Category Archives: Physiology

Physiology

This Key Protein Is Essential for Brain Cell Longevity and Growth – SciTechDaily

Recent research finds that the insulin receptor protein (INSR) is pivotal for brain stem cell longevity and growth.

Stem cells are the bodys raw materials they are the cells that give rise to all other cells with specialized functions. In the right circumstances, stem cells in the body divide to produce new cells known as daughter cells.

Humans contain neural stem cells in their brains. These brain stem cells may develop into neurons, astrocytes, or oligodendrocytes. Because neural stem cells generate all of the brains cell types, there is a multitude of stem cells in an embryos brain. In fact, the majority of brain cells are born in the embryo stage. These cells persist till adulthood and can be found in particular regions of the brain. Neural stem cells are essential for your brain to properly function.

According to research from Rutgers University, a receptor that was first identified as necessary for insulin action and is also found on neural stem cells found deep in the brains of mice is crucial for brain stem cell longevity, a finding that has important implications for brain health and future therapies for brain disorders.

The research, published in the journal Stem Cell Reports, focuses on a particular protein known as the insulin receptor (INSR), which is prevalent in neural stem cells in the brains subventricular zone. Neural stem cells give rise to the entire nervous system throughout development and persist into adulthood. Over the course of a persons life, these neural stem cells generate new neurons and non-neuronal cells that help the brains infrastructure and function.

Separately, while studying brain tumors, the researchers discovered that INSR plays an important role in the survival and maintenance of a population of specialized brain cancer cells known as glioblastoma (GBM) stem cells. They were able toreducethe growth of those primitive tumor-forming cells by inactivating the INSR in GBM stem cells.

Its important to understand the molecular mechanisms that are critical for the growth and sustenance of the brains stem cells under normal and abnormal growth states, said study author Steven Levison, a professor of neuroscience in the Department of Pharmacology, Physiology, and Neuroscience and director of the Laboratory for Regenerative Neurobiology at Rutgers New Jersey Medical School. Comprehending the signals that regulate these primitive cells could one day lead to new therapeutics for brain disorders.

Many neurodegenerative disorders, such as multiple sclerosis, Parkinsons disease, and Alzheimers disease, are connected with the destruction of brain cells, said co-author Teresa Wood, a Distinguished Professor and Rena Warshow Endowed Chair in Multiple Sclerosis in the Department of Pharmacology, Physiology, and Neuroscience at Rutgers New Jersey Medical School.

If we could influence how brain stem cells function then we can use this knowledge to replace diseased or dead brain cells with living ones, which would advance the treatment of neurological diseases and brain injuries, said Wood, who also teaches and conducts research at the Cancer Institute of New Jersey.

Cell receptors such as INSR are protein molecules that reside on the surfaces of cells. Substances, either natural or human-made, that open the lock of a receptor can spur a cell to divide, differentiate or die. By identifying which receptors perform these functions on specific cell types, and by understanding their structures and functions, scientists can design substances that act as keys to receptors, to turn them on or off.

Previous studies by this research team had shown that a certain key, the signaling protein that is known as the insulin-like growth factor-II (IGF-II), was necessary to maintain the neural stem cells in the two places of the adult brain that harbor these primitive cells. In the current experiment, scientists were looking to identify the receptor. To do so, they used genetic tools that allowed them to both delete the INSR and introduce a fluorescent protein so they could track the neural stem cells and the cells they generate. They found that the numbers of neural stem cells in the subventricular zone in the brains of mice lacking the INSR collapsed.

Adult neurogenesis the idea that new cells are produced in the adult brain has been a burgeoning field of scientific inquiry since the late 1990s, when researchers confirmed what had only been a theory in lab studies of human, primate, and bird brains. Neural stem cells in the adult are stem cells that can self-renew and produce new neurons and the supporting cells of the brain, oligodendrocytes, and astrocytes.

Given the widespread interest in stem cells as well as interest in whether alterations to adult stem cells might contribute to cancer, our research findings should be of interest, Levison said.

Other Rutgers authors included Shravanthi Chidambaram, Fernando J. Velloso, Deborah E. Rothbard, Kaivalya Deshpande, and Yvelande Cajuste of the Department of Pharmacology, Physiology, and Neuroscience at Rutgers New Jersey Medical School. Other participating investigators were at the University of Minnesota, the Albert Einstein College of Medicine, and Brown University.

Reference: Subventricular zone adult mouse neural stem cells require insulin receptor for self-renewal by Shravanthi Chidambaram, Fernando J. Velloso, Deborah E. Rothbard, Kaivalya Deshpande, Yvelande Cajuste, Kristin M. Snyder, Eduardo Fajardo, Andras Fiser, Nikos Tapinos, Steven W. Levison and Teresa L. Wood, 5 May 2022, Stem Cell Reports.DOI: 10.1016/j.stemcr.2022.04.007

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This Key Protein Is Essential for Brain Cell Longevity and Growth - SciTechDaily

Physiology

Stress Influences Your Heart Rate Variability and Performance – runnersworld.com

Stress is a normal part of life and your body is designed to react to it. According to the American Psychological Association, your body is well-equipped to handle small increases in stress levels, like running late for a meeting. But when stress becomes chronic or too intense, it can have negative effects on all systems of the bodyincluding negatively affecting your running performance.

You have probably experienced physiological changes like increased heart rate, heavy breathing, or sweating before the start of a race or a big presentation. One effect of stress that is not as noticeable is the change to heart rate variability (HRV), or the variation in the time between heartbeats measured in milliseconds. Paying attention to heart rate variability can help runners recognize when stress is impacting performance and when you need to make modifications to training or stress management.

Heres what to know about stress and heart rate variability, how this measure can be a tool to monitor your training, and ways to improve HRV to help manage stress and boost running performance.

Stress affects your heart via the autonomic nervous systemthe direct line between your heart and your brain. The autonomic nervous system consists of two parts: the sympathetic nervous system initiates the fight or flight response to stress, which triggers increases in heart rate and blood pressure, while the parasympathetic nervous system controls the relaxation response, lowering heart rate, and blood pressure.

We view heart rate variability as a reflection of the balance between the two primary arms of the nervous system, the sympathetic nervous system and the parasympathetic nervous system, Timothy Churchill, M.D., a cardiologist at the Cardiovascular Performance Program at Massachusetts General Hospital and an instructor at Harvard Medical School tells Runners World.

According to the Cleveland Clinic, your heart rates variability reflects the adaptability of your body. A higher heart rate variability is a good thing and can indicate your body is more resilient, whereas lower heart rate variability may reflect difficulty adapting to changes and may be considered a sign of current or future health problems.

We would think of [stress] as augmenting the sympathetic side of the nervous system and resulting in reduced heart rate variability, and theoretically manifesting in increasing the resting heart rate, adds Churchill. While both heart rate variability and resting heart rate are ways to see the effect of stress on the cardiovascular system, much of the research to date focuses on heart rate variability.

For example, a review published in Psychiatry Investigation in 2018 showed HRV variables changed in response to stress. Researchers induced stress in various ways, including simulating a medical emergency, responding to work or school-related stressors, or taking psychological tests in a lab environment. The most common effect of stress across studies was low parasympathetic activity, or an inability to calm down an activated sympathetic nervous system, resulting in low heart rate variability.

Churchill adds that the relationship between stress and heart rate variability applies to different forms of stress: emotional stress such as worrying about an exam or presentation, physiological stress like overtraining or dehydration, or environmental stress including heat or noise. Other factors like diet, sleep, and medications can also affect HRV.

However, stress doesnt always result in a decreased heart rate variability. Whether you frame your pre-race butterflies as excitement or anxiety can determine if it results in an increase or decrease in HRV. When we are interpreting stress as bad, as damaging, as anxiety and fear that are somehow detrimental, that is going to decrease heart rate variability. Thats going to decrease our objective performance. Thats going to decrease our feeling of competence. Its going to further increase anxiety, says Inna Khazan, Ph.D., clinical health and performance psychologist in Boston and lecturer in the psychiatry department at Harvard Medical School, tells Runners World. If in the same situation, the person interprets this sensation of physical activation as helpful and adaptive, that leads to the oppositeheart rate variability is higher. You get a much more positive response, both physiologically and emotionally.

