Impact of using a broad-based multi-institutional approach to build capacity for non-communicable disease research in Thailand.

Thailand's transition to high middle-income country status has been accompanied by demographic changes and associated shifts in the nation's public health challenges. These changes have necessitated a significant shift in public health focus from the treatment of infectious diseases to the more expensive and protracted management of non-communicable diseases (NCDs) in older adults.In 2010, in response to this shift in focus, the University of Michigan and colleagues at the Praboromarajchanok Institute for Health Workforce Development in Thailand began work on a broad-based multi-institutional programme for NCD research capacity-building in Thailand.To begin to build a base of intervention research we paired our programme's funded Thai postdoctoral fellows with United States mentors who have strong programmes of intervention research. One direct impact of the programme was the development of research 'hubs' focused upon similar areas of investigative focus such as self-management of cancer symptoms, self-management of HIV/AIDS and health technology information applications for use in community settings. Within these hubs, interventions with proven efficacy in the United States were used as a foundation for culturally relevant interventions in Thailand. The programme also aimed to develop the research support structures necessary within departments and colleges for grant writing and management, dissemination of new knowledge, and ethical conduct of human subject research.In an effort to capitalise on large national health datasets and big data now available in Thailand, several of the programme's postdoctoral fellows began projects that use data science methods to mine this asset. The investigators involved in these ground-breaking projects form the core of a network of research hubs that will be able to capitalise on the availability of lifespan health data from across Thailand and provide a robust working foundation for expansion of research using data science approaches.Going forward, it is vitally important to leverage this groundwork in order to continue fostering rapid growth in NCD research and training as well as to capitalise upon these early gains to create a sustaining influence for Thailand to lead in NCD research, improve the health of its citizens, and provide ongoing leadership in Southeast Asia.

Dynamic reciprocity of sodium and potassium channel expression in a macromolecular complex controls cardiac excitability and arrhythmia.

The cardiac electrical impulse depends on an orchestrated interplay of transmembrane ionic currents in myocardial cells. Two critical ionic current mechanisms are the inwardly rectifying potassium current (I(K1)), which is important for maintenance of the cell resting membrane potential, and the sodium current (I(Na)), which provides a rapid depolarizing current during the upstroke of the action potential. By controlling the resting membrane potential, I(K1) modifies sodium channel availability and therefore, cell excitability, action potential duration, and velocity of impulse propagation. Additionally, I(K1)-I(Na) interactions are key determinants of electrical rotor frequency responsible for abnormal, often lethal, cardiac reentrant activity. Here, we have used a multidisciplinary approach based on molecular and biochemical techniques, acute gene transfer or silencing, and electrophysiology to show that I(K1)-I(Na) interactions involve a reciprocal modulation of expression of their respective channel proteins (Kir2.1 and Na(V)1.5) within a macromolecular complex. Thus, an increase in functional expression of one channel reciprocally modulates the other to enhance cardiac excitability. The modulation is model-independent; it is demonstrable in myocytes isolated from mouse and rat hearts and with transgenic and adenoviral-mediated overexpression/silencing. We also show that the post synaptic density, discs large, and zonula occludens-1 (PDZ) domain protein SAP97 is a component of this macromolecular complex. We show that the interplay between Na(v)1.5 and Kir2.1 has electrophysiological consequences on the myocardium and that SAP97 may affect the integrity of this complex or the nature of Na(v)1.5-Kir2.1 interactions. The reciprocal modulation between Na(v)1.5 and Kir2.1 and the respective ionic currents should be important in the ability of the heart to undergo self-sustaining cardiac rhythm disturbances.

Nurses in the United States with a practice doctorate: implications for leading in the current context of health care.

The Institute of Medicine has recommended doubling the number of nurses with doctorates by 2020. The National Research Council has recommended a clearer distinction between doctoral preparation for a practice profession and that for the preparation of scientists. To support the central premise that both the research-oriented doctorate (PhD) and the practice-oriented doctorate, the doctor of nursing practice (DNP), are critical to achieve and expand doctoral education, we present current information regarding the impact of DNP programs, including enrollments, scholarly productivity of DNP graduates, and the employment setting of DNP scholars. Scholarly productivity was estimated by searching publication databases between 2005 and 2012 using three strategies to estimate the publication record of nurses who had earned a DNP degree. The large numbers of nurses receiving the DNP are helping to fulfill the Institute of Medicine's recommendation and are increasingly contributing to the scholarly output in the field, especially related to clinical practice.

