Reducing worry and rumination in young adults via a mobile phone app: study protocol of the ECoWeB (Emotional Competence for Well-Being in Young Adults) randomised controlled trial focused on repetitive negative thinking.

This is the final version. Available from BMC via the DOI in this record. Availability of data and materials: Anonymised datasets arising from this trial will be made available after the primary outcomes are published to researchers and other groups via request to a data committee within the Consortium via the University of Exeter’s open access data system Open Research Exeter (ORE). The results will additionally be updated on ClinicalTrials.gov Identifier: NCT04950257. The ECoWeB consortium plans to communicate trial results through peerreviewed open access publications and direct reports to TSC, sponsor, and participants.BACKGROUND: Promoting well-being and preventing poor mental health in young people is a major global priority. Building emotional competence skills via a mobile app may be an effective, scalable and acceptable way to do this. A particular risk factor for anxiety and depression is elevated worry and rumination (repetitive negative thinking, RNT). An app designed to reduce RNT may prevent future incidence of depression and anxiety. METHOD/DESIGN: The Emotional Competence for Well-Being in Young Adults study developed an emotional competence app to be tested via randomised controlled trials in a longitudinal prospective cohort. This off-shoot study adapts the app to focus on targeting RNT (worry, rumination), known risk factors for poor mental health. In this study, 16-24 year olds in the UK, who report elevated worry and rumination on standardised questionnaires are randomised to (i) receive the RNT-targeting app immediately for 6 weeks (ii) a waiting list control who receive the app after 6 weeks. In total, the study will aim to recruit 204 participants, with no current diagnosis of major depression, bipolar disorder or psychosis, across the UK. Assessments take place at baseline (pre-randomisation), 6 and 12 weeks post-randomisation. Primary endpoint and outcome for the study is level of rumination assessed on the Rumination Response Styles Questionnaire at 6 weeks. Worry, depressive symptoms, anxiety symptoms and well-being are secondary outcomes. Compliance, adverse events and potentially mediating variables will be carefully monitored. DISCUSSION: This trial aims to better understand the benefits of tackling RNT via an mobile phone app intervention in young people. This prevention mechanism trial will establish whether targeting worry and rumination directly via an app provides a feasible approach to prevent depression and anxiety, with scope to become a widescale public health strategy for preventing poor mental health and promoting well-being in young people. TRIAL REGISTRATION: ClinicalTrials.gov , NCT04950257 . Registered 6 July 2021 - Retrospectively registered.European Union’s Horizon 202

Promotion of mental health in young adults via mobile phone app: study protocol of the ECoWeB (emotional competence for well-being in Young adults) cohort multiple randomised trials

This is the final version. Available on open access from BMC via the DOI in this recordAvailability of data and materials: Anonymised datasets arising from this trial will be made available after the primary outcomes are published to researchers and other groups via request to a data committee within the Consortium via the University of Exeter’s open access data system Open Research Exeter (ORE). ECoWeB partners will have access to the final trial dataset, commensurate with the grant Consortium Agreement. The results will additionally be updated on ClinicalTrials.gov Identifier: NCT04148508. The ECoWeB consortium plans to communicate trial results through peer-reviewed open access publications and direct reports to TSC, sponsor, and participants.BACKGROUND: Promoting well-being and preventing poor mental health in young people is a major global priority. Building emotional competence (EC) skills via a mobile app may be an effective, scalable and acceptable way to do this. However, few large-scale controlled trials have examined the efficacy of mobile apps in promoting mental health in young people; none have tailored the app to individual profiles. METHOD/DESIGN: The Emotional Competence for Well-Being in Young Adults cohort multiple randomised controlled trial (cmRCT) involves a longitudinal prospective cohort to examine well-being, mental health and EC in 16-22 year olds across 12 months. Within the cohort, eligible participants are entered to either the PREVENT trial (if selected EC scores at baseline within worst-performing quartile) or to the PROMOTE trial (if selected EC scores not within worst-performing quartile). In both trials, participants are randomised (i) to continue with usual practice, repeated assessments and a self-monitoring app; (ii) to additionally receive generic cognitive-behavioural therapy self-help in app; (iii) to additionally receive personalised EC self-help in app. In total, 2142 participants aged 16 to 22 years, with no current or past history of major depression, bipolar disorder or psychosis will be recruited across UK, Germany, Spain, and Belgium. Assessments take place at baseline (pre-randomisation), 1, 3 and 12 months post-randomisation. Primary endpoint and outcome for PREVENT is level of depression symptoms on the Patient Health Questionnaire-9 at 3 months; primary endpoint and outcome for PROMOTE is emotional well-being assessed on the Warwick-Edinburgh Mental Wellbeing Scale at 3 months. Depressive symptoms, anxiety, well-being, health-related quality of life, functioning and cost-effectiveness are secondary outcomes. Compliance, adverse events and potentially mediating variables will be carefully monitored. CONCLUSIONS: The trial aims to provide a better understanding of the causal role of learning EC skills using interventions delivered via mobile phone apps with respect to promoting well-being and preventing poor mental health in young people. This knowledge will be used to develop and disseminate innovative evidence-based, feasible, and effective Mobile-health public health strategies for preventing poor mental health and promoting well-being. TRIAL REGISTRATION: ClinicalTrials.gov ( www.clinicaltrials.org ). Number of identification: NCT04148508 November 2019.European Union Horizon 202

Beta1-Adrenoceptor Polymorphism Predicts Flecainide Action in Patients with Atrial Fibrillation