As an indicator of adaptability and resiliency, runners can use heart rate variability as a training tool to suggest when you might be able to push harder or when you need some time to recover.

Low HRV might reflect being stressed, overworked, or inadequately rested. Training in that state of fatigue might make it feel like you are working harder to achieve a normal pace on the run or like you are not ready to tackle your next workout.

A review in the Journal of Exercise Physiology Online published in 2013 looked at how heart rate variability can be applied to exercise training, including running. The studies reviewed showed HRV can be an effective tool to prescribe exercise intensity, as well as monitor training to prevent and diagnose overtraining. The review added that age, gender, and athletic conditioning are independent factors that can also affect HRV and should be considered when prescribing training or recovery plans for individuals.

For the amateur runner, Churchill sees heart rate variability as a tool to assess if you are allowing your body sufficient time to recover from workouts, where low HRV is an indicator that more light or moderate work should replace harder efforts in your training plan. Probably the most underutilized element in training programs among amateur or recreational athletes is appropriate rest and recovery, he says. I think these metrics are one pathway that people can use to gain insight into that. Its a lens that people can use primarily to see if they should be modulating down their intensity and/or building more rest into their training programs.

While the most accurate way to measure heart rate variability is in a medical setting with an electrocardiogram (ECG), for the purposes of monitoring stressors and overtraining, many of the devices that runners already have can track your hearts response to stress.

While HRV can be a valuable metric to monitor your bodys readiness to perform, the data can also be tricky to interpret. According to Khazan, while there are normal ranges for heart rate variability, its not as simple as identifying ranges for normal resting heart rate because there are several ways to measure HRV. The most common ones are statistical analyses of the intervals between heartbeats like RMSSD (root mean square of successive differences) and SDNN (standard deviation of normal-to-normal interval).

Devices like those from Garmin, Whoop, and Apple collect heart rate variability data and may use the same measurements, like RMSSD, or create their own scores or variables based on these measures. For example, Garmin notes that it uses HRV in other measurements like the stress score and body battery.

With varying ways to measure and varying characteristics among individuals, its hard to prescribe a precise change in score at which to intervene, but using HRV numbers to identify whats normal for you, and then monitoring changes to those numbers, can still be a valuable tool. One day of lower HRV may not be a big deal, says Khazan, but if the trend continues for several days, you might want to pay attention to factors like stress, sleep, diet, and training load to get you back on track.

If you see a decline in HRV or youre simply seeking another way to optimize your performance, there are ways to improve heart rate variability. For example, practices like mindfulness can help in stress reduction and athletic performance. A study published in PLoS ONE in 2020 found an increase in HRV both during and following mindfulness practice, indicating the stress reduction benefits can stick around even after youre done.

Biofeedback trainingor the process of measuring your physiological responses, like heart rate and breathing, and displaying it visually on a device, so you can make changes in your body like altering your breathing and see how those responses changehas also shown success in increasing heart rate variability.

The most direct way to increase your heart rate variability is by practicing slow, paced breathing exercises. As you breathe in, your heart rate goes up; as you breathe out, your heart rate comes down. There is an optimal rate of breathing, that will produce maximum heart rate variability, Khazan explains. That breathing is called resonance frequency breathing rate. Its basically a way to stimulate the heart rate to increase as much as possible on each inhalation and decrease as much as possible in each exhalation.

If you look at it on a monitor, the goal is to get the ups and downs of your heart rate to look like a sine wave and coincide with your breath, says Tim Herzog, clinical and sport psychologist and certified mental performance coach in Annapolis, Maryland.

When you practice breathing at this resonance frequency rate its like a workout for your nervous system, says Herzog. Practicing your paced breathing while not running strengthens the connection between the brain and the heart and can increase heart rate variability that carries through even when you are not breathing at your resonance frequency rate.

The research suggests practicing breathing for twenty minutes twice a day, but Herzog encourages starting with whatever time you have available. By proactively engaging in our breathing regimen, we can manage to take that baseline level of anxiety down. So that when the stressor comes along, were starting from a lower place to begin with, Herzog says.

Professionals, like Herzog and Khazan, certified in biofeedback can help you identify that resonance frequency breathing rate, usually around six breaths per minute. Although working with a licensed counsellor has its advantages beyond biofeedback training, if you are not interested or able to work with a professional, there are ways to do it yourself.

Khazan helped develop the Optimal HRV app, which she says will determine your resonance frequency, provide biofeedback training, and track heart rate variability. It just requires a Bluetooth-enabled HRV reader, like a Polar chest strap or Biostrap. Khazan adds other apps, like Elite HRV and Heart Math, do slightly different things but are also good options for helping to increase HRV.

While there are limited controlled studies, biofeedback training seems to show promising positive effects on heart rate variability. A 2021 study published in the journal Applied Psychophysiology and Biofeedback looked at HRV, running, recovery and perceived exertion following a treadmill test before and after HRV biofeedback training. The study did not include a control group, but found improvements in HRV, time spent exercising, perceived exertion, and recovery time when participants used HRV biofeedback in recovery.

Research on specific performance improvements are harder to come by. A systematic review also published in the journal Applied Psychophysiology and Biofeedback in 2017 found improvements in psychological and performance outcomes including reduced anxiety, improved concentration, and improvement in skills like dribbling and shooting accuracy in basketball players.

In the one running study included in the review, runners who received biofeedback training showed greater improvements in their 5K times and VO2 max. However, upon further review of the specific study, the improvements in 5K times over a ten-week period were dramatic (18.27 minutes to 15.89 minutes) and call into question if other factors also contributed to the lower times.

Additionally, most of the studies included less than thirty participants, and vary in HRV biofeedback training guidelines, so results can be difficult to generalize across broader populations.

However, a systematic review and meta-analysis from 2020 in the journal Applied Psychophysiology and Biofeedback provides evidence that HRV biofeedback had positive effects on a variety of physical, behavioral, and cognitive conditions, athletic/artistic performance, depression, anxiety, and gastrointestinal problems.

Even if it doesnt result in a 5K personal best, HRV biofeedback training is safe, accessible, and easy to learn and may be a complementary practice to enhance your training and stress management.

Whether you try biofeedback training or decide to track your heart rate variability as you train for your next race, regardless of what the data says, Churchill reminds runners that the most important tool for maximizing performance is listening to your body: If your body tells you it needs rest and recovery, then you should be doing that.

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Stress Influences Your Heart Rate Variability and Performance - runnersworld.com

Physiology

How to use ‘flow state’ to do the impossible – Big Think

STEVEN KOTLER: Why does the impossible become possible? One of the really incredible things about being human is we're all built for peak performance. It comes as a fundamental part of being human. And what I mean by that is getting our biology to work for us rather than against us. This is not a new idea. William James said the great thing in all education is to get our nervous system to be our ally and not our enemy. And by our nervous system, right, he meant our brain and our biology. We're all capable of so much more than we know. When we hear something impossible has been done, we start thinking about it. And then you start asking questions, "Well, what would it look like when I did it?" And then you start thinking about, "How would you do it?" "How would you train it?" And you're like, "Oh wow, far out." "I guess that is possible."

My name is Steven Kotler. I'm a writer and a researcher. And my latest book is "The Art of Impossible." There's something in psychology and neuroscience we talk about as the Bannister Effect. This is the idea that you have to believe something is possible before it becomes possible. It's named after Roger Bannister. Roger Bannister was the first person to run a sub four mile. And before he did it, this was a great, crazy impossible. TV ANNOUNCER: May 6th, a British medical student Roger Bannister earns sports immortality, the first man to break the legendary four minute barrier running a mile in three minutes, 59, and four tenth seconds.

They really thought the first person who did it was gonna die from it. It was a total impossible. Bannister runs the first sub four mile. And then a month later, somebody breaks his record. And then a couple months after that, somebody shatters that new record. And within five years, teenagers have done it. So you gotta ask yourself, "What the hell happened?" Right? The same physical requirements for running a sub four mile haven't changed. All that's changed is the mental frame we've built a around the feat. What used to be impossible is now seen as possible. And we start thinking about it and the brain thinks in pictures, and it starts working out, "Well, what would that look like?" And then you start asking questions. "Well, how would you do it?" "How would you train it?" And it becomes a little more probable.

