How can a behavioral economics lens contribute to implementation science?

BACKGROUND: Implementation science in health is an interdisciplinary field with an emphasis on supporting behavior change required when clinicians and other actors implement evidence-based practices within organizational constraints. Behavioral economics has emerged in parallel and works towards developing realistic models of how humans behave and categorizes a wide range of features of choices that can influence behavior. We argue that implementation science can be enhanced by the incorporation of approaches from behavioral economics. Main body First, we provide a general overview of implementation science and ways in which implementation science has been limited to date. Second, we review principles of behavioral economics and describe how concepts from BE have been successfully applied to healthcare including nudges deployed in the electronic health record. For example, de-implementation of low-value prescribing has been supported by changing the default in the electronic health record. We then describe what a behavioral economics lens offers to existing implementation science theories, models and frameworks, including rich and realistic models of human behavior, additional research methods such as pre-mortems and behavioral design, and low-cost and scalable implementation strategies. We argue that insights from behavioral economics can guide the design of implementation strategies and the interpretation of implementation studies. Key objections to incorporating behavioral economics are addressed, including concerns about sustainment and at what level the strategies work. CONCLUSION: Scholars should consider augmenting implementation science theories, models, and frameworks with relevant insights from behavioral economics. By drawing on these additional insights, implementation scientists have the potential to boost efforts to expand the provision and availability of high quality care.

Acute effects of a ketone monoester, whey protein, or their coingestion on mTOR trafficking and protein-protein colocalization in human skeletal muscle.

We recently demonstrated that acute oral ketone monoester intake induces a stimulation of postprandial myofibrillar protein synthesis rates comparable to that elicited following the ingestion of 10 g whey protein or their coingestion. The present investigation aimed to determine the acute effects of ingesting a ketone monoester, whey protein, or their coingestion on mechanistic target of rapamycin (mTOR)-related protein-protein colocalization and intracellular trafficking in human skeletal muscle. In a randomized, double-blind, parallel group design, 36 healthy recreationally active young males (age: 24.2 ± 4.1 yr) ingested either: 1) 0.36 g·kg-1 bodyweight of the ketone monoester (R)-3-hydroxybutyl (R)-3-hydroxybutyrate (KET), 2) 10 g whey protein (PRO), or 3) the combination of both (KET + PRO). Muscle biopsies were obtained in the overnight postabsorptive state (basal conditions), and at 120 and 300 min in the postprandial period for immunofluorescence assessment of protein translocation and colocalization of mTOR-related signaling molecules. All treatments resulted in a significant (Interaction: P < 0.0001) decrease in tuberous sclerosis complex 2 (TSC2)-Ras homolog enriched in brain (Rheb) colocalization at 120 min versus basal; however, the decrease was sustained at 300 min versus basal (P < 0.0001) only in KET + PRO. PRO and KET + PRO increased (Interaction: P < 0.0001) mTOR-Rheb colocalization at 120 min versus basal; however, KET + PRO resulted in a sustained increase in mTOR-Rheb colocalization at 300 min that was greater than KET and PRO. Treatment intake increased mTOR-wheat germ agglutinin (WGA) colocalization at 120 and 300 min (Time: P = 0.0031), suggesting translocation toward the fiber periphery. These findings demonstrate that ketone monoester intake can influence the spatial mechanisms involved in the regulation of mTORC1 in human skeletal muscle.NEW & NOTEWORTHY We explored the effects of a ketone monoester (KET), whey protein (PRO), or their coingestion (KET + PRO) on mTOR-related protein-protein colocalization and intracellular trafficking in human muscle. All treatments decreased TSC2-Rheb colocalization at 120 minutes; however, KET + PRO sustained the decrease at 300 min. Only PRO and KET + PRO increased mTOR-Rheb colocalization; however, the increase at 300 min was greater in KET + PRO. Treatment intake increased mTOR-WGA colocalization, suggesting translocation to the fiber periphery. Ketone bodies influence the spatial regulation of mTOR.

