From Inputs to Impacts: Assessing and Communicating the Full Value of Biomedical Research.

Assessing and communicating the full value of biomedical research is essential to answer calls from the government and the public demanding accountability for the spending of public funds. In academic settings, however, research success is measured largely in terms of grant funding received or the number of peer-reviewed publications produced. These credible and time-tested metrics miss the full picture of the scientific process, which continues to confer benefits to patients, communities, and the health care system well after an article is published. In this context, in 2012, the Association of American Medical Colleges, in collaboration with RAND Europe, initiated a program to provide resources and guidance for leaders of medical schools and teaching hospitals interested in evaluating-in novel ways complementary to traditional methods-the outcomes and impacts of the research that emanates from their institutions. This Perspective provides context for this initiative and delineates the process through which researchers, evaluation experts, and other stakeholders-including legislators, health system leaders, and community members-identified and vetted novel "metrics that matter" in advance of a pilot test at the University of Wisconsin-Madison, which sought to assess and communicate its community-engaged science and scholarship.

The U.S. Public's Investment in Medical Research: An Evolving Social Contract.

Medical researchers and their institutions are operating under extraordinary financial stress. More than a decade after completion of the 5-year doubling of the National Institutes of Health budget, the medical research community must confront a significant loss in National Institutes of Health purchasing power and downward pressures in federal discretionary spending. In part, this trend results from a federal budget stalemate over the growth in entitlement programs, particularly spending on medical care. This article considers the changing nature of the federal investment in medical research and the potential for medical researchers and institutions conducting the full spectrum of research to improve health system performance and health equity. In our view, continued federal investments reflect an evolving social contract for research serving the public good; the term contract is used metaphorically to represent a figurative, implicit agreement between the scientific community and the public's representatives in government. Under this conceptual contract, the American people--who are ultimately the funders of research, research training and infrastructure--expect outcomes that lead to better health, security or other benefits. The evolving contract includes expectations for more accountability, transparency, sharing of results and resources, and better integration of research systems and cultures that used to take pride in boundaries and distinctions. We outline here some of the major movements of organizations realigning to social support, which are increasingly essential to sustain public investment in medical research.

MD-PhD training: looking back and looking forward.

MD-PhD programs provide rigorous, integrated training for physician-scientists, enabling them to frame scientific questions in unique ways and to apply clinical insight to fundamental science. Few would question the influential contributions of MD-PhD physician-scientists in advancing medical science. In this issue of Academic Medicine, Jeffe et al affirm high levels of excellence in educational outcomes from MD-PhD training programs at U.S. MD-granting medical schools, especially programs that receive funding from the NIH Medical Scientist Training Program (MSTP). The author of this commentary observes that, in the face of current economic pressures, comprehensive, longitudinal national outcomes data from MSTP- and non-MSTP-funded MD-PhD programs will help verify the value provided by MD-PhD physician-scientists. She proposes that MD-PhD programs should better prepare the next generation of physician-scientists for future research environments, which will provide new technologies, venues, and modalities. These research environments will be more closely integrated within health care delivery systems, extend into diverse communities and regions, and employ complex technologies. MD-PhD physician-scientists also will train and gain expertise in broadening areas of research, such as health policy, health economics, clinical epidemiology, and medical informatics. Program leaders are ideally situated to foster innovative learning environments and methodologies. By sharing their innovations, they can help ensure production of a diverse MD-PhD physician-scientist workforce, prepared to engage in myriad research opportunities to meet patient and population needs in a new environment.

Training the translational research teams of the future: UC Davis-HHMI Integrating Medicine into Basic Science program.