What it essentially says is that look, there's a very, very, very tight coupling between our psychology and our physiology. And if we can pre-wire our brain with the patterns we're gonna perform ahead of time. When we actually start to perform those patterns, you're gonna get dopamine from pattern matching. It may help drive us into flow. And flow is an optimized state of consciousness where feel our best and we perform our best. This idea dates back all the way to Goethe who uses the German word "rausch," which means overflowing with joy. Neitzche actually wrote about flow. William James worked on the topic, but Mihaly Csikszentmihalyi is often referred to as the godfather of flow psychology. And he went around the world talking to people about the times in their lives when they felt their best, and they performed their best.

Everywhere he went, people said the same thing. They said, "You know, when I'm at my best, "when I'm feeling my best, "when I'm performing my best, "I'm in this alterative of consciousness "where every action, "every decision I make seems to flow "effortlessly, perfectly, seamlessly from the last." So that's where the term flow comes from. It's actually another phenomenological description of the state. Flow actually feels flowy. When psychologists wanna know if you were in flow, they say, well, "Was there complete concentration on the task at hand?" "Was there a merger of action and awareness?" "Did self vanish?" "Did time dilate?" And this is an experience we all have, right? You get so sucked into what you're doing, you look up, and five hours go by in like five minutes. Because we don't register peak performance as a sensation, what we feel on the inside is sense of control. The ability to control things that we normally can't control.

This is a basketball player in the zone talking about seeing the hoop and suddenly it's as big as a hula hoop. And throughout all aspects of performance, both mental and physical go through the roof. Across the board flow tends to show up, whenever we see the impossible become possible. Productivity, motivation, skyrocket in flow and sometimes 500% above baseline. And that seems like a huge stratospheric number. And it would be very, very suspicious if it wasn't in line with all the other research. For example, the Department of Defense looked at soldiers in flow, and they were looking at learning. Turns out we will learn 240 to 500% faster than normal when we're in flow. We see creativity spike 400 to 700% in flow. On the physical side flow will amplify strength, stamina, endurance.

This might sound like, "What the hell?" "Why would one state of consciousness amplify all these different things?" Like, what is going on? That almost doesn't make any sense until you remember that it was evolution that shaped flow. Evolution itself is predominantly a reaction to scarcity, right? Resources get scarce. That's the biggest driver on evolution, and we have two options. We can fight over dwindling resources, or we can flee or avoid becoming somebody else's resources, or we can get cooperative, get creative, get innovative, and make new resources.

This is everything that flow amplifies. Flow is universal in humans. Actually universal in most mammals and definitely all social mammals. So all the systems that produce flow are in all of us. What we're getting is everything we need to fight or flee, or get creative, get cooperative and make new resources. That was the largest lesson that 30 years in studying peak performance has taught me, is that we're all hardwired for flow, and flow is a massive amplification of what's possible for ourselves.

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How to use 'flow state' to do the impossible - Big Think

Physiology

Psychological Health Outcomes A Narrative Review in US Vet | COPD – Dove Medical Press

Introduction

Approximately 78% of adults in the United States (US) currently identify as Veterans of the Armed Forces; of these, approximately 4249% are recipients of Veteran Affairs (VA) benefits, which include services such as healthcare, disability compensation or pension, loan and insurance programs, and burial services.1,2 In general, Veterans who complete a minimum 24 months of service with an honorable discharge are eligible for healthcare through the Veterans Health Administration (VHA), one of the largest nationally integrated systems. Although VA benefits are available to most Veterans, due to priority assignments for enrollment (based on service connection, disability, and income) and copays, the approximately 9 million Veterans who currently utilize VA healthcare and participate in VA-sponsored research represent a unique subset of the Veteran population.1,2

Recipients of VA healthcare are typically older than the general population (median age 64 versus 38 years, respectively) and are predominantly (91%) male, although enrollment of female Veterans is rising.1,2 The proportion of Veterans who utilize VA with an annual household income less than $35,000 is higher than that of the general US population (43% versus 26%)1,3 as is the prevalence of ever-smoking (60% versus 3540%).1,2,4 Economic disadvantage and increased rates of smoking, coupled with service-related and occupational exposures, have likely contributed to the high prevalence and rising incidence of chronic respiratory diseases, including chronic obstructive pulmonary disease (COPD), among Veterans.5,6

COPD is not objectively different in terms of disease manifestation in Veterans compared to civilians.7 However, the prevalence of COPD among Veterans, which is currently estimated to be between 8% and 19%,6,8 is higher than among the general population (6%).9 Importantly, COPD is likely underdiagnosed among Veterans, with only a minority of individuals with objective airflow limitation on lung function testing reporting a clinical diagnosis of COPD.10 Veterans with COPD have increased all-cause and respiratory-related health-care utilization as well as higher rates of comorbid conditions relative to Veterans without COPD.6 Moreover, the prevalence of mental health conditions, particularly alcohol and substance abuse, is higher in Veterans compared to civilians.11 Comorbid mental health conditions commonly serve as a barrier to utilization and/or responsiveness to evidence-based care, such as self-management interventions.12 Given the prevalence and significant burden of COPD within the VHA, substantial resources have been applied towards both clinical and research initiatives to improve outcomes for Veterans with COPD.

The VHA provides evidence-based treatment to Veterans with COPD in order to optimize physiological, physical, and psychological health. These treatments and interventions are comprehensively described in the Global Initiative for Obstructive Lung Disease (GOLD) guidelines.13 Notably, Veterans with COPD and VHA researchers have contributed to early research examining such treatments and interventions to improve COPD outcomes. The objective of this paper is to provide a narrative review of interventions for key physiological, physical, and psychological health outcomes in US Veterans. Articles were identified if they were conducted with US Veterans and broadly addressed interventions for physiological, physical, or psychological outcomes.

Due to the high burden of COPD within the VA, Veterans and VHA investigators have been involved in studies which have contributed to the collective knowledge on COPD physiology. Physiological and clinical outcomes which have been examined among Veterans with COPD have included lung function, hypoxemia, and systemic effects associated with disease, such as alterations in body composition and bone mineral density. These studies support current evidence-based guidelines which include both pharmacological and non-pharmacological management of both stable COPD and acute exacerbations of COPD. Key studies examining these physiological and clinical outcomes are summarized below.

Longitudinal studies based within the VHA, such as the Normative Aging Study (NAS), have resulted in an improved understanding of and delineation between healthy aging and disease processes such as COPD.14,15 Comprised of over 2000 participants who were first enrolled in 1963 who have triennial follow-up data,16 the NAS represents a rich source of multi-dimensional information contributing to studies which have identified environmental (eg, smoking, air pollution)17,18 as well as genetic, epigenetic, and genomic risk factors that affect lung function and COPD susceptibility.14,15,17,19

VHA research was a key stakeholder in establishing the detrimental effects of hypoxemia on not only end organ function but also reactive vasoconstriction in the pulmonary vasculature leading to pulmonary hypertension and cor pulmonale. Sentinel publications supported by the VHA include a brief report by Renzetti et al20 in 1968 which established the associations between COPD and mortality, spirometric lung function, and hypoxemia. Findings from this observational report gave rise to numerous subsequent studies, both within and outside of the VHA, which established the safety and benefit of supplemental oxygen on exercise tolerance and dyspnea,21 cardiovascular parameters,21 and survival22 among COPD patients with significant hypoxemia. As research practices evolved over the decades from single-site studies to multi-center collaborative initiatives, VA investigators continued to contribute to research on the management of hypoxemia in COPD patients. Multiple VA facilities served as research study sites for the Long-Term Oxygen Treatment Trial (LOTT) which examined oxygen supplementation for COPD patients with moderate resting or exercise-induced hypoxemia.23 While the benefits of oxygen supplementation in COPD patients with severe resting hypoxemia (defined as an oxygen saturation (SpO2) <89% or an arterial oxygen tension, PaO2 55 mmHg, or PaO259 or SpO289% with signs of cor pulmonale) had been previously established,24,25 LOTT demonstrated that routine supplementation in moderate resting (SpO2 8993%) or exercise-induced hypoxemia (SpO2 8090%) was not associated with improved all-cause mortality or time to first hospitalization,23 leading to a significant revision of management guidelines issued by the VHA, professional societies, and the GOLD recommendations.13 Current guidelines on the initiation of oxygen supplementation (as outlined above) as well as the titration of supplemental oxygen to a goal SpO2 >9092% represent the integrated results of trials conducted both within and outside the VHA.

