Evan D. Muse

Can Mobile Health Technologies Transform Health Care

There is substantial enthusiasm for the concept of mobile health (mHealth), a broad term typically used to describe the use of mobile telecommunication technologies for the delivery of health care and in support of wellness. In 2011, US Secretary of Health and Human Services Kathleen Sebelius referred to mHealth as “the biggest technology breakthrough of our time” and maintained that its use would “address our greatest national challenge.”1 This level of exuberance for mHealth is driven by the convergence of 3 powerful forces. First is the unsustainability of current health care spending and the recognition of the need for disruptive solutions. Second is the rapid and ongoing growth in wireless connectivity— there now are more than 3.2 billion unique mobile users worldwide—and the remarkable capability this brings for the bidirectional instantaneous transfer of information. Third is the need for more precise and individualized medicine; a refinement in phenotypes that mandates novel, personal data streams well beyond the occasional vital sign or laboratory data available through intermittent clinic visits. But there are multiple obstacles to the acceptance and widespread utilization of mHealth technologies. Foremost are the complexities of the health care system, especially the current drivers of reimbursement. In addition, clinicians are concerned about the possible further weakening of the patient-physician relationship and the possible increase in their workload. Also, and somewhat paradoxically, the unbridled enthusiasm of the mHealth technology development community, coupled with consumers’ appetite for alternative health and wellness resources, can create challenges to the appropriate use and validation of mHealth technologies. For example, there are tens of thousands (estimates vary between 30 000 to more than 90 000) health care– related apps available for download, in contrast to the US Food and Drug Administration estimate of the approximately 100 it has reviewed. This lack of oversight is worrisome and contributes to the increasingly high likelihood of useless and possibly even dangerous apps being downloaded by unsuspecting consumers.2 When such a high level of interest and promise coexists with such a paucity of evidence, there is potential for hype to dominate the discussion around mHealth. To move beyond that, in this Viewpoint we offer examples of how mHealth technologies can transform health care by addressing inefficient practices and challenges faced by consumers and clinicians in the current system.

The emerging field of mobile health

Mobile technologies can transform clinical research and health care worldwide—and save money. The surge in computing power and mobile connectivity have fashioned a foundation for mobile health (mHealth) technologies that can transform the mode and quality of clinical research and health care on a global scale. Unimpeded by geographical boundaries, smartphone-linked wearable sensors, point-of-need diagnostic devices, and medical-grade imaging, all built around real-time data streams and supported by automated clinical decision–support tools, will enable care and enhance our understanding of physiological variability. However, the path to mHealth incorporation into clinical care is fraught with challenges. We currently lack high-quality evidence that supports the adoption of many new technologies and have financial, regulatory, and security hurdles to overcome. Fortunately, sweeping efforts are under way to establish the true capabilities and value of the evolving mHealth field.

Glucagon receptor activates extracellular signal-regulated protein kinase 1/2 via cAMP-dependent protein kinase

We prepared a stable cell line expressing the glucagon receptor to characterize the effect of Gs-coupled receptor stimulation on extracellular signal-regulated protein kinase 1/2 (ERK1/2) activity. Glucagon treatment of the cell line caused a dose-dependent increase in cAMP concentration, activation of cAMP-dependent protein kinase (PKA), and transient release of intracellular calcium. Glucagon treatment also caused rapid dose-dependent phosphorylation and activation of mitogen-activated protein kinase kinase/ERK kinase (MEK1/2) and ERK1/2. Inhibition of either PKA or MEK1/2 blocked ERK1/2 activation by glucagon. However, no significant activation of several upstream activators of MEK, including Ras, Rap1, and Raf, was observed in response to glucagon treatment. In addition, chelation of intracellular calcium reduced glucagon-mediated ERK1/2 activation. In transient transfection experiments, glucagon receptor mutants that bound glucagon but failed to increase intracellular cAMP and calcium concentrations showed no glucagon-stimulated ERK1/2 phosphorylation. We conclude that glucagon-induced MEK1/2 and ERK1/2 activation is mediated by PKA and that an increase in intracellular calcium concentration is required for maximal ERK activation.

Molecular Autopsy for Sudden Unexpected Death

Molecular Autopsy for Sudden Unexpected Death Approximately 11 000 individuals younger than 45 years in the United States die suddenly and unexpectedly each year from conditions including sudden infant death, pulmonary embolism, ruptured aortic aneurysm, and sudden cardiac death (SCD). Sometimes the cause of death is not determined, even after a clinical autopsy, leaving living relatives with an inaccurate or ambiguous family health history. Moreover, the rate of clinical autopsy has declined from approximately 50% fifty years ago to less than 10% in 2008, contributing further to uncertain family health histories.1 This uncertainty may be partially resolved with postmortem genetic testing (“molecular autopsy”).2 Initial studies, limited to cardiac channelopathy and epilepsy genes, have yielded molecular diagnoses in approximately 25% of cases.3,4 A more comprehensive molecular autopsy program, expanded beyond SCD, has the potential to provide more accurate family health information to a wider spectrum of afflicted families. Here we report preliminary results from a systematic, prospective, family-based, molecular autopsy study.

