Expression of a beta-adrenergic receptor kinase 1 inhibitor prevents the development of myocardial failure in gene-targeted mice.

Heart failure is accompanied by severely impaired beta-adrenergic receptor (betaAR) function, which includes loss of betaAR density and functional uncoupling of remaining receptors. An important mechanism for the rapid desensitization of betaAR function is agonist-stimulated receptor phosphorylation by the betaAR kinase (betaARK1), an enzyme known to be elevated in failing human heart tissue. To investigate whether alterations in betaAR function contribute to the development of myocardial failure, transgenic mice with cardiac-restricted overexpression of either a peptide inhibitor of betaARK1 or the beta2AR were mated into a genetic model of murine heart failure (MLP-/-). In vivo cardiac function was assessed by echocardiography and cardiac catheterization. Both MLP-/- and MLP-/-/beta2AR mice had enlarged left ventricular (LV) chambers with significantly reduced fractional shortening and mean velocity of circumferential fiber shortening. In contrast, MLP-/-/betaARKct mice had normal LV chamber size and function. Basal LV contractility in the MLP-/-/betaARKct mice, as measured by LV dP/dtmax, was increased significantly compared with the MLP-/- mice but less than controls. Importantly, heightened betaAR desensitization in the MLP-/- mice, measured in vivo (responsiveness to isoproterenol) and in vitro (isoproterenol-stimulated membrane adenylyl cyclase activity), was completely reversed with overexpression of the betaARK1 inhibitor. We report here the striking finding that overexpression of this inhibitor prevents the development of cardiomyopathy in this murine model of heart failure. These findings implicate abnormal betaAR-G protein coupling in the pathogenesis of the failing heart and point the way toward development of agents to inhibit betaARK1 as a novel mode of therapy

The Impatient May Use Limited Optimism to Minimize Regret

Discounted-sum games provide a formal model for the study of reinforcement learning, where the agent is enticed to get rewards early since later rewards are discounted. When the agent interacts with the environment, she may regret her actions, realizing that a previous choice was suboptimal given the behavior of the environment. The main contribution of this paper is a PSPACE algorithm for computing the minimum possible regret of a given game. To this end, several results of independent interest are shown. (1) We identify a class of regret-minimizing and admissible strategies that first assume that the environment is collaborating, then assume it is adversarial---the precise timing of the switch is key here. (2) Disregarding the computational cost of numerical analysis, we provide an NP algorithm that checks that the regret entailed by a given time-switching strategy exceeds a given value. (3) We show that determining whether a strategy minimizes regret is decidable in PSPACE

Feasibility study of peer-led and school-based social network Intervention (STASH) to promote adolescent sexual health.

BACKGROUND: Effective sex education is the key to good sexual health. Peer-led approaches can augment teacher-delivered sex education, but many fail to capitalise on mechanisms of social influence. We assessed the feasibility of a novel intervention (STASH) in which students (aged 14-16) nominated as influential by their peers were recruited and trained as Peer Supporters (PS). Over a 5-10-week period, they spread positive sexual health messages to friends in their year group, both in-person and via social media, and were supported to do so via weekly trainer-facilitated meetings. The aims of the study were to assess the feasibility of STASH (acceptability, fidelity and reach), to test and refine the programme theory and to establish whether the study met pre-set progression criteria for continuation to larger-scale evaluation. METHODS: The overall design was a non-randomised feasibility study of the STASH intervention in 6 schools in Scotland. Baseline (n=680) and follow-up questionnaires (approx. 6 months later; n=603) were administered to the intervention year group. The control group (students in year above) completed the follow-up questionnaire only (n=696), 1 year before the intervention group. The PS (n=88) completed a brief web survey about their experience of the role; researchers interviewed participants in key roles (PS (n=20); PS friends (n=22); teachers (n=8); trainers (n=3)) and observed 20 intervention activities. Activity evaluation forms and project monitoring data also contributed information. We performed descriptive quantitative analysis and thematic qualitative analysis. RESULTS: The PS role was acceptable; on average across schools >50% of students nominated as influential by their friends, signed up and were trained (n=104). This equated to 13% of the year group. Trained PS rarely dropped out (97% completion rate) and 85% said they liked the role. Fidelity was good (all bar one trainer-led activity carried out; PS were active). The intervention had good reach; PS were reasonably well connected and perceived as 'a good mix' and 58% of students reported exposure to STASH. Hypothesised pre-conditions, contextual influences and mechanisms of change for the intervention were largely confirmed. All bar one of the progression criteria was met. CONCLUSION: The weight of evidence supports continuation to full-scale evaluation. TRIAL REGISTRATION: Current controlled trials ISRCTN97369178