Veterans and VHA investigators have contributed substantially to studies of medications, such as bronchodilators, that improve symptoms through improvements in lung function by increasing airway diameter and decreasing air trapping and hyperinflation. Early trials examined systemic bronchodilators, such as theophylline26 and metaproterenol,27,28 and were later supplanted by studies of inhaled beta-agonists and antimuscarinic agents,29 the two dominant classes of bronchodilators in use today. Use of long-acting inhaled beta-agonists and antimuscarinic agents is currently recommended as first-line, evidence-based maintenance therapies for COPD.13 Additional studies of pharmacological agents have included investigations of the effect of morphine on dyspnea,30 an important strategy for the palliative care of Veterans with advanced chronic lung disease associated with air hunger.

Significant morbidity is attributed to acute exacerbations of COPD and investigations into pharmacological strategies to treat and prevent these events have also involved Veteran populations. In a multi-center, randomized controlled trial (RCT) sponsored by the VA Cooperative Studies Program (CSP), systemic corticosteroids for Veterans hospitalized with acute exacerbations of COPD were found to reduce the incidence of a combined endpoint of all-cause mortality, mechanical ventilation, readmission for COPD, or escalation of therapy relative to placebo.31 Systemic corticosteroids are now considered the standard of care for management of acute exacerbations of COPD,13 although the optimal doses and duration of therapy remain active areas of investigation.

Significant resources have also been allocated to preventing acute exacerbations among COPD patients. Multiple VA medical centers served as research study sites for a RCT of chronic macrolide therapy using azithromycin to target chronic airways inflammation and prevent acute exacerbations of COPD.32 Findings from the study, which examined daily azithromycin taken for a year in addition to usual therapy, were notable for decreased COPD exacerbations and improved health-related quality of life (HRQoL), but also increased risk for hearing loss. Chronic suppressive macrolide therapy is now endorsed by the GOLD guidelines as an adjunctive maintenance medication for exacerbation-prone individuals.13

The performance of roflumilast, another pharmacological agent for the prevention of exacerbations, was examined relative to chronic suppressive azithromycin use among Veterans. In this observational study, the unified medical records system within the VHA, known as the Corporate Data Warehouse, was examined along with Medicare usage data for 3875 Veterans. Results showed that roflumilast, an oral selective phosphodiesterase-4 inhibitor, was associated with increased all-cause mortality and COPD-related hospitalizations relative to chronic suppressive macrolide therapy.33 The findings from this study supported the need for head-to-head studies of chronic macrolide therapy relative to roflumilast which are currently being investigated through an ongoing RCT (clinicaltrials.gov NCT04069312).

Although airflow obstruction is the defining feature of COPD, there is increasing appreciation of the extra-pulmonary and systemic consequences of COPD. Due to the higher rates of and cumulative exposure to smoking, as well as intermittent use of systemic corticosteroids, COPD has been identified as an independent risk factor for osteoporosis among Veterans.34 The clinical consequences of the increased prevalence of osteoporosis were subsequently confirmed in a study of 87,360 Veterans aged >50 years with newly diagnosed COPD between 1999 and 2003, where high rates of hip and wrist fragility fractures were observed.35 Additional findings from this study included low rates of bone mineral density testing and anti-resorptive treatment (eg, bisphosphonates)35 and identified a crucial need for screening for bone health among Veterans with COPD.

In addition to bone health, there has been increasing attention given to the impact of differences in body mass and body composition among Veterans with COPD. Body-mass index (BMI), a widely used metric of the weight-to-height relationship, is an integral component of the BMI, obstruction, dyspnea, and exercise limitation (BODE) index, which correlates with mortality and exacerbation frequency in COPD and has been validated in Veterans.36 In addition to body mass, the role of fat-free mass, a proxy measure for muscle mass, and its relationship with functional outcomes and exercise tolerance in Veterans with COPD represent important future areas of research.37

Other work in Veterans to improve physical outcomes in COPD has focused less on the individual patient, and more on the quality and type of care the patient receives. Although the majority of COPD-related care is managed by primary care providers, Veteran access to specialty care and referrals patterns to pulmonologists for COPD are comparable to those in the general community.38 A significant proportion of the morbidity and direct costs associated with COPD within the VHA arise from hospitalizations due to acute exacerbations of COPD.8 In an effort to develop and introduce programs to reduce COPD hospitalizations, the VHA sponsored a multicenter RCT examining the efficacy of a multidisciplinary comprehensive care management plan comprised patient and primary care provider education, the development of an action plan for exacerbation management, and proactive case management relative to usual care.39 Unfortunately, the study was terminated prematurely in 2012 due to increased rates of COPD-related hospitalizations and excess all-cause mortality in the intervention (comprehensive care) arm.39 Notably, similar results for comprehensive care programs at non-VHA hospitals have subsequently been reported,40 supporting that additional research and alternative strategies for preventing COPD hospitalizations are needed.

While effective strategies to prevent COPD hospitalizations remain an active field of investigation, programs to reduce the length of stay and prevent re-admissions have also received priority within the VHA. VHA-wide initiatives to reduce hospital utilization through expanded outpatient care resulted in a 51% reduction in length of stay for COPD exacerbations over 19941998, notably without increased mortality or non-VA hospital use.41 Additionally, individual programs focused on coordinated transitional care, a nurse-driven, telephone-based program targeting high-risk patients with comorbid COPD and congestive heart failure prior to discharge to home at an urban VA medical center resulted in a 54% reduction in 30-day re-hospitalization risk and was shown to be cost-effective.42 Moreover, one study examined the association of using non-VA outpatient care (both VA and non-VA care [ie, dual-care], and non-VA care only) and VA-only care with 30-day re-admission among Veterans. Overall, compared to Veterans who received VA-only care, Veterans who received dual-care and non-VA care only were 20% more likely to be readmitted for a COPD-specific exacerbation.43 These initiatives likely explain the recent finding of lower rates for 30-day re-admissions following hospitalizations for COPD at VA relative to non-VA hospitals.44

An overarching goal in the treatment of Veterans with COPD is to maximize physical function. However, the clinical course of COPD can contribute to a vicious cycle of reduced function. Patients who experience dyspnea, a major symptom of COPD, tend to avoid physical activities that worsen dyspnea, causing further muscle deconditioning and reductions in exercise capacity.45 Pain is another common symptom of COPD, which can also contribute to lower physical function.46 Physical outcomes, such as dyspnea, exercise capacity, physical activity (PA), and pain, reflect potentially modifiable risk factors of all-cause and respiratory-related mortality.47 As such, there has been great interest within VHA to develop effective interventions to improve physical outcomes in Veterans with COPD. The following sections detail several of these interventions, and highlight the impact of these interventions on dyspnea, PA, exercise capacity, pain, and risk for acute COPD exacerbations.