How should institutions help clinicians to practise greener anaesthesia: first-order and second-order responsibilities to practice sustainably.

There is a need for all industries, including healthcare, to reduce their greenhouse gas emissions. In anaesthetic practice, this not only requires a reduction in resource use and waste, but also a shift away from inhaled anaesthetic gases and towards alternatives with a lower carbon footprint. As inhalational anaesthesia produces greenhouse gas emissions at the point of use, achieving sustainable anaesthetic practice involves individual practitioner behaviour change. However, changing the practice of healthcare professionals raises potential ethical issues. The purpose of this paper is twofold. First, we discuss what moral duties anaesthetic practitioners have when it comes to practices that impact the environment. We argue that behaviour change among practitioners to align with certain moral responsibilities must be supplemented with an account of institutional duties to support this. In other words, we argue that institutions and those in power have second-order responsibilities to ensure that practitioners can fulfil their first-order responsibilities to practice more sustainably. The second goal of the paper is to consider not just the nature of second-order responsibilities but the content. We assess four different ways that second-order responsibilities might be fulfilled within healthcare systems: removing certain anaesthetic agents, seeking consensus, education and methods from behavioural economics. We argue that, while each of these are a necessary part of the picture, some interventions like nudges have considerable advantages.

The skeletal muscle fiber periphery: A nexus of mTOR-related anabolism.

Skeletal muscle anabolism is driven by numerous stimuli such as growth factors, nutrients (i.e., amino acids, glucose), and mechanical stress. These stimuli are integrated by the mechanistic target of rapamycin (mTOR) complex 1 (mTORC1) signal transduction cascade. In recent years, work from our laboratory and elsewhere has sought to unravel the molecular mechanisms underpinning the mTOR-related activation of muscle protein synthesis (MPS), as well as the spatial regulation of these mechanisms within the skeletal muscle cell. These studies have suggested that the skeletal muscle fiber periphery is a region of central importance in anabolism (i.e., growth/MPS). Indeed, the fiber periphery is replete with the substrates, molecular machinery, and translational apparatus necessary to facilitate MPS. This review provides a summary of the mechanisms underpinning the mTOR-associated activation of MPS from cell, rodent, and human studies. It also presents an overview of the spatial regulation of mTORC1 in response to anabolic stimuli and outlines the factors that distinguish the periphery of the cell as a highly notable region of skeletal muscle for the induction of MPS. Future research should seek to further explore the nutrient-induced activation of mTORC1 at the periphery of skeletal muscle fibers.

How financial incentives in parenting skills programs affect engagement and outcomes: a systematic review and meta-analysis protocol.

OBJECTIVE: This systematic review will investigate the effects of financial incentives on engagement with and outcomes of evidence-based parenting skills programs to prevent and treat disruptive behavior disorders. INTRODUCTION: Evidence-based parenting skills programs are a first-line treatment in disruptive behavior disorders (ie, oppositional defiant disorder, conduct disorder, and attention-deficit/hyperactivity disorder), but fewer than half of referred parents complete these programs. When untreated, children affected by disruptive behavior disorders are at elevated risk of incarceration, drug misuse, and educational under-performance. Financial incentives can improve parents' engagement with parenting skills programs, and are increasingly popular strategies in public health policy to increase rates of compliance with health interventions. However, no previous systematic review or meta-analysis of financial incentives in parenting skills programs has been conducted. INCLUSION CRITERIA: Randomized controlled trials or quasi-experimental studies (ie, studies with a control group allocated through a non-random process) testing the effects of financial incentives on engagement will be included. Study participants must be in a guardian role to a person under 18 years of age. There will be no restrictions on country setting. Only English-language publications will be included. METHODS: We will search PubMed, CINAHL, Sociological Abstracts, Cochrane Trials, and PsycINFO databases for relevant articles. Two independent reviewers will screen abstracts for eligibility. Data will be extracted from eligible articles by 2 researchers and results will be presented in tabular and narrative format, along with a meta-analysis using a random effects model and assessment of heterogeneity. SYSTEMATIC REVIEW REGISTRATION NUMBER: PROSPERO CRD42022336210.