Mind-body interventions for vasomotor symptoms in healthy menopausal women and breast cancer survivors. A systematic review

Mind–body therapies are commonly recommended to treat vasomotor symptoms, such as hot flushes and night sweats (HFNS). The purpose of this systematic review was to evaluate the available evidence to date for the efficacy of different mind–body therapies to alleviate HFNS in healthy menopausal women and breast cancer survivors. Randomized controlled trials (RCTs) were identified using seven electronic search engines, direct searches of specific journals and backwards searches through reference lists of related publications. Outcome measures included HFNS frequency and/or severity or self-reported problem rating at post-treatment. The methodological quality of all studies was systematically assessed using predefined criteria. Twenty-six RCTs met the inclusion criteria. Interventions included yoga (n = 5), hypnosis (n = 3), mindfulness (n = 2), relaxation (n = 7), paced breathing (n = 4), reflexology (n = 1) and cognitive behavioural therapy (CBT) (n = 4). Findings were consistent for the effectiveness of CBT and relaxation therapies for alleviating troublesome vasomotor symptoms. For the remaining interventions, although some trials indicated beneficial effects (within groups) at post-treatment and/or follow up, between group findings were mixed and overall, methodological differences across studies failed to provide convincing supporting evidence. Collectively, findings suggest that interventions that include breathing and relaxation techniques, as well as CBT, can be beneficial for alleviating vasomotor symptoms. Additional large, methodologically rigorous trials are needed to establish the efficacy of interventions on vasomotor symptoms, examine long-term outcomes and understand how they work

Effectiveness of community interventions for protecting and promoting the mental health of working-age adults experiencing financial uncertainty: a systematic review

BACKGROUND: The COVID-19 pandemic has created a period of global economic uncertainty. Financial strain, personal debt, recent job loss and housing insecurity are important risk factors for the mental health of working-age adults. Community interventions have the potential to attenuate the mental health impact of these stressors. We examined the effectiveness of community interventions for protecting and promoting the mental health of working-age adults in high-income countries during periods of financial insecurity. METHODS: Eight electronic databases were systematically screened for experimental and observational studies published since 2000 measuring the effectiveness of community interventions on mental health outcomes. We included any non-clinical intervention that aimed to address the financial, employment, food or housing insecurity of participants. A review protocol was registered on the PROSPERO database (CRD42019156364) and results are reported in accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. RESULTS: From 2326 studies screened, 15 met our inclusion criteria. Five categories of community intervention were identified: advice services colocated in healthcare settings; link worker social prescribing; telephone debt advice; food insecurity interventions; and active labour market programmes. In general, the evidence for effective and cost-effective community interventions delivered to individuals experiencing financial insecurity was lacking. From the small number of studies without a high risk of bias, there was some evidence that financial insecurity and associated mental health problems were amenable to change and differences by subpopulations were observed. CONCLUSION: There is a need for well-controlled studies and trials to better understand effective ingredients and to identify those interventions warranting wider implementation