Pulmonary rehabilitation (PR) is a well-established treatment of COPD, effectively improving exercise capacity, dyspnea, and HRQoL.48 PR is a comprehensive intervention that focuses on exercise training and self-management education. It typically occurs 23 times a week across 812 weeks. Access to traditional, in-person PR can be difficult. In the VA with regional medical centers, distance is a significant barrier. In the National Emphysema Treatment Trial, participants who lived greater than 36 miles from the treatment facility were 51% less likely to complete PR compared to those who lived less than 6 miles away.49 In one urban VA medical center, 25% of initially evaluated Veterans never started PR, 29% dropped-out, while only 46% completed a full course of 18 sessions.50 Some Veterans who would benefit from PR decline participation due to access-related barriers, such as time and distance to travel to the program.50,51 Earlier work within VA compared outcomes in Veterans who completed PR to Veterans who were referred to PR but declined.52 Overall, Veterans with COPD who completed PR significantly improved exercise capacity, as measured with the 6-minute walk test (6MWT) by an average of 75 m and reported a decrease in dyspnea on the UCSD Shortness of Breath Questionnaire by 7.3 points.52 Additionally, COPD-related acute emergency visits and hospitalizations declined post-PR.52 More recently, predictors of Veterans PR engagement were examined through a retrospective study of Veterans who attended their initial PR intake session between 2010 and 2018.50 Participants who dropped out of PR (ie, dropped out before session 18) compared to completers (ie, Veterans who completed all 18 session) had worse dyspnea, as measured by the Chronic Respiratory Questionnaire-Self-Reported (CRQ-SR) at baseline, and were more likely to be current smokers and have a history of alcohol use disorder. No differences emerged between those who never started and those who dropped out.50 Thus, while PR is unequivocally effective for improving physical outcomes, it is important that future work continue to address ongoing access barriers to PR.

Patients with COPD tend to engage in significantly less daily PA compared to healthy-matched controls.53 Physical activity as an outcome is important in COPD, as it is directly associated with poor health outcomes such as increased risk of acute exacerbations and increased mortality, independent of lung function.54 Many factors can contribute to lower levels of PA, including physiologic, behavioral, and environmental factors.55 As such, there has been a substantial amount of work within VA to develop effective interventions that promote and sustain PA and exercise.

There have been several related RCTs examining the effectiveness of a web-mediated, pedometer-based PA intervention in Veterans with COPD (Taking Healthy Steps,56 Every Step Counts,57 and Walking and Education to Breathe58). This web intervention provides Veterans with COPD personalized daily step count goals, iterative feedback, disease-specific education, motivational tips, and an online community forum. Taking Healthy Steps was a RCT conducted virtually in a national sample of Veterans with COPD identified by diagnosis code. Compared to those who were randomly assigned to use a pedometer alone, those who were assigned to the website walked on average 779 more steps per day at 4 months.56 Every Step Counts used a more well-characterized cohort (ie, COPD diagnosis validated via spirometry). Compared to the pedometer-only control group, Veterans assigned to the website significantly increased their daily step count by 804 steps at 3 months.57 Those assigned to the intervention also demonstrated a significant reduced risk of experiencing a COPD acute exacerbation across a 12-month follow-up.59 Walking and Education to Breathe, the most recent RCT, evaluated the effectiveness of the intervention across two VA sites to include a more heterogeneous sample, and examined if lengthening the duration of the intervention period to 6 months would translate into improvements in exercise capacity. At 6 months, participants who were assigned to the web-based intervention walked on average 1312 more steps per day compared to those who were assigned to usual care.58 Across these three studies, despite the significant improvements in daily step count (7791312), there were no significant differences between the intervention and control groups in changes with respect to exercise capacity (6MWT distance) or dyspnea (mMRC).5658

Additionally, a priority in PR is to facilitate behavior change so patients will sustain engagement in long-term exercise. However, it remains difficult to maintain improvements in exercise after PR. Coultas et al tested the efficacy of a 20-week, telephone-based lifestyle PA intervention compared to usual care in COPD patients eligible for PR. They did not find significant differences for their primary outcome of 6MWT distance; however, subgroup analysis found that among Veterans with moderate COPD, the intervention resulted in stability of 6MWT distance at 18 months compared to participants who received usual care.60

In addition to daily walking, the effectiveness of alternative exercise forms, such as Tai Chi and yoga, has been explored in Veterans with COPD. Tai Chi may be a promising intervention to support physical outcomes. Compared to a mind-body breathing intervention, a Tai Chi intervention resulted in more substantial improvements in exercise capacity (6MWT distance) among persons with COPD.61 Similarly, a recent pilot RCT found that Tai Chi after completion of PR may support maintaining exercise capacity (6MWT distance) compared to usual care in persons with COPD after completing PR.62 Results from another RCT suggest that Tai Chi over 6 months may help to maintain exercise capacity.63 However, participants in the RCT reported barriers to attending the Tai Chi program similar to those reported for center-based PR (ie, distance, time).63 One recent pilot examined the effect of yoga training on inspiratory muscle performance.64 Inspiratory muscle strength is impaired in patients with COPD and leads to debilitating dyspnea and poor functional performance.65 Veterans were assigned to a 6-week yoga training program that included poses (asana) and controlled breathing (pranayama). Inspiratory muscle performance (measured via the Test of Incremental Respiratory Endurance) significantly improved from baseline, although no significant improvements were seen in exercise capacity (6MWT distance).64

In many patients with COPD, dynamic hyperinflation of the lungs during exercise is a major contributor to decreased exercise capacity.66 A recent study in Veterans examined if breathing retraining coupled with exercise training, a cornerstone of PR,48 would improve exercise capacity more than exercise training alone.67 Exercise training occurred via treadmill and took place three times every week for 12 weeks. The researchers used a metronome to provide acoustic feedback to train participants to achieve a slower respiratory rate and prolonged exhalation. Overall, despite achieving changes in breathing pattern with breathing retraining, improvements in exercise duration and dynamic hyperinflation were not significantly different with exercise training plus breathing retraining versus with exercise training alone.68

Depressive disorders are by far the most studied psychological disorder among Veterans with COPD. Rates of depressive disorder diagnosed by structured clinical interview range from 38% to 86% based on the study sample.69,70 Rates of diagnosed anxiety disorders range from 23% to 61%.69,70 Despite the high prevalence of depression and anxiety in Veterans with COPD, only a third receive any mental health treatment.69 In cross-sectional studies of Veterans, clinically significant depression symptoms were associated with low PA levels,71 worse self-reported functional impairment,7274 greater dyspnea,72 and worse HRQoL.72,73 Moreover, epidemiological studies in large samples of Veterans with COPD have shown that depression is associated with 1.53 times higher 30-day mortality compared to Veterans without depression.75 Depression was also associated with 1.36 times increased risk of 30-day hospital readmission for COPD acute exacerbation.75 Clinically significant anxiety among Veterans with COPD shows similar associations to health and functional outcomes such as depression. Anxiety symptoms are associated with greater self-reported functional impairment and worse HRQoL. One study found a significant association between clinically significant anxiety and greater daily PA,71 a finding that requires replication in prospective studies. Anxiety is associated with 1.72 times higher 30-day mortality compared to Veterans without anxiety and 1.22 times increased risk of 30-day hospital readmission for COPD acute exacerbation.75

Insomnia is an independent psychological disorder characterized by difficulty initiating or maintaining sleep, or early morning awakenings that cause significant distress and occur outside the diagnosis of another mental health condition.76 Research on insomnia in Veterans remains scarce. In one study, insomnia was found to occur in 27% (50 of 183) of Veterans with COPD. A much larger percentage of Veterans reported sleep complaints with 50% of the sample reporting at least one or more sleep complaint more than three times per week.77

A key outcome in Veterans with COPD, HRQoL reflects an individuals perception of their quality of life when they consider their overall health (eg, 36-Item Short Form Survey (SF-36))78 or in reference to their COPD diagnosis (eg, The Chronic Respiratory Questionnaire).79 Illness intrusiveness, a psychological construct, describes the extent to which an individual perceives their illness to impede in their daily life and valued activities and can be assessed with self-report measures. It is a meaningful treatment outcome for Veterans with COPD who prioritize daily functioning. The VHA has prioritized intervention development to improve psychological outcomes in Veterans with COPD. The following sections describe several of these interventions and their impact on psychological outcomes.