BACKGROUND: Antiarrhythmic action of flecainide is based on sodium channel blockade. Beta(1)-adrenoceptor (beta(1)AR) activation induces sodium channel inhibition, too. The aim of the present study was to evaluate the impact of different beta(1)AR genotypes on antiarrhythmic action of flecainide in patients with structural heart disease and atrial fibrillation. METHODOLOGY/PRINCIPAL FINDINGS: In 145 subjects, 87 with atrial fibrillation, genotyping was performed to identify the individual beta(1)AR Arg389Gly and Ser49Gly polymorphism. Resting heart rate during atrial fibrillation and success of flecainide-induced cardioversion were correlated with beta(1)AR genotype. The overall cardioversion rate with flecainide was 39%. The Arg389Arg genotype was associated with the highest cardioversion rate (55.5%; OR 3.30; 95% CI; 1.34-8.13; p = 0.003) compared to patients with Arg389Gly (29.5%; OR 0.44; 95% CI; 0.18-1.06; p = 0.066) and Gly389Gly (14%; OR 0.24; 95% CI 0.03-2.07; p = 0.17) variants. The single Ser49Gly polymorphism did not influence the conversion rate. In combination, patients with Arg389Gly-Ser49Gly genotype displayed the lowest conversion rate with 20.8% (OR 0.31; 95% CI; 0.10-0.93; p = 0.03). In patients with Arg389Arg variants the heart rate during atrial fibrillation was significantly higher (110+/-2.7 bpm; p = 0.03 vs. other variants) compared to Arg389Gly (104.8+/-2.4 bpm) and Gly389Gly (96.9+/-5.8 bpm) carriers. The Arg389Gly-Ser49Gly genotype was more common in patients with atrial fibrillation compared to patients without atrial fibrillation (27.6% vs. 5.2%; HR 6.98; 95% CI; 1.99-24.46; p<0.001). CONCLUSIONS: The beta(1)AR Arg389Arg genotype is associated with increased flecainide potency and higher heart rate during atrial fibrillation. The Arg389Gly-Ser49Gly genotype might be of predictive value for atrial fibrillation

Perceived threat predicts the neural sequelae of combat stress

Exposure to severe stressors increases the risk for psychiatric disorders in vulnerable individuals, but can lead to positive outcomes for others. However, it remains unknown how severe stress affects neural functioning in humans and what factors mediate individual differences in the neural sequelae of stress. The amygdala is a key brain region involved in threat detection and fear regulation, and previous animal studies have suggested that stress sensitizes amygdala responsivity and reduces its regulation by the prefrontal cortex. In this study, we used a prospective design to investigate the consequences of severe stress in soldiers before and after deployment to a combat zone. We found that combat stress increased amygdala and insula reactivity to biologically salient stimuli across the group of combat-exposed individuals. In contrast, its influence on amygdala coupling with the insula and dorsal anterior cingulate cortex was dependent on perceived threat, rather than actual exposure, suggesting that threat appraisal affects interoceptive awareness and amygdala regulation. Our results demonstrate that combat stress has sustained consequences on neural responsivity, and suggest a key role for the appraisal of threat on an amygdala-centered neural network in the aftermath of severe stress

Tumor interactions with soluble factors and the nervous system

In the genomic era of cancer research, the development of metastases has been attributed to mutations in the tumor that enable the cells to migrate. However, gene analyses revealed that primary tumors and metastases were in some cases genetically identical and the question was raised whether metastasis formation might be an inherent feature of certain tumor cells. In contradiction to this view, the last decade of cancer research has brought to light, that tumor cell migration, similar to leukocyte and fibroblast migration, is a highly regulated process. The nervous system plays an important role in this regulation, at least in two respects: firstly, neurotransmitters are known to regulate the migratory activity of tumor cells, and secondly, nerve fibers are used as routes for perineural invasion. We also summarize here the current knowledge on the innervation of tumors. Such a process might establish a neuro-neoplastic synapse, with the close interaction of tumor cells and nerve cells supporting metastasis formation

Pioglitazone alleviates cardiac and vascular remodelling and improves survival in monocrotaline induced pulmonary arterial hypertension

Pulmonary arterial hypertension (PAH) is a fatal disease with limited therapeutic options. Pathophysiological changes comprise obliterative vascular remodelling of small pulmonary arteries, elevated mean pulmonary arterial systolic pressure (PASP) due to elevated resistance of pulmonary vasculature, adverse right ventricular remodelling, and heart failure. Recent findings also indicate a role of increased inflammation and insulin resistance underlying the development of PAH. We hypothesized that treatment of this condition with the peroxisome proliferator-activated receptor-gamma (PPAR gamma) activator pioglitazone, known to regulate the expression of different genes addressing insulin resistance, inflammatory changes, and vascular remodelling, could be a beneficial approach. PAH was induced in adult rats by a single subcutaneous injection of monocrotaline (MCT). Pioglitazone was administered for 2 weeks starting 3 weeks after MCT-injection. At day 35, hemodynamics, organ weights, and -indices were measured. We performed morphological and molecular characterization of the pulmonary vasculature, including analysis of the degree of muscularization, proliferation rates, and medial wall thickness of the small pulmonary arteries. Furthermore, markers of cardiac injury, collagen content, and cardiomyocyte size were analyzed. Survival rates were monitored throughout the experimental period. Pioglitazone treatment improved survival, reduced PASP, muscularization of small pulmonary arteries, and medial wall thickness. Further, MCT-induced right ventricular hypertrophy and fibrosis were attenuated. This was accompanied with reduced cardiac expression of brain natriuretic peptide, as well as decreased cardiomyocyte size. Finally, pulmonary macrophage content and osteopontin gene expression were attenuated. Based on the beneficial impact of pioglitazone, activation of PPAR gamma might be a promising treatment option in PAH