A null mutation of the neuronal sodium channel NaV1.6 disrupts action potential propagation and excitation-contraction coupling in the mouse heart.

Evidence supports the expression of brain-type sodium channels in the heart. Their functional role, however, remains controversial. We used global Na(V)1.6-null mice to test the hypothesis that Na(V)1.6 contributes to the maintenance of propagation in the myocardium and to excitation-contraction (EC) coupling. We demonstrated expression of transcripts encoding full-length Na(V)1.6 in isolated ventricular myocytes and confirmed the striated pattern of Na(V)1.6 fluorescence in myocytes. On the ECG, the PR and QRS intervals were prolonged in the null mice, and the Ca(2+) transients were longer in the null cells. Under patch clamping, at holding potential (HP) = -120 mV, the peak I(Na) was similar in both phenotypes. However, at HP = -70 mV, the peak I(Na) was smaller in the nulls. In optical mapping, at 4 mM [K(+)](o), 17 null hearts showed slight (7%) reduction of ventricular conduction velocity (CV) compared to 16 wild-type hearts. At 12 mM [K(+)](o), CV was 25% slower in a subset of 9 null vs. 9 wild-type hearts. These results highlight the importance of neuronal sodium channels in the heart, whereby Na(V)1.6 participates in EC coupling, and represents an intrinsic depolarizing reserve that contributes to excitation.

Case Studies: Person-Centered Health Coaching in People With Negative Social Determinants of Health.

Social determinants of health are the conditions in the environment that influence health outcomes, such as housing, transportation, and neighborhoods. In this report, we examine 3 cases of participants with social risk factors who participated in a health coaching intervention study. The study was a science-based, nurse health coaching model provided to older adult participants in a Midwestern state designed to equip and empower them to achieve and maintain their health and optimum function to support independent living at home. The program was an 8-week virtual coaching method using weekly, 30-minute, 2-way video coaching sessions with participants. For each of the 3 cases, we describe the patterns of engagement, early and later health goals as coaching progressed, and the types of outcomes achieved. From these case studies, we illustrate how social determinants may affect the types of goals, processes, and potential outcomes achieved by participants of health coaching programs. From these insights, we propose directions in health policy and services and future research considerations.

A randomized trial of a theory-driven model of health coaching for older adults: short-term and sustained outcomes.

BACKGROUND: Healthy Lifetime, a theoretically driven, personalized health coaching program delivered electronically, including face-to-face videoconferencing, was developed to intervene in early aging to stave off functional decline and minimize the onset/exacerbation of chronic conditions. OBJECTIVE: To determine the efficacy of a theoretically driven, personalized health coaching program in participants 50 years and older with one or more chronic conditions using a randomized, controlled, pragmatic clinical trial methodology. METHODS: Participants were randomly assigned to the HL (n = 59) or a usual care (n = 63) group. The HL group received health coaching from a trained nurse over eight weeks. Outcomes were measured at baseline, eight weeks, and 20 weeks (after the 12-week no-treatment phase). Regression modeling with fixed-effect repeated measures was used to account for the longitudinal data collection. RESULTS: For the HL group, health habits increased at 8 weeks (3.1 units; SE = 1.0; p = .0005; effect size = .15). This difference was sustained at 20 weeks (2.4 units, SE = 0.2; p = .0005). Independent self-care agency improved at 8 weeks in individuals with high blood pressure (13.5 units; SE = 4.37; p = .0023; effect size = .3). However, that difference was not sustained at 20 weeks (p = .47). No significant improvements were shown in the usual care group at 8 weeks or 20 weeks. CONCLUSIONS: HL participants significantly improved their health habits at 8 weeks and sustained this improvement at week 20 (after a 12-week no-treatment phase) vs. the usual care group. Changing health habits alone has been shown to reduce all-cause morbidity and mortality in chronic disease. The high-functioning, community-dwelling older adults with chronic diseases we studied is an important target population for primary care practices to intervene early in aging to stave off the complications of chronic disease and functional decline. TRIAL REGISTRATION: ClinicalTrials.gov (record NCT05070923, 07/10/2021).

A major role for HERG in determining frequency of reentry in neonatal rat ventricular myocyte monolayer.