Cardiovascular and nervous system changes during meditation

Background: A number of benefits have been described for the long-term practice of meditation, yet little is known regarding the immediate neurological and cardiovascular responses to meditation. Wireless sensor technology allows, for the first time, multi-parameter and quantitative monitoring of an individuals responses during meditation. The present study examined inter-individual variations to meditation through continuous monitoring of EEG, blood pressure, heart rate and its variability (HRV) in novice and experienced meditators. Methods: Participants were 20 experienced and 20 novice meditators involved in a week-long wellness retreat. Monitoring took place during meditation sessions on the first and last full days of the retreat. All participants wore a patch that continuously streamed ECG data, while half of them also wore a wireless EEG headset plus a non-invasive continuous blood pressure monitor. Results: Meditation produced variable but characteristic EEG changes, significantly different from baseline, even among novice meditators on the first day. In addition, although participants were predominately normotensive, the mean arterial blood pressure fell a small (2–3 mmHg) but significant (p < 0.0001) amount during meditation. The effect of meditation on HRV was less clear and influenced by calculation technique and respiration. No clear relationship between EEG changes, HRV alterations, or mean blood pressure during meditation was found. Conclusion: This is the first study to investigate neurological and cardiovascular responses during meditation in both novice and experienced meditators using novel, wearable, wireless devices. Meditation produced varied inter-individual physiologic responses. These results support the need for further investigation of the short- and long-term cardiovascular effects of mental calm and individualized ways to achieve it.

Dissociated sterol-based liver X receptor agonists as therapeutics for chronic inflammatory diseases

Liver X receptor (LXR), a nuclear hormone receptor, is an essential regulator of immune responses. Activation of LXR‐mediated transcription by synthetic agonists, such as T0901317 and GW3965, attenuates progression of inflammatory disease in animal models. However, the adverse effects of these conventional LXR agonists in elevating liver lipids have impeded exploitation of this intriguing mechanism for chronic therapy. Here, we explore the ability of a series of sterol‐based LXR agonists to alleviate inflammatory conditions in mice without hepatotoxicity. We show that oral treatment with sterol‐based LXR agonists in mice significantly reduces dextran sulfate sodium colitis‐induced body weight loss, which is accompanied by reduced expression of inflammatory markers in the large intestine. The anti‐inflammatory property of these agonists is recapitulated in vitro in mouse lamina propria mononuclear cells, human colonic epithelial cells, and human peripheral blood mononuclear cells. In addition, treatment with LXR agonists dramatically suppresses inflammatory cytokine expression in a model of traumatic brain injury. Importantly, in both disease models, the sterol‐based agonists do not affect the liver, and the conventional agonist T0901317 results in significant liver lipid accumulation and injury. Overall, these results provide evidence for the development of sterol‐based LXR agonists as novel therapeutics for chronic inflammatory diseases.—Yu, S., Li, S., Henke, A., Muse, E. D., Cheng, B., Welzel, G., Chatterjee, A. K., Wang, D., Roland, J., Glass, C. K., Tremblay, M. Dissociated sterol‐based liver X receptor agonists as therapeutics for chronic inflammatory diseases. FASEB J. 30, 2570‐2579 (2016). www.fasebj.org

Cell-specific discrimination of desmosterol and desmosterol mimetics confers selective regulation of LXR and SREBP in macrophages

