrolateral prefrontal cortex (VLPFC), whereas in subjects with low early-life EA reappraisal predominantly involved RSFC between right CMA, premotor and supplementary motor regions. For subjects with high EA, reappraisal use was associated with a decrease in negative mood whereas it was associated with an increase in positive mood for subjects with low EA. The general findings of the study suggest that reappraisal use might act as a protective factor, notably for individuals who were exposed to ELS, and that this is mediated by alteration of amygdala-centered RSFC.

The interaction of corticotropin-releasing hormone receptor gene and early life stress on emotional empathy.

Early life stress (ELS) is associated with increased vulnerability for depression, changes to the corticotropin-releasing hormone (CRH) system and structural and functional changes in hippocampus. Single nucleotide polymorphisms in the CRH receptor 1 (CRHR1) gene interact with ELS to predict depression, cognitive functions and hippocampal activity. Social cognition has been related to hippocampal function and might be crucial for maintaining mental health. However, the interaction of CRHR1 gene variation and ELS on social cognition has not been investigated yet. We assessed social cognition in 502 healthy subjects to test effects of ELS and the CRHR1 gene. Participants were genotyped for rs110402 and rs242924. ELS was assessed by Childhood Trauma Questionnaire, social cognition was measured via Multifaceted Empathy Test and Empathy Quotient. Severity of ELS was associated with decreased emotional, but not cognitive empathy. Subjects with the common homozygous GG GG genotype showed decreased implicit emotional empathy after ELS exposure regardless of its severity. The results reveal that specific CRHR1 polymorphisms moderate the effect of ELS on emotional empathy. Exposure to ELS in combination with a vulnerable genotype results in impaired emotional empathy in adulthood, which might represent an early marker of increased vulnerability after ELS.

The SITLESS project: exercise referral schemes enhanced by self-management strategies to battle sedentary behaviour in older adults: study protocol for a randomised controlled trial.

BACKGROUND: Older adults are the fastest growing segment of the world's population. Recent evidence indicates that excessive sitting time is harmful to health, independent of meeting the recommended moderate to vigorous physical activity (PA) guidelines. The SITLESS project aims to determine whether exercise referral schemes (ERS) can be enhanced by self-management strategies (SMSs) to reduce sedentary behaviour (SB), increase PA and improve health, quality of life and function in the long term, as well as psychosocial outcomes in community-dwelling older European citizens from four countries, within a three-armed pragmatic randomised controlled trial, compared with ERS alone and also with general recommendations about PA. METHODS: A total of 1338 older adults will be included in this study, recruited from four European countries through different existing primary prevention pathways. Participants will be randomly allocated into an ERS of 16 weeks (32 sessions, 45-60 min per session), ERS enhanced by seven sessions of SMSs and four telephone prompts, or a control group. Outcomes will be assessed at baseline, month 4 (end of ERS intervention), month 16 (12 months post intervention) and month 22 (18 months post intervention). Primary outcomes will include measures of SB (time spent sedentary) and PA (counts per minute). Secondary outcomes will include muscle and physical function, health economics' related outcomes, anthropometry, quality of life, social networks, anxiety and depressive symptoms, disability, fear of falling, executive function and fatigue. A process evaluation will be conducted throughout the trial. The full analysis set will follow an intention-to-treat principle and will include all randomised participants for whom a baseline assessment is conducted. The study hypothesis will be tested with mixed linear models with repeated measures, to assess changes in the main outcomes (SB and PA) over time (baseline to month 22) and between study arms. DISCUSSION: The findings of this study may help inform the design and implementation of more effective interventions to reduce SB and increase PA levels, and hence improve long-term health outcomes in the older adult population. SITLESS aims to support policy-makers in deciding how or whether ERS should be further implemented or restructured in order to increase its adherence, impact and cost-effectiveness. TRIAL REGISTRATION: ClinicalTrials.gov, NCT02629666 . Registered 19 November 2015.

Biomarkers associated with sedentary behaviour in older adults: A systematic review.