CBT is a time-limited, collaborative, present-focused, skills-based intervention that focuses on behavioral and cognitive change to treat psychological disorders. CBT is transdiagnostic, thus applicable in the treatment of the most common psychological disorders in COPD. Fundamental to CBT is that suffering is not directly caused by events themselves, but is a result of clients interpretation, appraisal, meaning, and behavioral response attached to events. Thus, treatment focuses on addressing the connection between events, thoughts, emotions, and behaviors while challenging and modifying unhelpful patterns.80

While CBT has been studied by several research groups in civilian samples with COPD, only one research group in the US accounts for almost all empirical research on the efficacy of CBT in Veterans with COPD. Cully et al81 conducted an RCT comparing brief cognitive behavioral therapy (bCBT) to enhanced usual care (EUC) in 302 Veterans with either heart failure (HF) or COPD and clinically significant depression and/or anxiety symptoms. The primary outcomes were depression and anxiety symptoms measured by validated self-report measures. HRQoL was the secondary outcome.

bCBT was delivered in six sessions either in-person or by telephone based on patient preference with two booster sessions provided over four months. Each session focused on a particular skill and the number of sessions varied based on patient preference and discussion with their therapist. Skill sessions focused on modification of unhelpful thinking patterns, behavioral activation, relaxation, and chronic disease self-management. Content was adapted to focus on the intersection between physical symptoms and mental health. Like traditional CBT, bCBT addressed topics such as usual and past coping styles and strengths and resources in the patients life. Skills were taught alongside practice assignments focused on goal setting and modifying behavior and thinking patterns. Therapists for the study ranged from psychology and social work trainees to staff psychologists and physician assistants. The EUC group received assessment of mental health symptoms and a note in their chart for their primary care provider to address these concerns. Outcomes were assessed at baseline and 4 (post-intervention), 8, and 12 months.

At 4 months, there were meaningful improvements in depression and anxiety symptoms in patients with COPD or HF. Veterans with COPD showed significant improvement in all domains of HRQoL. At 12 months, differences were maintained between the treatment and control group, but there was no further improvement in symptoms.81

Stemming from this parent study, secondary analyses were conducted in several separate articles and provide important insights into the optimization of psychological health in Veterans with COPD. First, the impact of bCBT on illness intrusiveness was examined among Veterans with COPD in the parent study.82 Illness intrusiveness was measured with the Illness Intrusiveness Rating Scale (IIRS) which provides a total score, as well as three validated subscales: Relationships (eg, family, civil engagement), Intimacy (eg, sexual functioning, relationship with spouse), and Instrumental (eg, health, work, active recreation). bCBT significantly improved IIRS total score at four months compared to EUC. At the subscale level, differences were found for Intimacy and Instrumental but not Relationships.

Second, in a separate study,83 bCBT was found to result in a significant reduction of high-frequency suicidal ideation (SI) in the bCBT group compared to the EUC at 4- and 8-month time points after controlling for baseline SI but the treatment effect was not sustained at 12 months. Specifically, at 4 and 8 months, respectively, participants who received bCBT compared to EUC had 72% and 68% lower likelihood of reporting high-frequency SI.

Third, predictors of treatment response to bCBT were explored in secondary analysis.84 Multivariate regression models examined whether hypothesized baseline variables including baseline depression or anxiety symptoms, functional limitations, self-efficacy for disease management, adaptive coping, maladaptive coping, number of sessions attended, and working alliance (ie, relationship between therapist and client) predicted improvement in primary outcomes of depression symptoms or anxiety symptoms. The same predictors emerged for both improvement in depression and anxiety symptoms. Participants with greater physical functioning impairment and lower self-efficacy showed less improvement in anxiety and depression symptoms. Those with greater baseline depression or anxiety showed greater improvement in symptoms.

The fourth and final study stemming from the parent study describes a utilization analysis of the content delivered in bCBT.85 They found that participants who received the physical health and thoughts modules earlier in treatment had a greater likelihood of remaining in treatment. Results have important clinical implications suggesting that early psychoeducation and skill building should focus on the intersection between physical and mental health, as well as dysfunctional or unhelpful thought patterns to optimize treatment completion rates. Together, these studies offer important data on the efficacy of bCBT, as well as treatment predictors.

As described in the physical outcomes section, PR is the standard of care for Veterans with COPD targeting exercise capacity and physical functioning. However, PR also improves many psychological outcomes, but studies with Veteran samples are limited. In a retrospective study, Veterans with COPD who participated in twice weekly outpatient PR for 18 weeks demonstrated significant improvement in depression symptoms over the course of PR. Greater reduction in depression over the course of treatment was significantly associated with greater improvement in CRQ-SR total score and the following subscales: fatigue, mastery, and emotional function.86 Similar findings were documented in a prior study examining the relation between change in depression symptoms and change in CRQ-SR subscales. In a sample of 81 Veterans enrolled in 8 weeks of biweekly PR, significant improvements were found for depression symptoms but not anxiety symptoms. Moreover, change in depression symptoms, but not anxiety symptoms, was associated with change in CRQ-SR domains of fatigue, emotion, and mastery.87 PR, a core treatment for Veterans with COPD and significant depression symptoms, improves physical functioning and psychological outcomes. However, depression and anxiety symptoms, particularly in Veterans with more than one mental health diagnosis and/or lifetime/chronic course of psychological disorders may require more intensive outpatient therapy specifically for mental health following PR or concurrently. Re-assessment of depression and anxiety symptoms is important at the end of PR to determine treatment needs.

Other work within VA has examined the effect of PR on insomnia. A recent retrospective study examined subjective and objective sleep changes after eight weeks of conventional, in-person, structured PR and 12 months of an unstructured exercise program.88 Despite sustained improvements in exercise capacity (measured via the 6MWT distance; mean improvement 68.8 m) and dyspnea (measured via the mMRC; mean difference 0.4 points), neither subjective sleep (measured via the Pittsburgh Sleep Quality Index) nor objective sleep (measured via actigraphy) improved.88

Surprisingly, research testing PA interventions in Veterans with COPD has not found significant improvements in depression or anxiety symptoms. One VA-based study compared the effects of a 4-month pedometer plus internet-mediated intervention to waitlist control (pedometer) on HRQoL in Veterans with COPD measured at 4 and 12 months.56,89,90 While HRQoL improved in the intervention group compared to the control group at 4 months, there was no difference at 12 months. Moreover, no change in depression scores was observed at either 4 or 12 months. However, these results are confounded by the fact that the treatment of anxiety and depression was not the main focus nor well characterized in the sample. For example, participants were not recruited based on significant levels of depression and anxiety nor was the intervention personalized in any way to participants based on their depression and/or anxiety levels.

Research on pharmacotherapy to improve psychological outcomes in individuals with COPD is limited in both civilian and Veterans samples. Drawing from the general literature, a Cochrane review published in 2018 found insufficient evidence for pharmacotherapy for the treatment of depression in individuals with COPD.91 In their review of the literature on anti-depressants for depression in COPD, no recommendation was made for any anti-depressant type. Rather, non-pharmacological treatments, such as collaborative care models and CBT, were encouraged as first-line therapy.92

Pharmacological treatment of COPD is focused on maximizing lung function, reducing risk for acute exacerbations, and symptoms management, namely the reduction of dyspnea.93 More recently, advances in COPD treatment have utilized precision medicine to target COPD in its early stages or before disease onset.94 However, to our knowledge, there are few funded research studies in the VHA focused on early COPD or prevention efforts. This is notable given that Veterans of the Iraq and Afghanistan conflicts will be entering midlife and have already been identified to be at greater risk for respiratory diseases given environmental exposures.95 Prior studies in civilians have begun to characterize those who may have early COPD targeting adults <50 years of age with 10 pack-years of smoking history with evidence of lung function abnormality by CT or spirometry that do not meet criteria for COPD.96 Improved understanding of Preserved Ratio Impaired Spirometry, a classification of individuals who have proportional reductions in FEV1 and FVC but preserved ratio, provides a group of individuals at higher risk for transitioning to COPD and may particularly benefit from early intervention.97 Advances in imaging technology can help identify those who may be at-risk for COPD.98 At least one funded study within the VHA is exploring the application of computation imaging technology (CT) using Quantitative Imaging Analysis (QIA) to identify structural defects in the lungs before disease onset. By targeting individuals in the early COPD stage, effective clinical management can be offered and presents a vital area for future research in Veterans.