Significance The beneficial effects of LXR-pathway activation have long been appreciated, but clinical application of synthetic LXR ligands has been limited by coactivation of SREBP1c and consequent hypertriglyceridemia. Natural LXR ligands such as desmosterol do not promote hypertriglyceridemia because of coordinate down-regulation of the SREBP pathway. Here we demonstrate that synthetic desmosterol mimetics activate LXR in macrophages both in vitro and in vivo while suppressing SREBP target genes. Unexpectedly, desmosterol and synthetic desmosterol mimetics have almost no effect on LXR activity in hepatocytes in comparison with conventional synthetic LXR ligands. These findings reveal cell-specific differences in LXR responses to natural and synthetic ligands in macrophages and liver cells that provide a conceptually new basis for future drug development. Activation of liver X receptors (LXRs) with synthetic agonists promotes reverse cholesterol transport and protects against atherosclerosis in mouse models. Most synthetic LXR agonists also cause marked hypertriglyceridemia by inducing the expression of sterol regulatory element-binding protein (SREBP)1c and downstream genes that drive fatty acid biosynthesis. Recent studies demonstrated that desmosterol, an intermediate in the cholesterol biosynthetic pathway that suppresses SREBP processing by binding to SCAP, also binds and activates LXRs and is the most abundant LXR ligand in macrophage foam cells. Here we explore the potential of increasing endogenous desmosterol production or mimicking its activity as a means of inducing LXR activity while simultaneously suppressing SREBP1c-induced hypertriglyceridemia. Unexpectedly, while desmosterol strongly activated LXR target genes and suppressed SREBP pathways in mouse and human macrophages, it had almost no activity in mouse or human hepatocytes in vitro. We further demonstrate that sterol-based selective modulators of LXRs have biochemical and transcriptional properties predicted of desmosterol mimetics and selectively regulate LXR function in macrophages in vitro and in vivo. These studies thereby reveal cell-specific discrimination of endogenous and synthetic regulators of LXRs and SREBPs, providing a molecular basis for dissociation of LXR functions in macrophages from those in the liver that lead to hypertriglyceridemia.

Validation of a genetic risk score for atrial fibrillation: A prospective multicenter cohort study

Background Atrial fibrillation (AF) is the most commonly encountered arrhythmia and is associated with an elevated risk of stroke. Improving the identification of patients with the highest risk for AF to enable appropriate surveillance and treatment, if necessary, is critical to reducing AF-associated morbidity and mortality. Multiple common single nucleotide polymorphisms (SNPs) are unequivocally associated with the lifetime risk of AF. In the current study we aimed to prospectively validate an AF genetic risk score (GRS) in previously undiagnosed patients at risk for AF. Methods and findings Individuals 40 years of age or older with 1 clinical risk factor for AF, presenting with symptoms of AF, or with a first diagnosis of AF, were enrolled for genetic testing and ambulatory cardiac rhythm monitoring with an adhesive patch monitor or a long-term Holter monitor (mean wear time 10 days 21 hours and 13 days 18 hours, respectively). An AF event was the first diagnosis of AF by ECG, patch monitor, or long-term Holter monitor. The AF GRS was determined for each participant based on the weighted contribution of 12 genetic risk loci. Of 904 participants, 85 manifested AF. Their mean age was 66.2 (SD 11.8) years; 38% of participants were male. Participants in the highest quintile of AF GRS were more likely (odds ratio 3.11; 95% CI 1.27–7.58; p = 0.01) to have had an AF event than participants in the lowest quintile after adjusting for age, sex, smoking status, BMI, hypertension, diabetes mellitus, heart failure, and prior myocardial infarction. Study limitations included an ethnically homogenous population, a restricted rhythm monitoring period, and the evolving discovery of SNPs associated with AF. Conclusions Prospective assessment of a GRS for AF identified participants with elevated risk of AF beyond established clinical criteria. Accordingly, a GRS for AF could be incorporated into overall risk assessment to better identify patients at the highest risk of developing AF, although further testing in larger populations is needed to confirm these findings. Trial registration ClinicalTrials.gov NCT01970969

Interventions for Increasing Physical Activity: From “Ingenious Toys” to mHealth∗

The ABC ’s of primary and secondary cardiovascular disease prevention are not complete without D (diet and weight management) and certainly without E (exercise) [(1)][1]. Although coming in last in the helpful mnemonic, exercise certainly is not the least important. The benefits of increased

Moving Beyond Clinical Risk Scores with a Mobile App for the Genomic Risk of Coronary Artery Disease

Primary prevention of coronary artery disease (CAD) is important for individuals at increased risk, and largely consists of healthy lifestyle modifications and initiation of medications when appropriate – including statins. Defining the inherent risk for any given individual typically relies on traditional risk factors established decades ago by the Framingham Heart Study. Unfortunately, recent studies have indicated that these traditional clinical risk factors systematically overestimate the risk of CAD across all major ancestries. This has increased the number of patients that would be eligible for statin therapy for the primary prevention of CAD but would likely receive little benefit and potentially incur negative consequences. On the other hand, researchers have demonstrated that genetic factors can effectively identify a subset of high risk individuals, and that the benefit from statin therapy is greatest among individuals with the highest genetic risk score (GRS). These individuals also receive the greatest absolute benefit from healthy lifestyle choices, being able to titrate their risk to normal levels despite high genetic predisposition. However, it is not yet possible for the average individual to discover their genetic risk because no tools are currently available to make such a determination. Here, we present a free mobile app – MyGeneRank – that can provide this information. Individuals may choose to use this knowledge to complement traditional risk assessments, and make critical decisions regarding lifelong statin therapy and lifestyle changes. As of 1/25/2017, MyGeneRank is currently in closed beta and will soon be available to the public.