The ethics of synthetic biology research and development:a principlist approach

A principlist approach is adopted to analyse the ethical status of synthetic biology (synbio) research and development. The principle of nonmaleficence generates precaution-driven conclusions that are excessively restrictive to the field of synbio. The principle of beneficence is best served by permitting synbio research to flourish and not have it treated as a special case warranting the imposition of a high degree of external and self-regulation. Synbio may offend the principle of justice in certain circumstances; however, such issues are largely restricted to the initial stages of synbio innovation, whilst in the longer term the development of the field can be expected to promote just ends. The principle of respect for autonomy entails that scientists ought to be afforded a broad scope to freely pursue synbio research and development in a curiosity-driven fashion. In balancing the various conclusions under the four principles, the author concludes that society has an ethical obligation to support the development of synbio research and development and not restrict this important nascent field by the imposition of stern regulation

Evaluation of the current knowledge limitations in breast cancer research: a gap analysis

BACKGROUND A gap analysis was conducted to determine which areas of breast cancer research, if targeted by researchers and funding bodies, could produce the greatest impact on patients. METHODS Fifty-six Breast Cancer Campaign grant holders and prominent UK breast cancer researchers participated in a gap analysis of current breast cancer research. Before, during and following the meeting, groups in seven key research areas participated in cycles of presentation, literature review and discussion. Summary papers were prepared by each group and collated into this position paper highlighting the research gaps, with recommendations for action. RESULTS Gaps were identified in all seven themes. General barriers to progress were lack of financial and practical resources, and poor collaboration between disciplines. Critical gaps in each theme included: (1) genetics (knowledge of genetic changes, their effects and interactions); (2) initiation of breast cancer (how developmental signalling pathways cause ductal elongation and branching at the cellular level and influence stem cell dynamics, and how their disruption initiates tumour formation); (3) progression of breast cancer (deciphering the intracellular and extracellular regulators of early progression, tumour growth, angiogenesis and metastasis); (4) therapies and targets (understanding who develops advanced disease); (5) disease markers (incorporating intelligent trial design into all studies to ensure new treatments are tested in patient groups stratified using biomarkers); (6) prevention (strategies to prevent oestrogen-receptor negative tumours and the long-term effects of chemoprevention for oestrogen-receptor positive tumours); (7) psychosocial aspects of cancer (the use of appropriate psychosocial interventions, and the personal impact of all stages of the disease among patients from a range of ethnic and demographic backgrounds). CONCLUSION Through recommendations to address these gaps with future research, the long-term benefits to patients will include: better estimation of risk in families with breast cancer and strategies to reduce risk; better prediction of drug response and patient prognosis; improved tailoring of treatments to patient subgroups and development of new therapeutic approaches; earlier initiation of treatment; more effective use of resources for screening populations; and an enhanced experience for people with or at risk of breast cancer and their families. The challenge to funding bodies and researchers in all disciplines is to focus on these gaps and to drive advances in knowledge into improvements in patient care

A meta-analytic review of stand-alone interventions to improve body image

Objective Numerous stand-alone interventions to improve body image have been developed. The present review used meta-analysis to estimate the effectiveness of such interventions, and to identify the specific change techniques that lead to improvement in body image. Methods The inclusion criteria were that (a) the intervention was stand-alone (i.e., solely focused on improving body image), (b) a control group was used, (c) participants were randomly assigned to conditions, and (d) at least one pretest and one posttest measure of body image was taken. Effect sizes were meta-analysed and moderator analyses were conducted. A taxonomy of 48 change techniques used in interventions targeted at body image was developed; all interventions were coded using this taxonomy. Results The literature search identified 62 tests of interventions (N = 3,846). Interventions produced a small-to-medium improvement in body image (d+ = 0.38), a small-to-medium reduction in beauty ideal internalisation (d+ = -0.37), and a large reduction in social comparison tendencies (d+ = -0.72). However, the effect size for body image was inflated by bias both within and across studies, and was reliable but of small magnitude once corrections for bias were applied. Effect sizes for the other outcomes were no longer reliable once corrections for bias were applied. Several features of the sample, intervention, and methodology moderated intervention effects. Twelve change techniques were associated with improvements in body image, and three techniques were contra-indicated. Conclusions The findings show that interventions engender only small improvements in body image, and underline the need for large-scale, high-quality trials in this area. The review identifies effective techniques that could be deployed in future interventions