There is a need for successful models of how to recruit, train, and retain bench scientists at the earliest stages of their careers into translational research. One recent, promising model is the University of California Davis Howard Hughes Medical Institute Integrating Medicine into Basic Science (HHMI-IMBS) program, part of the HHMI Med into Grad initiative. This paper outlines the HHMI-IMBS program's logic, design, and curriculum that guide the goal of research that moves from bedside to bench. That is, a curriculum that provides graduate students with guided translational training, clinical exposure, team science competencies, and mentors from diverse disciplines that will advance the students careers in clinical translational research and re-focusing of research to answer clinical dilemmas. The authors have collected data on 55 HHMI-IMBS students to date. Many of these students are still completing their graduate work. In the current study the authors compare the initial two cohorts (15 students) with a group of 29 control students to examine the program success and outcomes. The data indicate that this training program provides an effective, adaptable model for training future translational researchers. HHMI-IMBS students showed improved confidence in conducting translational research, greater interest in a future translational career, and higher levels of research productivity and collaborations than a comparable group of predoctoral students.

Making equity a value in value-based health care.

Equity in health and health care in America continues to be a goal unmet. Certain demographic groups in the United States-including racial and ethnic minorities and individuals with lower socioeconomic status-have poorer health outcomes across a wide array of diseases, and have higher all-cause mortality. Yet despite growing understanding of how social-, structural-, and individual-level factors maintain and create inequities, solutions to reduce or eliminate them have been elusive. In this article, the authors envision how disparities-related provisions in the Affordable Care Act and other recent legislation could be linked with new value-based health care requirements and payment models to create incentives for narrowing health care disparities and move the nation toward equity.Specifically, the authors explore how recent legislative actions regarding payment reform, health information technology, community health needs assessments, and expanding health equity research could be woven together to build an evidence base for solutions to health care inequities. Although policy interventions at the clinical and payer levels alone will not eliminate disparities, given the significant role the social determinants of health play in the etiology and maintenance of inequity, such policies can allow the health care system to better identify and leverage community assets; provide high-quality, more equitable care; and demonstrate that equity is a value in health.

The implications of comparative effectiveness research for academic medicine.

With growing constraints on government spending, policy makers are investing in comparative effectiveness research (CER) to attempt to bring the power of science to bear on the problems of suboptimal outcomes and high cost in the U.S. health care system. This commitment of resources to CER reflects confidence that better evidence can help clinicians and patients make better decisions, consistent with the long tradition of medical schools' and teaching hospitals' use of science to inform medical care. Thus, CER offers a great opportunity, albeit with some considerable challenges, for academic medicine to play a central role in comprehensive health care reform. Certainly, many scientists conducting CER will learn their methodological rigor in the training programs of academic health centers. Numerous new CER research teams will be needed, establishing effective partnerships far outside the walls of the traditional academic setting. And the clinicians interpreting the medical literature and applying the insights from CER to the unique problems of individual patients will need to learn this evidence-based, patient-centered care from the educators, mentors, and role models at U.S. medical and other health science schools and teaching hospitals. Achieving this will require investment in research infrastructure, adaptations of institutional culture, development of new disciplines and research methods, establishment of new collaborations, training of new faculty, and the expansion and refocusing of educational capacity. By successfully responding to this challenge, academic medicine can further strengthen its long-standing commitment to the scientific practice of medicine and the use of evidence in patient-centered, personalized care.

Distinct tachykinin NK(1) receptor function in primate nucleus tractus solitarius neurons is dysregulated after second-hand tobacco smoke exposure.

BACKGROUND AND PURPOSE: Second-hand tobacco smoke (SHS) exposure in children increases the risk of asthma and sudden infant death syndrome. Epidemiological and experimental data have suggested SHS can alter neuroplasticity in the CNS, associated with substance P. We hypothesized that exposure to SHS in young primates changed the effect of substance P on the plasticity of neurons in the nucleus tractus solitarius (NTS), where airway sensory information is first processed in the CNS. EXPERIMENTAL APPROACH: Thirteen-month-old rhesus monkeys were exposed to filtered air (FA, n= 5) or SHS (n= 5) for >6 months from 50 days of their fetal age. Whole-cell patch-clamp recordings were performed on NTS neurons in brainstem slices from these animals to record the intrinsic cell excitability in the absence or presence of the NK(1) receptor antagonist, SR140333 (3 µM). KEY RESULTS: Neurons were electrophysiologically classified based on their spiking onset from a hyperpolarized membrane potential into two phenotypes: rapid-onset spiking (RS) and delayed-onset spiking (DS) types. In RS neurons, SR140333 reduced the spiking response, similarly in both FA- and SHS-exposed animals. In DS neurons, SR140333 almost abolished the spiking response in FA-exposed animals, but had no effect in SHS-exposed animals. CONCLUSIONS AND IMPLICATIONS: The contribution of NK(1) receptors to cell excitability depended on firing phenotype of primate NTS neurons and was disrupted by SHS exposure, specifically in DS neurons. Our findings reveal a novel NK(1) receptor function in the primate brainstem and support the hypothesis that chronic exposure to SHS in children causes tachykinin-related neuroplastic changes in the CNS.