Take patients seriously when they say financial incentives help with adherence.

Small financial incentives have been proven effective at promoting healthy behaviours across medicine, including in psychiatry. There are a range of philosophical and practical objections to financial incentives. Drawing on the existing literature, specifically attempts to use financial incentives to promote antipsychotic adherence, we propose a 'patient-centred' view of evaluating financial incentive regimes. We argue that there is evidence that mental health patients like financial incentives, considering them fair and respectful. The enthusiasm of mental health patients for financial incentives lends support to their use, although it does not invalidate all objections against them.

Technology Matters: Digital micro interventions to support parenting: Evaluating time out apps.

Digital interventions to support parenting skills are popular but engagement can be low. Digital micro interventions such as apps targeting specific aspects of parenting are a novel development with the potential to overcome this challenge. Time out is an evidence-based component of many parenting skills training programmes and is an appropriate target for digital micro intervention. We describe the eight requirements of high-quality time out according to the literature and how these can be supported by an app. Searches of the App Store, Google Play, and Alexa Skills in the UK identified six apps designed to support time out. Current time out apps all promoted consistency, but they all risked low-quality time out through inappropriate initiation, duration, and termination. Professionals in child and adolescent mental health should explore the details of any digital micro interventions being used by parents for time out and provide appropriate counselling. We recommend that all future digital micro interventions in this area should incorporate evidence-based guidance.

Commitment devices: beyond the medical ethics of nudges.

Commitment devices (CDs) can help people overcome self-control problems to act on their plans and preferences. In these arrangements, people willingly make one of their options worse in order to change their own future behaviour, often by setting aside a sum of money that they will forfeit it if they fail to complete the planned action. Such applications of behavioural science have been used to help people stick to healthier lifestyle choices, overcome addictions and adhere to medication; they are acceptable to many patients and even relatively small sums can be effective. Some authors have objected to the use of nudges in healthcare. Engelen has listed nine potential objections to nudges in relation to means (why nudge rather than persuade?), ends (what action is being promoted?) and agents (who is nudging whom?). These objections are shown to lack force in the context of CDs. Instead, an analysis specific to the ethical issues in CDs is employed. CDs exclude certain groups including so-called 'naifs' and risk increasing health inequality. CDs may promote the wrong behaviour and people might legitimately change their minds. Intermediaries might encounter perverse incentives. Approaches to overcoming these problems are described and eight key ethical considerations for those considering implementing CDs in the future are described. Altogether this paper illustrates the advantages of appraising the ethics of behavioural science in medicine on a case-by-case basis.

Leucine ingestion promotes mTOR translocation to the periphery and enhances total and peripheral RPS6 phosphorylation in human skeletal muscle.

The activation of the mechanistic target of rapamycin complex 1 (mTORC1), a master regulator of protein synthesis, by anabolic stimuli (such as muscle contraction or essential amino acids) involves its translocation to the cell periphery. Leucine is generally considered the most anabolic of amino acids for its ability to independently modulate muscle protein synthesis. However, it is currently unknown if free leucine impacts region-specific mTORC1-mediated phosphorylation events and protein-protein interactions. In this clinical trial (NCT03952884; registered May 16, 2019), we used immunofluorescence methods to investigate the role of dietary leucine on the postprandial regulation of mTORC1 and ribosomal protein S6 (RPS6), an important downstream readout of mTORC1 activity. Eight young, healthy, recreationally active males (n = 8; 23 ± 3 yrs) ingested 2 g of leucine with vastus lateralis biopsies collected at baseline, 30, 60, and 180 min postprandial. Leucine promoted mTOR translocation to the periphery (~ 18-29%; p ≤ 0.012) and enhanced mTOR localization with the lysosome (~ 16%; both p = 0.049) at 30 and 60 min post-feeding. p-RPS6Ser240/244 staining intensity, a readout of mTORC1 activity, was significantly elevated at all postprandial timepoints in both the total fiber (~ 14-30%; p ≤ 0.032) and peripheral regions (~ 16-33%; p ≤ 0.014). Additionally, total and peripheral p-RPS6Ser240/244 staining intensity at 60 min was positively correlated (r = 0.74, p = 0.036; r = 0.80, p = 0.016, respectively) with rates of myofibrillar protein synthesis over 180 min. The ability of leucine to activate mTORC1 in peripheral regions favors an enhanced rate of MPS, as this is the intracellular space thought to be replete with the cellular machinery that facilitates this anabolic process.