OBJECTIVE: Pathomechanisms of sedentary behaviour (SB) are unclear. We conducted a systematic review to investigate the associations between SB and various biomarkers in older adults. METHODS: Electronic databases were searched (MEDLINE, EMBASE, CINAHL, AMED) up to July 2015 to identify studies with objective or subjective measures of SB, sample size ≥50, mean age ≥60years and accelerometer wear time ≥3days. Methodological quality was appraised with the CASP tool. The protocol was pre-specified (PROSPERO CRD42015023731). RESULTS: 12701 abstracts were retrieved, 275 full text articles further explored, from which 249 were excluded. In the final sample (26 articles) a total of 63 biomarkers were detected. Most investigated markers were: body mass index (BMI, n=15), waist circumference (WC, n=15), blood pressure (n=11), triglycerides (n=12) and high density lipoprotein (HDL, n=15). Some inflammation markers were identified such as interleukin-6, C-reactive protein or tumor necrosis factor alpha. There was a lack of renal, muscle or bone biomarkers. Randomized controlled trials found a positive correlation for SB with BMI, neck circumference, fat mass, HbA1C, cholesterol and insulin levels, cohort studies additionally for WC, leptin, C-peptide, ApoA1 and Low density lipoprotein and a negative correlation for HDL. CONCLUSION: Most studied biomarkers associated with SB were of cardiovascular or metabolic origin. There is a suggestion of a negative impact of SB on biomarkers but still a paucity of high quality investigations exist. Longitudinal studies with objectively measured SB are needed to further elucidate the pathophysiological pathways and possible associations of unexplored biomarkers.

Protein biomarkers in Parkinson's disease: Focus on cerebrospinal fluid markers and synaptic proteins.

Despite extensive research, to date, no validated biomarkers for PD have been found. This review seeks to summarize studies approaching the detection of biomarker candidates for PD and introduce promising ones in more detail, with special attention to synaptic proteins. To this end, we performed a PubMed search and included studies using proteomic tools (2-dimensional difference in gel electrophoresis and/or mass spectrometry) for the comparison of samples from PD and control patients. We found 27 studies reporting more than 500 differentially expressed proteins in which a total of 28 were detected in 2 and 17 in 3 or more independent studies, including posttranslationally modified proteins. In addition, of these 500 proteins, 25 were found to be brain specific, and 14 were enriched in synapses. Special attention was given to the applicability of the biomarker regarding sampling procedures, that is, using CSF/serum material for diagnosis. Furthermore, presynaptic proteins involved in vesicle membrane fusion seem to be interesting candidates for future analyses. Nonetheless, even though such promising biomarker candidates for PD exist, validation of these biomarkers in large-scale clinical studies is necessary to evaluate the diagnostic potential. © 2016 International Parkinson and Movement Disorder Society.

Long-term weight change: association with impaired glucose metabolism in young Austrian adults.

Little is known about the associations between long-term weight change and the natural history of impaired fasting glucose (IFG) in young adults. We investigated the association between long-term body mass index (BMI) change and the risk of IFG using data of 24,930 20- to 40-year-old participants from the Vorarlberg Health Monitoring and Promotion Program (VHM&PP) cohort. Poisson models were applied to estimate the 10-year risk for new development of IFG (≥ 5.6 mmol/L), and persistence of IFG. Over 10 years, most men (68.2%) and women (70.0%) stayed within their initial BMI category. The risk for incident IFG was highest for men and women with persisting obesity (37.4% and 24.1%) and lowest with persisting normal weight (15.7% and 9.3%). Men transitioning from normal to overweight increased their risk of incident IFG by factor 1.45 (95%-CI: 1.31, 1.62), women by 1.70 (95%-CI: 1.50, 1.93), whereas transitioning from overweight to normal weight decreased the risk in men by 0.69 (95%-CI: 0.53, 0.90) and 0.94 (95%-CI: 0.66, 1.33) in women. Relative risks for men and women transitioning from obesity to overweight were 0.58 and 0.44, respectively. In conclusion, 10 year weight increase was associated with an increased IFG risk, weight decrease with a decreased risk of IFG in young adults.