Moving comparative effectiveness research into practice: implementation science and the role of academic medicine.

The success of the federal investment in comparative effectiveness research will hinge on using the power of science to guide reforms in health care delivery and improve patient-centered outcomes. Translating the results of comparative effectiveness research into practice calls for the rigors of implementation science to ensure the efficient and systematic uptake, dissemination, and endurance of these innovations. Academic medicine can help answer the call by thoroughly integrating its research and training missions with clinical care that is focused on patient-centered outcomes; building multidisciplinary teams that include a wide range of experts such as clinicians, clinical and implementation scientists, systems engineers, behavioral economists, and social scientists; and training future care providers, scientists, and educators to carry innovations forward.

Commentary: Putting evidence to work: an expanded research agenda for academic medicine in the era of health care reform.

The historic Patient Protection and Affordable Care Act (HR 3590) signed into law by President Obama has brought into sharp focus the need and opportunity for an expanded continuum of biomedical research. An updated research agenda must build on basic science and classical clinical investigation to place a more deliberate emphasis on patient- and population-outcome-oriented science and to apply science to help transform our current inefficient and expensive health care system into a more evidence-based system of effective, coordinated, safe, and patient-centered health care. If academic medicine is to play a leading role in this 21st-century transformation of health care through research, as it did in the 20th century, those in the community must think strategically about what needs to be done to be part of the solution for transforming the nation's health care delivery systems and prevention strategies, and the changes in institutional, organizational, and individual behaviors and values required to get there. Not all institutions will engage in the science called for in health care reform, but for those institutions with the interest, capacity, and resources to move forward, what is needed?

House-dust mite allergen and ozone exposure decreases histamine H3 receptors in the brainstem respiratory nuclei.

Allergic airway diseases in children are a common and a growing health problem. Changes in the central nervous system (CNS) have been implicated in contributing to some of the symptoms. We hypothesized that airway allergic diseases are associated with altered histamine H3 receptor expression in the nucleus tractus solitarius (NTS) and caudal spinal trigeminal nucleus, where lung/airway and nasal sensory afferents terminate, respectively. Immunohistochemistry for histamine H3 receptors was performed on brainstem sections containing the NTS and the caudal spinal trigeminal nucleus from 6- and 12-month-old rhesus monkeys who had been exposed for 5 months to house dust mite allergen (HDMA)+O3 or to filtered air (FA). While histamine H3 receptors were found exclusively in astrocytes in the caudal spinal trigeminal nucleus, they were localized to both neuronal terminals and processes in the NTS. HDMA+O3 exposure significantly decreased histamine H3 receptor immunoreactivity in the NTS at 6 months and in the caudal spinal trigeminal nucleus at 12 months of age. In conclusion, exposing young primates to HDMA+O3 changed histamine H3 receptor expression in CNS pathways involving lung and nasal afferent nerves in an age-related manner. Histamine H3 receptors may be a therapeutic target for allergic asthma and rhinitis in children.

Retrograde release of endocannabinoids inhibits presynaptic GABA release to second-order baroreceptive neurons in NTS.