Similarly, identification of predictive biomarkers within COPD remains an active area of research with many unanswered questions.94 While review of the research on biomarkers of COPD is beyond the scope of this paper, more research is needed exploring COPD biomarkers in Veterans with careful delineation of endotypes connected to the proposed biomarker and clinical manifestation of disease activity.99 For example, past research in civilians established an association between epigenetic changes and inflammatory-response cytokines in COPD patients undergoing a prolonged, 24-session exercise training regimen.100 Early changes were observed in DNA methylation between baseline and after the first session but no changes were observed in H4 acetylation status at any point during the intervention. Inflammatory markers changed in response to the exercise intervention with an increase in interleukin-6 (IL-6) and a decrease in growth factor-beta after session 24.

In Veteran samples using a cross-sectional design, greater daily step count and higher 6MWT distance were associated with lower systematic inflammation, as measured by CRP and IL-6.101 After controlling for age, FEV1% predicted, pack-years smoked, cardiac disease, current statin use, history of acute exacerbations, and season, each 1000-step increase in daily step count was significantly associated with 0.94 mg/L and 0.96 pg/mL decrease in CRP level. Similarly, for every 30-m increase in 6MWT distance, there was a 0.94 pg/mL decrease in CRP and 0.96 pg/mL decrease in IL-6 level. While not causal, these studies point to potential epigenetic changes associated with exercise-induced inflammatory biomarkers in COPD.

Research with Veteran samples has established correlations between epigenetic markers of biological age and functioning in COPD.102 At baseline, epigenetic age and age acceleration, measures that capture the difference between biological and chronological age, were inversely associated with 6MWT distance and PA after adjusting for chronological age, sex, race, smoking status, pack-years, BMI, cohort, and estimated cell counts. Importantly, longitudinal change in one of the measures of epigenetic age was inversely associated with change in 6MWT distance at 12 weeks, suggesting that epigenetic age may represent a potentially modifiable molecular signature of exercise capacity.102 Potential applications of epigenetics and biomarkers for the prediction of clinical outcomes, such as COPD acute exacerbations or response to exercise training programs such as pulmonary rehabilitation, represent active areas of investigation.

While PA promotion interventions show promising short- and some long-term benefit in terms of increasing daily PA and reducing COPD acute exacerbation risk, improvements in exercise capacity have not been observed.58 In the next decade, RCTs are needed to test the dose of PA promotion (ie, duration, intensity) required to sustain functional improvements. Long-term trials testing beyond 12 months are necessary. Moreover, development and testing of novel interventions that leverage varying levels of Veteran engagement, such as hybrid approaches that combine self-guided and in-person/provider-delivered components are needed to examine the impact of frequency of promotional and supportive messages and check-ins from staff.58 Additionally, little is known about the social context and its association with short- and long-term adoption of PA. Studies exploring the role caregivers, family members, and friends in the adoption and maintenance of PA in COPD are needed, particularly given that social context has proved important for the success of COPD self-management efforts.103,104 Finally, it is important to consider the effects of the COVID-19 pandemic on habitual PA and exercise patterns.105,106 Indoor walking and exercise in malls, gyms, and senior centers have been reduced and alternatives are not always available. As such, innovative research is needed to better understand how patients with COPD prefer to engage in PA in their current environments and preferences for in-home exercises.

Notably, the VHA is a leader in telemedicine and prioritized access to care well before the COVID-19 pandemic107 which only expanded over the last two years.108 The VHA system provides iPad, with built in internet access, at no cost to Veterans without a personal device and/or internet access. Moreover, the VA has an established Care Coordination/Home Telehealth (CCHT)109 for chronic diseases including COPD, which provides home equipment for daily monitoring and disease management by a nurse care coordinator. In 2017, from funding through the VAs Office of Rural Health, home-based PR was offered across 13 VA medical centers. While several studies in civilians have established the efficacy of home-based PR,110,111 until 2017 only hospital-based PR was offered in the VHA system. Based on home-based cardiac rehabilitation provided in the VA,112 home-based PR involves an initial in-person evaluation, followed by 11 weekly telephone or video appointments, an in-person evaluation at week 12, and follow-up phone/video calls at 3 and 6 months. A final in-person evaluation occurs at 12 months from the start of the program.112 However, the extent to virtual only rehabilitation and exercise programs are available to Veterans varies by VA. Future research is needed to demonstrate implementation of existing evidence-based PR programs delivered virtually in the VHA as part of routine clinical care.

There is extensive evidence documenting increased inflammatory markers in psychological disorders and, in particular, major depressive disorder. Increases in pro-inflammatory markers including peripheral blood IL-1, IL-6, Tumor Necrosis Factor (TNF) and C-reactive protein (CRP) are well documented.113 Yet, the role of inflammation and shared pathways between depression and COPD remain inconclusive. Limited cross-sectional research on civilians with COPD has found that greater depression symptoms are associated with higher TNF- and sTNFR after adjusting for possible confounders.114,115 However, one prospective study did not find a significant association between depression and inflammatory markers in individuals with stable COPD.116 Janssen et al116 measured several inflammatory markers (white blood cell, hsCRP, IL6, fibrinogen) in COPD patients at baseline and 36-month follow-up. They classified individuals as having persistent systemic inflammation if they had 2 or more markers elevated in the upper quartile at baseline and follow-up or no inflammation corresponding to no elevation in inflammation at either time point. They found no association between baseline depression scores and inflammation group after adjusting for confounders, and no differences were found either in change in depression scores or mean levels at follow-up between inflammation groups. Nonetheless, given the notable role of inflammation in both COPD and depression, as well as the heterogeneity of both diseases, future research examining the association between inflammation and depression in COPD utilizing prospective designs is needed. Furthermore, reduction in inflammatory markers reflects a meaningful marker of treatment response in COPD100,101 and depression,117 thus it is plausible that targeting both COPD symptoms and depression concurrently could result in greater reduction in inflammatory markers corresponding to treatment response compared standalone therapies that separately target physical functioning and psychological symptoms.

In order to advance interventions for psychological outcomes in COPD, it is critical that researchers begin dually targeting both physical functioning and psychological outcomes. For example, past research with patients with diabetes and HF found that combining a physical intervention (ie, exercise) with psychotherapy (ie, CBT) produced superior outcomes in both functioning and mental health symptoms.118,119 Yet, up to this point, two independent bodies of literature have focused on separately addressing physical functioning via pulmonary rehabilitation and exercise, and mental health through psychotherapy/behavioral interventions. One funded study in the VHA is testing the integration of a pedometer-based walking intervention with CBT in a 12-week virtual intervention with Veterans with COPD, low PA levels, and clinically significant depression and/or anxiety symptoms (NCT04953806). The intervention will target daily step count and self-reported physical disability, as well as depression and anxiety symptoms.

While research establishing the efficacy of treatments for COPD has been fruitful, implementation of guideline-based care remains fraught with health-care inequities. Women Veterans hospitalized for COPD are less likely to have received inhaler therapies prior to admission compared to men.43 In addition, women are less likely during the course of a COPD hospitalization to receive appropriate inhaler combinations and more likely to receive inappropriate inhaler combinations.43 Moreover, women, racial and ethnic minorities, and individuals with drug and alcohol use disorders are less likely to have pulmonary function tests performed, possibly leading to delays in diagnosis and under-treatment.120 In considering optimizing outcomes, it is imperative to consider and equally target health-care inequities that serve as barriers to guideline-based care. Similarly, enhanced recruitment of underserved groups (ie, lower socioeconomic status, racial and ethnic minorities) in COPD research studies is needed. Research and quality improvement projects are important to examine system and individual-level approaches to ensure equity in guideline-based care for all Veterans with COPD. Funding for COPD research that include focus on minority healthcare is needed.

The coming decade will see an increase in COPD prevalence in US Veterans as Vietnam era Veterans fully reach older adulthood and Iraq and Afghanistan conflict Veterans enter midlife. A multi-pronged agenda targeting system-level factors that increase access and improve care delivery, as well as bench and clinical research will be needed to advance our understanding, treatment, and management of COPD in Veterans. Partnerships with all stakeholders including patients, university-affiliated hospitals, industry, and the international research community will be critical to accelerate the development and implementation of novel treatments to improve physiological, physical, and psychological health outcomes for this heterogenous disease.

This work was supported, in part, by the following grants from the US Department of Veterans Affairs Rehabilitation Research and Development Service: Merit Award I01 RX001150 (M.L.M.); Career Development Award-2 (CDA2) Award 1IK2RX003527-01A2 (P.M.B.); and CDA2 Award IK2RX002165 (E.S.W.).