Identification of underexplored mesenchymal and vascular-related cell populations in human skeletal muscle.

Skeletal muscle repair and maintenance are directly and indirectly supported by interstitial cell populations such as vascular cells and fibro-adipogenic progenitors (FAPs), a subset of which express Twist2 and possess direct myogenic potential. Furthermore, work in rodents has highlighted the potential of pericytes to act as progenitor cells, giving rise to muscle cells and transdifferentiating into endothelial cells. However, less is understood about these populations in human skeletal muscle. Here, we performed single-cell RNA sequencing (scRNAseq) on ∼2,000 cells isolated from the human semitendinosus muscle of young individuals. This demonstrated the presence of a vascular-related cell type that expressed pericyte and pan-endothelial genes that we localized to large blood vessels within skeletal muscle cross sections and termed endothelial-like pericytes (ELPCs). RNA velocity analysis indicated that ELPCs may represent a "transition state" between endothelial cells and pericytes. Analysis of published scRNAseq data sets revealed evidence for ELPCs in trunk and heart musculature, which showed transcriptional similarity. In addition, we identified a subset of FAPs expressing TWIST2 mRNA and protein. Human TWIST2-expressing cells were anatomically and transcriptionally comparable to mouse Twist2 cells as they were restricted to the myofiber interstitium, expressed fibrogenic genes but lacked satellite cell markers, and colocalized with the FAPs marker PDGFRα in human muscle cross sections. Taken together, these results highlight the complexity of stromal cells residing in human skeletal muscle and support the utility of scRNAseq for discovery and characterization of poorly described cell populations.

Essential Amino Acid Ingestion Facilitates Leucine Retention and Attenuates Myofibrillar Protein Breakdown following Bodyweight Resistance Exercise in Young Adults in a Home-Based Setting.

Home-based resistance exercise (RE) has become increasingly prevalent, but its effects on protein metabolism are understudied. We tested the effect of an essential amino acid formulation (EAA+: 9 g EAAs, 3 g leucine) and branched-chain amino acids (BCAAs: 6 g BCAAs, 3 g leucine), relative to a carbohydrate (CHO) placebo, on exogenous leucine retention and myofibrillar protein breakdown following dynamic bodyweight RE in a home-based setting. Twelve recreationally active adults (nine male, three female) participated in a double-blind, placebo-controlled, crossover study with four trial conditions: (i) RE and EAA+ (EX-EAA+); (ii) RE and BCAAs (EX-BCAA); (iii) RE and CHO placebo (EX-CHO); and (iv) rest and CHO placebo (REST-CHO). Total exogenous leucine oxidation and retention (estimates of whole-body anabolism) and urinary 3-methylhistidine:creatinine ratio (3MH:Cr; estimate of muscle catabolism) were assessed over 5 h post-supplement. Total exogenous leucine oxidation and retention in EX-EAA+ and EX-BCAA did not significantly differ (p = 0.116) but were greater than EX-CHO (p < 0.01). There was a main effect of condition on urinary 3MH:Cr (p = 0.034), with post hoc analysis revealing a trend (p = 0.096) for reduced urinary 3MH:Cr with EX-EAA+ (32%) compared to EX-CHO. By direct comparison, urinary 3MH:Cr was significantly lower (23%) in EX-EAA+ than EX-BCAA (p = 0.026). In summary, the ingestion of EAA+ or BCAA provided leucine that was ~60% retained for protein synthesis following home-based bodyweight RE, but EAA+ most effectively attenuated myofibrillar protein breakdown.