In prior studies, we found that activation of cannabinoid-1 receptors in the nucleus tractus solitarii (NTS) prolonged baroreflex-induced sympathoinhibition in rats. In many regions of the central nervous system, activation of cannabinoid-1 receptors presynaptically inhibits γ-aminobutyric acid (GABA) release, disinhibiting postsynaptic neurons. To determine if cannabinoid-1 receptor-mediated presynaptic inhibition of GABA release occurs in the NTS, we recorded miniature inhibitory postsynaptic currents in anatomically identified second-order baroreceptive NTS neurons in the presence of ionotropic glutamate receptor antagonists and tetrodotoxin. The cannabinoid-1 receptor agonists, WIN 55212-2 (0.3-30 µM) and methanandamide (3 µM) decreased the frequency of miniature inhibitory postsynaptic currents in a concentration-dependent manner, an effect that was blocked by the cannabinoid-1 receptor antagonist, N-(piperidin-1-yl)-5-(4-iodophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide (AM 251, 5 µM). Importantly, depolarization of second-order baroreceptive neurons decreased the frequency of miniature inhibitory postsynaptic currents; an effect which was blocked by the cannabinoid-1 receptor antagonist. The data indicate that depolarization of second-order baroreceptive NTS neurons induces endocannabinoid release from the neurons, leading to activation of presynaptic cannabinoid-1 receptors, inhibition of GABA release and subsequent enhanced baroreflex signaling in the NTS. The data suggest that endocannabinoid signaling in the NTS regulates short-term synaptic plasticity and provide a mechanism for endocannabinoid modulation of central baroreflex control.

Postexercise hypotension: central mechanisms.

A single bout of exercise can lead to a postexercise decrease in blood pressure in hypertensive individuals, called postexercise hypotension. Compelling evidence suggests that the central baroreflex pathway plays a crucial role in the development of postexercise hypotension. This review focuses on the exercise-induced changes in brainstem nuclei involved in blood pressure regulation.

Issues and challenges of non-tenure-track research faculty: the UC Davis School of Medicine experience.

Nationally, medical schools are appointing growing numbers of research faculty into non-tenure-track positions, paralleling a similar trend in universities. The American Association of University Professors (AAUP) issued a statement expressing concern that the marked growth in non-tenure-track faculty can undermine educational quality, academic freedom, and collegiality. Like other medical schools, the UC Davis School of Medicine has had a rise in non-tenure-track faculty in order to enhance its research mission, in particular in the Salaried Adjunct faculty track (SalAdj). SalAdj faculty have more difficulty in achieving promotion, report inequitable treatment and less quality of life, have less opportunity to participate in governance, and feel second-class and insecure. These issues reflect those described by the AAUP. The authors describe the efforts at UC Davis to investigate and address these issues, implementation of a plan for improvement based on task force recommendations, and the lessons learned. Supporting transfer to faculty tracks in the academic senate, enhancing financial support, ensuring eligibility for internal grants, and equitable space assignments have contributed to an improved career path and more satisfaction among SalAdj faculty. Challenges in addressing these issues include limited availability of tenure-track positions, financial resources, adequate communication regarding change, and compliance with existing faculty search policies.

Secondhand smoke exposure alters K+ channel function and intrinsic cell excitability in a subset of second-order airway neurons in the nucleus tractus solitarius of young guinea pigs.

Extended exposure to secondhand smoke (SHS) in infants and young children increases the incidence of cough, wheeze, airway hyper-reactivity and the prevalence and earlier onset of asthma. The adverse effects may result from environmentally-induced plasticity in the neural network regulating cough and airway function. Using whole-cell patch-clamp recordings in brainstem slices containing anatomically identified second-order lung afferent neurons in the nucleus tractus solitarius (NTS), we determined the effects of extended SHS exposure in young guinea pigs for a duration equivalent to human childhood on the intrinsic excitability of NTS neurons. SHS exposure resulted in marked decreases in the intrinsic excitability of a subset of lung afferent second-order NTS neurons. The neurons exhibited a decreased spiking capacity, prolonged action potential duration, reduced afterhyperpolarization, decrease in peak and steady-state outward currents, and membrane depolarization. SHS exposure effects were mimicked by low concentrations of the K+ channel blockers 4-aminopyridine and/or tetraethyl ammonium. The data suggest that SHS exposure downregulates K+ channel function in a subset of NTS neurons, resulting in reduced cell excitability. The changes may help to explain the exaggerated neural reflex responses in children exposed to SHS.