RATIONALE: the rapid delayed rectifier potassium current, I(Kr), which flows through the human ether-a-go-go-related (hERG) channel, is a major determinant of the shape and duration of the human cardiac action potential (APD). However, it is unknown whether the time dependency of I(Kr) enables it to control APD, conduction velocity (CV), and wavelength (WL) at the exceedingly high activation frequencies that are relevant to cardiac reentry and fibrillation. OBJECTIVE: to test the hypothesis that upregulation of hERG increases functional reentry frequency and contributes to its stability. METHODS AND RESULTS: using optical mapping, we investigated the effects of I(Kr) upregulation on reentry frequency, APD, CV, and WL in neonatal rat ventricular myocyte (NRVM) monolayers infected with GFP (control), hERG (I(Kr)), or dominant negative mutant hERG G628S. Reentry frequency was higher in the I(Kr)-infected monolayers (21.12 ± 0.8 Hz; n=43 versus 9.21 ± 0.58 Hz; n=16; P<0.001) but slightly reduced in G628S-infected monolayers. APD(80) in the I(Kr)-infected monolayers was shorter (>50%) than control during pacing at 1 to 5 Hz. CV was similar in both groups at low frequency pacing. In contrast, during high-frequency reentry, the CV measured at varying distances from the center of rotation was significantly faster in I(Kr)-infected monolayers than controls. Simulations using a modified NRVM model predicted that rotor acceleration was attributable, in part, to a transient hyperpolarization immediately following the AP. The transient hyperpolarization was confirmed experimentally. CONCLUSIONS: hERG overexpression dramatically accelerates reentry frequency in NRVM monolayers. Both APD and WL shortening, together with transient hyperpolarization, underlies the increased rotor frequency and stability.

Thailand's Challenges of Achieving Health Equity in the Era of Non-Communicable Disease.

Thailand is an exemplar of the challenges faced in addressing the increasing dual demands of aging populations and increasing incidence of non-communicable disease (NCDs). By understanding the dilemmas and solutions posed by Thailand, we propose a framework of key factors to be addressed in order to accelerate capacity in addressing the NCDs challenges in aging populations. Methods proposed by world health organizations to improve population health could impact NCDs if Quality Adjusted Life Years (QALYs) are increased as well as life expectancy through these measures. Four recommendations for achieving these objectives are discussed: expand investments in health care infrastructure for NCDs prevention and early detection; expand public health policies to full population health goals; expand to universal coverage for health care access; engage multi-sectoral constituencies in policy and strategic implementation programs for health. With the emergence of an aging population and the inevitable rise in NCDs, the Thai government is engaging each element of our recommendations and grappling with the policy trade-offs in the context of broader economic and other strategic goals. The experience of Thailand in achieving its goal of population health is a case study of focus, perseverance, and consistent policy strategies.

The Impact of Nurse Health-Coaching Strategies on Cognitive-Behavioral Outcomes in Older Adults.

The practice of nurse health coaching (NHC) draws from the art and science of nursing, behavioral sciences, and evidence-based health-coaching methods. This secondary analysis of the audio-recorded natural language of participants during NHC sessions of our recent 8-week RCT evaluates improvement over time in cognitive−behavioral outcomes: change talk, resiliency, self-efficacy/independent agency, insight and pattern recognition, and building towards sustainability. We developed a measurement tool for coding, Indicators of Health Behavior Change (IHBC), that was designed to allow trained health-coach experts to assess the presence and frequency of the indicators in the natural language content of participants. We used a two-step method for randomly selecting the 20 min audio-recorded session that was analyzed at each time point. Fifty-six participants had high-quality audio recordings of the NHC sessions. Twelve participants were placed in the social determinants of health (SDH) group based on the following: low income (

Healthy Lifetime (HL): An Internet-Based Behavioral Health Coaching Protocol for Older Adults.

By 2060, the number of Americans 65 years and older will more than double, comprising nearly one-quarter of the population in the United States. While there are many advantages to living longer, a byproduct of aging is also a growing incidence of chronic illness and functional health limitations associated with a concurrent rise in chronic disease and disability that impair independent living in the community. We describe a personalized, behavioral health coaching protocol for early intervention that is delivered online to enhance a participant's independent functioning and to increase their self-care capacity with a goal to maintain independent living throughout aging. The electronic platform provides secure access to fillable surveys, health tracking, "just in time" communication with coaches and scheduling of two-way videos launched from the platform site. The 2-month protocol used two-way video conferencing which allowed high fidelity communication to sustain a complex behavioral intervention. Participants indicate high satisfaction with the intervention, the use of the platform, and the technology. While many health systems across the U.S. have ramped up virtual delivery of care in a proactive manner with now more than 70% of out-patient visits conducted through virtual delivery modes in some health systems, there remains much unevenness in this capability across the U.S. Our approach is to create a stable, interoperable, virtual outreach system for personalized professional health coaching that is complementary to medically oriented services that supports the health and functioning of participants as they age.