Walking or body weight squat "activity snacks" increase dietary amino acid utilization for myofibrillar protein synthesis during prolonged sitting.

Interrupting prolonged sitting with intermittent exercise enhances postprandial glycemic control but has unknown effects on sensitizing skeletal muscle to dietary amino acids. We hypothesized that brief walking or body weight squats would enhance the utilization of dietary phenylalanine for myofibrillar protein synthesis (MyoPS) during prolonged sitting. Participants (7 males and 5 females; ∼23 yr; ∼25.1 kg/m2; ∼7,300 steps/day) completed three 7.5-h trials consisting of prolonged sitting (SIT) or sitting with intermittent (every 30 min) walking (WALK) or body weight squatting (SQUAT). Two mixed-macronutrient meals (∼55:30:15% carbohydrate:fat:protein), enriched with l-[ring-2H5]phenylalanine or l-[ring-13C6]phenylalanine, were provided to mimic breakfast and lunch. Tracer incorporation into myofibrillar protein was determined from the vastus lateralis with MyoPS estimated using plasma enrichment as precursor surrogate. Phosphorylation of candidate anabolic signaling proteins was determined by immunoblotting. There was no difference between conditions (P ≥ 0.78) in the time course or area under the curve for plasma phenylalanine enrichment. MyoPS was greater (P < 0.05, weighted planned comparison) in SQUAT (0.103 ± 0.030%/h) and WALK (0.118 ± 0.037%/h) compared with SIT (0.080 ± 0.032%/h). When compared with SIT, there were moderate-to-large effect sizes, respectively, for SQUAT [effect size (ES) = 0.75; 95% CI -0.10-1.55] and WALK (ES = 1.10; 95% CI 0.20-1.91). Fold change in rpS6Ser240/244 phosphorylation was greater in SQUAT compared with SIT (7.6 ± 2.7 vs. 1.6 ± 0.45-fold, P < 0.05) with no difference (P ≥ 0.21) in any other targets measured (4E-BP1Thr37/46, eEF2Thr56, mTORSer2448, ERK1/2Thr202/Tyr204). Interrupting prolonged sitting with short "activity snacks" improves the utilization of dietary amino acids for MyoPS. The long-term impact of this practical lifestyle modification for muscle mass or quality should be investigated.NEW & NOTEWORTHY Prolonged sitting can impair postprandial glycemia, lipidemia, and insulin sensitivity regardless of previous health status. We demonstrate that interrupting prolonged sitting with brief periods of activity, such as body weight squats or short bouts of walking, improves the efficiency of dietary amino acid utilizations for muscle contractile protein synthesis. This further emphasizes the importance of minimizing sedentary time to improve the postprandial metabolism of all macronutrients.

Can incentives improve antipsychotic adherence in major mental illness? A mixed-methods systematic review.

OBJECTIVES: Incentives have been effectively used in several healthcare contexts. This systematic review aimed to ascertain whether incentives can improve antipsychotic adherence, what ethical and practical issues arise and whether existing evidence resolves these issues. DESIGN: Systematic review of MEDLINE, EMBASE and PsycINFO. Searches on 13 January 2021 (no start date) found papers on incentives for antipsychotics. Randomised controlled trials (RCTs), cohort studies, qualitative research and ethical analyses were included. Papers measuring impact on adherence were synthesised, then a typology of ethical and policy issues was compiled, finally the empirical literature was compared with this typology to describe current evidence and identify remaining research questions. RESULTS: 26 papers were included. 2 RCTs used contingent financial incentives for long-acting injectable antipsychotic preparations. Over 12 months, there were significantly larger increases in adherence among the intervention groups versus control groups in both RCTs. There were no consistently positive secondary outcomes. 39 ethical and practical issues were identified. 12 of these are amenable to empirical study but have not been researched and for 7 the current evidence is mixed. CONCLUSIONS: In keeping with other areas of healthcare, antipsychotic adherence can be increased with financial incentives. Payments of 2.5 times minimum wage changed behaviour. The typology of issues reported in this systematic review provides a template for future policy and ethical analysis. The persistence of the effect and the impact of incentives on intrinsic motivation require further research. PROSPERO REGISTRATION NUMBER: CRD42020222702.