Secondhand tobacco smoke exposure differentially alters nucleus tractus solitarius neurons at two different ages in developing non-human primates.

Exposing children to secondhand tobacco smoke (SHS) is associated with increased risk for asthma, bronchiolitis and SIDS. The role for changes in the developing CNS contributing to these problems has not been fully explored. We used rhesus macaques to test the hypothesis that SHS exposure during development triggers neuroplastic changes in the nucleus tractus solitarius (NTS), where lung sensory information related to changes in airway and lung function is first integrated. Pregnant monkeys were exposed to filtered air (FA) or SHS for 6 h/day, 5 days/week starting at 50-day gestational age. Mother/infant pairs continued the exposures postnatally to age 3 or 13 months, which may be equivalent to approximately 1 or 4 years of human age, respectively. Whole-cell recordings were made of second-order NTS neurons in transverse brainstem slices. To target the consequences of SHS exposure based on neuronal subgroups, we classified NTS neurons into two phenotypes, rapid-onset spiking (RS) and delayed-onset spiking (DS), and then evaluated intrinsic and synaptic excitabilities in FA-exposed animals. RS neurons showed greater cell excitability especially at age of 3 months while DS neurons received greater amplitudes of excitatory postsynaptic currents (EPSCs). Developmental neuroplasticity such as increases in intrinsic and synaptic excitabilities were detected especially in DS neurons. In 3 month olds, SHS exposure effects were limited to excitatory changes in RS neurons, specifically increases in evoked EPSC amplitudes and increased spiking responses accompanied by shortened action potential width. By 13 months, the continued SHS exposure inhibited DS neuronal activity; decreases in evoked EPSC amplitudes and blunted spiking responses accompanied by prolonged action potential width. The influence of SHS exposure on age-related and phenotype specific changes may be associated with age-specific respiratory problems, for which SHS exposure can increase the risk, such as SIDS and bronchiolitis in infants and asthma in older children.

A novel postsynaptic group II metabotropic glutamate receptor role in modulating baroreceptor signal transmission.

The nucleus tractus solitarius (NTS) is essential for orchestrating baroreflex control of blood pressure. When a change in blood pressure occurs, the information is transmitted by baroreceptor afferent fibers to the central network by glutamate binding to ionotropic glutamate receptors on second-order baroreceptor neurons. Glutamate also activates presynaptic group II and III metabotropic glutamate receptors (mGluRs), depressing both glutamate and GABA release to modulate baroreceptor signal transmission. Here we present a novel role for postsynaptic group II mGluRs to further fine-tune baroreceptor signal transmission at the first central synapses. In a brainstem slice with ionotropic glutamate and GABA receptors blocked, whole-cell patch-clamp recordings of second-order baroreceptor neurons revealed that two group II mGluR agonists evoked concentration-dependent membrane hyperpolarizations. The hyperpolarization remained when a presynaptic contribution was prevented with Cd(2+), was blocked by a postsynaptic intervention of intracellular dialysis of the G-protein signaling inhibitor, was mimicked by endogenous release of glutamate by tractus solitarius stimulation, and was prevented by a group II mGluR antagonist. Postsynaptic localization of group II mGluRs was confirmed by fluorescent confocal immunohistochemistry and light microscopy. Group II mGluR induced-currents consisted of voltage-dependent outward and inward components, prevented by tetraethylammonium chloride and tetrodotoxin, respectively. In contrast to group II mGluR-induced hyperpolarization, there was no effect on intrinsic excitability as determined by action potential shape or firing in response to depolarizing current injections. The data suggest a novel mechanism for postsynaptic group II mGluRs to fine-tune baroreceptor signal transmission in the NTS.

Central neuroplasticity and decreased heart rate variability after particulate matter exposure in mice.