Structural heterogeneity promotes triggered activity, reflection and arrhythmogenesis in cardiomyocyte monolayers.

Patients with structural heart disease are predisposed to arrhythmias by incompletely understood mechanisms. We hypothesized that tissue expansions promote source-to-sink mismatch leading to early after-depolarizations (EADs) and reflection of impulses in monolayers of well-polarized neonatal rat ventricular cardiomyocytes.We traced electrical propagation optically in patterned monolayers consisting of two wide regions connected by a thin isthmus.Structural heterogeneities provided a substrate for EADs, retrograde propagation along the same pathway (reflection) and reentry initiation. Reflection always originated during the action potential (AP) plateau at the distal expansion. To determine whether increased sodium current(INa) would promote EADs, we employed adenoviral transfer of Nav1.5 (Ad-Nav1.5). Compared with uninfected and adenoviral expression of green fluorescent protein (Ad-GFP; viral control),Ad-Nav1.5 significantly increased Nav1.5 protein expression, peak and persistent INa density, A Pupstroke velocity, AP duration, conduction velocity and EAD incidence, as well as reflection incidence (29.2%, n =48 vs. uninfected, 9.4%, n =64; and Ad-GFP, 4.8%, n =21). Likewise,the persistent INa agonist veratridine (0.05­3 µM) prolonged the AP, leading to EADs and reflection. Reflection led to functional reentry distally and bigeminal and trigeminal rhythms proximally. Reflection was rare in the absence of structural heterogeneities.Computer simulations demonstrated the importance of persistent INa in triggering reflection and predicted that the gradient between the depolarizing cells at the distal expansion and the repolarizing cells within the isthmus enabled retrograde flow of depolarizing electrotonic current to trigger EADs and reflection. A combination of a substrate (structural heterogeneity) and a trigger (increased persistent INa and EADs) promotes reflection and arrhythmogenesis.

The ionic bases of the action potential in isolated mouse cardiac Purkinje cell.

BACKGROUND: Collecting electrophysiological and molecular data from the murine conduction system presents technical challenges. Thus, only little advantage has been taken of numerous genetically engineered murine models to study excitation through the cardiac conduction system of the mouse. OBJECTIVE: To develop an approach for isolating murine cardiac Purkinje cells (PCs), to characterize major ionic currents and to use the data to simulate action potentials (APs) recorded from PCs. METHODS: Light microscopy was used to isolate and identify PCs from apical and septal cells. Current and voltage clamp techniques were used to record APs and whole cell currents. We then simulated a PC AP on the basis of our experimental data. RESULTS: APs recorded from PCs were significantly longer than those recorded from ventricular cells. The prominent plateau phase of the PC AP was very negative (≈-40 mV). Spontaneous activity was observed only in PCs. The inward rectifier current demonstrated no significant differences compared to ventricular myocytes (VMs). However, sodium current density was larger, and the voltage-gated potassium current density was significantly less in PCs compared with myocytes. T-type Ca(2+) currents (I(Ca,T)) were present in PCs but not VMs. Computer simulations suggest that I(Ca,T) and cytosolic calcium diffusion significantly modulate AP profile recorded in PCs, as compared to VMs. CONCLUSIONS: Our study provides the first comprehensive ionic profile of murine PCs. The data show unique features of PC ionic mechanisms that govern its excitation process. Experimental data and numerical modeling results suggest that a smaller voltage-gated potassium current and the presence of I(Ca,T) are important determinants of the longer and relatively negative plateau phase of the APs.

Left-to-right ventricular differences in I(KATP) underlie epicardial repolarization gradient during global ischemia.