Challenges of rapamycin repurposing as a potential therapeutic candidate for COVID-19: implications for skeletal muscle metabolic health in older persons.

The novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) emerged as the causative agent of the ongoing coronavirus disease 2019 (COVID-19) pandemic that has spread worldwide, resulting in over 6 million deaths as of March 2022. Older people have been disproportionately affected by the disease, as they have a greater risk of hospitalization, are more vulnerable to severe infection, and have higher mortality than younger patients. Although effective vaccines have been rapidly developed and administered globally, several clinical trials are ongoing to repurpose existing drugs to combat severe infection. One such drug, rapamycin, is currently under study for this purpose, given its immunosuppressant effects that are mediated by its inhibition of the mechanistic target of rapamycin (mTOR), a master regulator of cell growth. Consistent with this premise, acute rapamycin administration in young healthy humans blocks or attenuates mTOR and its downstream effectors, leading to the inhibition of muscle protein synthesis (MPS). Skeletal muscle mass declines when MPS is chronically lower than muscle protein breakdown. This is consequential for older people who are more susceptible to anabolic resistance (i.e., the blunting of MPS) due to reduced activity, sedentariness, or bed rest such as that associated with COVID-19 hospitalization, and who have also demonstrated a delayed or blunted ability to regain inactivity-induced muscle loss. The lack of studies investigating rapamycin administration on skeletal muscle in older people, and the emergence of effective antiviral medications against severe infection, may indicate the reduced relevance of drug repurposing for present or future pandemics.

A non-invasive 13CO2 breath test detects differences in anabolic sensitivity with feeding and heavy resistance exercise in healthy young males: a randomized control trial.

There are limited tools to measure anabolic sensitivity non-invasively in response to acute physiological stimuli, which represents a challenge for research in free-living settings and vulnerable populations. We tested the ability of a stable isotope breath test to detect changes in leucine oxidation (OX) and leucine retention (intake-OX) across a range of anabolic sensitivities. Healthy males ingested a beverage containing 0.25 g·kg-1 protein and 0.75 g·kg-1 carbohydrate with the leucine content enriched to 5% with l-[1-13C]leucine at rest (FED) or after a bout of resistance exercise (EXFED), with a parallel group consuming only the tracer (FAST). Concurrent primed-constant infusions of l-[5,5,5-2H3]leucine revealed high peripheral bioavailability for FED (∼81%), EXFED (∼80%), and FAST (∼117%). After beverage ingestion, whole-body protein synthesis was greater in FED and EXFED than FAST. OX was greater in FED and EXFED than FAST, with OX lower in EXFED than FED. Leucine retention demonstrated expected physiological differences in anabolic sensitivity (EXFED > FED > FAST). We demonstrated that a non-invasive breath test based on an amino acid (leucine) that is preferentially metabolized in peripheral (muscle) tissues can detect differences in anabolic sensitivity. Future studies could examine this test within a variety of populations experiencing muscle growth or atrophy. This study was registered as a Clinical Trial at ClinicalTrials.gov (no. NCT04887727). Novelty: An oral l-[1-13C]leucine breath test can detect greater anabolic sensitivity after feeding and resistance exercise. This tool may be applied in growing (e.g., children) or wasting (e.g., aging) populations where invasive procedures are not possible.