BACKGROUND: Epidemiologic studies show that exposure to fine particulate matter [aerodynamic diameter < or = 2.5 microm (PM(2.5))] increases the total daily cardiovascular mortality. Impaired cardiac autonomic function, which manifests as reduced heart rate variability (HRV), may be one of the underlying causes. However, the cellular mechanism(s) by which PM(2.5) exposure induces decreased HRV is not known. OBJECTIVES: We tested the hypothesis that exposure to PM(2.5) impairs HRV by decreasing the excitability of the cardiac vagal neurons in the nucleus ambiguus. We also determined the effect of iron on PM-exposure-induced decrease in HRV. METHODS: We measured 24-hr HRV in time domains from electrocardiogram telemetry recordings obtained in conscious, freely moving mice after 3 days of exposure to PM(2.5) in the form of soot only or iron-soot. In parallel studies, we determined the intrinsic properties of identified cardiac vagal neurons, retrogradely labeled with a fluorescent dye applied to the sinoatrial node. RESULTS: Soot-only exposure decreased short-term HRV (root mean square of successive difference). With the addition of iron, all HRV parameters were significantly reduced. In nonexposed mice, vagal blockade significantly reduced all HRV parameters, suggesting that HRV is, in part, under vagal regulation in mice. Iron-soot exposure had no significant effect on resting membrane potential but decreased spiking responses of the identified cardiac vagal neurons to depolarizations (p < 0.05). The decreased spiking response was accompanied with a higher minimal depolarizing current required to evoke spikes and a lower peak discharge frequency. CONCLUSIONS: The data suggest that PM-induced neuroplasticity of cardiac vagal neurons may be one mechanism contributing to the cardiovascular consequences associated with PM(2.5) exposure seen in humans.

Generational forecasting in academic medicine: a unique method of planning for success in the next two decades.

Multigenerational teams are essential to the missions of academic health centers (AHCs). Generational forecasting using Strauss and Howe's predictive model, "the generational diagonal," can be useful for anticipating and addressing issues so that each generation is effective. Forecasts are based on the observation that cyclical historical events are experienced by all generations, but the response of each generation differs according to its phase of life and previous defining experiences. This article relates Strauss and Howe's generational forecasts to AHCs. Predicted issues such as work-life balance, indebtedness, and succession planning have existed previously, but they now have different causes or consequences because of the unique experiences and life stages of current generations. Efforts to address these issues at the authors' AHC include a work-life balance workgroup, expanded leave, and intramural grants.

Exercise reduces GABA synaptic input onto nucleus tractus solitarii baroreceptor second-order neurons via NK1 receptor internalization in spontaneously hypertensive rats.

A single bout of mild to moderate exercise can lead to a postexercise decrease in blood pressure in hypertensive subjects, namely postexercise hypotension (PEH). The full expression of PEH requires a functioning baroreflex, hypertension, and activation of muscle afferents (exercise), suggesting that interactions in the neural networks regulating exercise and blood pressure result in this fall in blood pressure. The nucleus tractus solitarii (NTS) is the first brain site that receives inputs from nerves carrying blood pressure and muscle activity information, making it an ideal site for integrating cardiovascular responses to exercise. During exercise, muscle afferents excite NTS GABA neurons via substance P and microinjection of a substance P-neurokinin 1 receptor (NK1-R) antagonist into the NTS attenuates PEH. The data suggest that an interaction between the substance P NK1-R and GABAergic transmission in the NTS may contribute to PEH. We performed voltage clamping on NTS baroreceptor second-order neurons in spontaneously hypertensive rats (SHRs). All animals were killed within 30 min and the patch-clamp recordings were performed 2-8 h after the sham/exercise protocol. The data showed that a single bout of exercise reduces (1) the frequency but not the amplitude of GABA spontaneous IPSCs (sIPSCs), (2) endogenous substance P influence on sIPSC frequency, and (3) sIPSC frequency response to exogenous application of substance P. Furthermore, immunofluorescence labeling in NTS show an increased substance P NK1-R internalization on GABA neurons. The data suggest that exercise-induced NK1-R internalization results in a reduced intrinsic inhibitory input to the neurons in the baroreflex pathway.