BACKGROUND: The ionic mechanisms of electrical heterogeneity in the ischemic ventricular epicardium remain poorly understood. OBJECTIVE: This study sought to test the hypothesis that the adenosine triphosphate (ATP)-activated K+ current (I(KATP)) plays an important role in mediating repolarization differences between the right ventricle (RV) and left ventricle (LV) during global ischemia. METHODS: Electrical activity in Langendorff-perfused guinea pig hearts was recorded optically during control, ischemia, and reperfusion. Patch-clamp experiments were used to quantify I(KATP) density in isolated myocytes. Molecular correlates of I(KATP) (Kir6/SUR) were probed via reverse transcriptase-polymerase chain reaction. The role of I(KATP) in modulating repolarization was studied using computer simulations. RESULTS: Action potential duration (APD) was similar between LV and RV in control hearts, but significantly different in global ischemia. Pretreatment of hearts with 10 µM glibenclamide (I(KATP) blocker) abolished the APD gradient during ischemia. In the absence of ischemia, pinacidil (I(KATP) opener) tended to shorten the APD more in the LV, and caused a small but significant increase in APD dispersion. In voltage clamp experiments, the density of the whole-cell current activated by pinacidil at depolarized potentials was significantly larger in LV, compared with RV epicardial myocytes. The mRNA levels of Kir6.1/Kir6.2 were significantly higher in LV compared with RV. Simulations showed that I(KATP) is the main determinant of LV-RV APD gradient, whereas cell-to-cell coupling modified the spatial distribution of this APD gradient. CONCLUSION: I(KATP) is an important determinant of the epicardial LV-RV APD gradient during global ischemia, in part due to a higher current density and molecular expression in the LV.

Loss of H3K4 methylation destabilizes gene expression patterns and physiological functions in adult murine cardiomyocytes.

Histone H3 lysine 4 (H3K4me) methyltransferases and their cofactors are essential for embryonic development and the establishment of gene expression patterns in a cell-specific and heritable manner. However, the importance of such epigenetic marks in maintaining gene expression in adults and in initiating human disease is unclear. Here, we addressed this question using a mouse model in which we could inducibly ablate PAX interacting (with transcription-activation domain) protein 1 (PTIP), a key component of the H3K4me complex, in cardiac cells. Reducing H3K4me3 marks in differentiated cardiomyocytes was sufficient to alter gene expression profiles. One gene regulated by H3K4me3 was Kv channel-interacting protein 2 (Kcnip2), which regulates a cardiac repolarization current that is downregulated in heart failure and functions in arrhythmogenesis. This regulation led to a decreased sodium current and action potential upstroke velocity and significantly prolonged action potential duration (APD). The prolonged APD augmented intracellular calcium and in vivo systolic heart function. Treatment with isoproterenol and caffeine in this mouse model resulted in the generation of premature ventricular beats, a harbinger of lethal ventricular arrhythmias. These results suggest that the maintenance of H3K4me3 marks is necessary for the stability of a transcriptional program in differentiated cells and point to an essential function for H3K4me3 epigenetic marks in cellular homeostasis.

Increased tyrosine phosphorylation mediates the cooling-induced contraction and increased vascular reactivity of Raynaud's disease.

OBJECTIVE: Increased levels of protein tyrosine kinase (PTK) are mechanistically associated with increased contractile responsiveness to cooling. This study tests the hypothesis that increased PTK activity mediates the increased vascular reactivity to agonists and cooling associated with primary Raynaud's disease (RD). METHODS: The response of dermal arterioles isolated from control (n = 29) and RD (n = 29) subjects to contractile and dilatory agents at 37 degrees C and 31 degrees C was characterized using the microvessel perfusion technique. Fluorescence immunohistochemistry was used to measure tyrosine phosphorylation. RESULTS: At 37 degrees C, arteries from RD patients exhibited similar sensitivity to the specific alpha(2)-adrenergic agonist UK 14,304, to serotonin, and to angiotensin II. At 31 degrees C, however, the response to all 3 agonists was greater in the arterioles from the RD patients than in those from the control subjects. Agonist-induced contraction at both temperatures was reversed by cumulative addition of the PTK inhibitors genistein (1-30 microM) and tyrphostin 47 (0.1-10 microM). All arterioles from control subjects relaxed slightly in response to cooling, whereas more than half of those from RD patients contracted. This cooling-induced contraction was reversed by the cumulative addition of genistein. The 3 agonists elicited large increases in tyrosine phosphorylation only in arterial segments from RD patients at 31 degrees C. Cooling from 37 degrees C to 31 degrees C elicited a large increase in tyrosine phosphorylation in arterioles from RD patients, but not those from control subjects. All increases in tyrosine phosphorylation could be prevented by genistein. CONCLUSION: Increased tyrosine phosphorylation mediates cooling-induced contraction and the increased vascular reactivity of skin arterioles from individuals with RD.