The authors report no conflicts of interest in this work.

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27. Berger R, Smith D. Effect of inhaled metaproterenol on exercise performance in patients with stable fixed airway obstruction. Am Rev Respir Dis. 1988;138(3):624629. doi:10.1164/ajrccm/138.3.624

28. Jenne JW, Ridley DJ, Marcucci RA, Druz WS, Rook JC. Objective and subjective tremor responses to oral beta 2 agents on first exposure. A comparison of metaproterenol and terbutaline. Am Rev Respir Dis. 1982;126(4):607610. doi:10.1164/arrd.1982.126.4.607

29. Ashutosh K, Dev G, Steele D. Nonbronchodilator effects of pirbuterol and ipratropium in chronic obstructive pulmonary disease. Chest. 1995;107(1):173178. doi:10.1378/chest.107.1.173

30. Beauford W, Saylor TT, Stansbury DW, Avalos K, Light RW. Effects of nebulized morphine sulfate on the exercise tolerance of the ventilatory limited COPD patient. Chest. 1993;104(1):175178. doi:10.1378/chest.104.1.175

31. Niewoehner DE, Erbland ML, Deupree RH, et al. Effect of systemic glucocorticoids on exacerbations of chronic obstructive pulmonary disease. Department of Veterans Affairs Cooperative Study Group. N Engl J Med. 1999;340(25):19411947. doi:10.1056/NEJM199906243402502

32. Albert RK, Connett J, Bailey WC, et al. Azithromycin for prevention of exacerbations of COPD. N Engl J Med. 2011;365(8):689698. doi:10.1056/NEJMoa1104623

33. Lam J, Tonnu-Mihara I, Kenyon NJ, Kuhn BT. Comparative effectiveness of roflumilast and azithromycin for the treatment of chronic obstructive pulmonary disease. Chronic Obstr Pulm Dis. 2021;8(4):450463. doi:10.15326/jcopdf.2021.0224

34. Yeh SS, Phanumas D, Hafner A, Schuster MW. Risk factors for osteoporosis in a subgroup of elderly men in a Veterans Administration nursing home. J Investig Med. 2002;50(6):452457. doi:10.1136/jim-50-06-05

35. Morden NE, Sullivan SD, Bartle B, Lee TA. Skeletal health in men with chronic lung disease: rates of testing, treatment, and fractures. Osteoporos Int. 2011;22(6):18551862. doi:10.1007/s00198-010-1423-y

36. Cote CG, Pinto-Plata VM, Marin JM, Nekach H, Dordelly LJ, Celli BR. The modified BODE index: validation with mortality in COPD. Eur Respir J. 2008;32(5):12691274. doi:10.1183/09031936.00138507

37. Tunsupon P, Mador MJ. The influence of body composition on pulmonary rehabilitation outcomes in chronic obstructive pulmonary disease patients. Lung. 2017;195(6):729738. doi:10.1007/s00408-017-0053-y

38. Nunez ER, Johnson SW, Qian SX, et al. Patterns of pulmonary consultation for veterans with incident chronic obstructive pulmonary disease. Ann Am Thorac Soc. 2021;18(7):12491252. doi:10.1513/AnnalsATS.202008-1075RL

39. Fan VS, Gaziano JM, Lew R, et al. A comprehensive care management program to prevent chronic obstructive pulmonary disease hospitalizations: a randomized, controlled trial. Ann Intern Med. 2012;156(10):673683. doi:10.7326/0003-4819-156-10-201205150-00003

40. Aboumatar H, Naqibuddin M, Chung S, et al. Effect of a hospital-initiated program combining transitional care and long-term self-management support on outcomes of patients hospitalized with chronic obstructive pulmonary disease: a randomized clinical trial. JAMA. 2019;322(14):13711380. doi:10.1001/jama.2019.11982

41. Ashton CM, Souchek J, Petersen NJ, et al. Hospital use and survival among Veterans Affairs beneficiaries. N Engl J Med. 2003;349(17):16371646. doi:10.1056/NEJMsa003299

42. Reese RL, Clement SA, Syeda S, et al. Coordinated-transitional care for veterans with heart failure and chronic lung disease. J Am Geriatr Soc. 2019;67(7):15021507. doi:10.1111/jgs.15978

43. Rinne ST, Elwy AR, Bastian LA, Wong ES, Wiener RS, Liu C-F. Impact of multisystem health care on readmission and follow-up among veterans hospitalized for chronic obstructive pulmonary disease. Med Care. 2017;55:S20S25. doi:10.1097/mlr.0000000000000708

44. LaBedz SL, Krishnan JA, Chung YC, et al. Chronic obstructive pulmonary disease outcomes at veterans affairs versus non-veterans affairs hospitals. Chronic Obstr Pulm Dis. 2021;8(3):306313. doi:10.15326/jcopdf.2021.0201

45. ODonnell DE, Milne KM, James MD, De Torres JP, Neder JA. Dyspnea in COPD: new mechanistic insights and management implications. Adv Ther. 2020;37(1):4160. doi:10.1007/s12325-019-01128-9

46. Hajghanbari B, Garland SJ, Road JD, Reid WD. Pain and physical performance in people with COPD. Respir Med. 2013;107(11):16921699. doi:10.1016/j.rmed.2013.06.010

47. Wan E, Goldstein R, Kantorowski A, Moy M. Association between exercise capacity and physical activity with long-term all-cause and cause-specific mortality among US veterans with COPD. In: TP41. TP041 DIAGNOSIS and RISK ASSESSMENT in COPD. American Thoracic Society; 2021:A2284A2284.

48. Spruit MA, Pitta F, McAuley E, ZuWallack RL, Nici L. Pulmonary rehabilitation and physical activity in patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 2015;192(8):924933. doi:10.1164/rccm.201505-0929CI

49. Fan VS, Giardino ND, Blough DK, Kaplan RM, Ramsey SD; Nett Research Group. Costs of pulmonary rehabilitation and predictors of adherence in the National Emphysema Treatment Trial. COPD. 2008;5(2):105116. doi:10.1080/15412550801941190

50. Bamonti PM, Boyle JT, Goodwin CL, et al. Predictors of outpatient pulmonary rehabilitation uptake, adherence, completion, and treatment response among male US veterans with chronic obstructive pulmonary disease. Arch Phys Med Rehabil. 2021. doi:10.1016/j.apmr.2021.10.021

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Psychological Health Outcomes A Narrative Review in US Vet | COPD - Dove Medical Press

Physiology

Carson Daly Recalls Having Panic Attacks on The Voice , Says He’s in ‘Better Place’ Now with His Anxiety – Yahoo Entertainment

carson daly

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Carson Daly is detailing the "high-panic moments" he experiences while hosting The Voice.

The 48-year-old television personality recently spoke to USA Today about being diagnosed with general anxiety disorder (GAD) and said that being open about his struggles has put him in a "much better place."

"You may know me from MTV or as a celebrity of whatever you think of me. You may think my life's perfect. I've got kids. I always look happy on TV or when you watch me on The Voice. But that's just not how it works," Daly told the outlet. "It's not like that."

"On The Voice, when I'm live on Monday nights, most of the time, my right hand is in my right pocket, and I'm literally gripping onto the flesh of my thigh because I'm waiting for a high-panic moment to pass," he added.

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The Voice - Season 12

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Although his panic attacks and hyperventilation can come and go, Daly said he's "on a really good path," and that sharing his story and learning more about anxiety has really helped him.

"Once you realize that other people have [GAD] that it's an actual diagnosable thing, and there is a whole psychology and physiology behind it you have context, and I think learning about all that, talking about it, exploring it has just ripped the veil," he said.

Daly will continue sharing his personal experience with anxiety through a new summer segment on the Today show called "Mind Matters," launching Tuesday. He told USA that the show will allow him to destigmatize issues around mental health.

"I shared my story haphazardly one day, and now this mental health area has become kind of my place at NBC News and within the show and the creation of 'Mind Matters' to find other stories of people like me, whether they're famous or not," he said.

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"It's just inspiring," Daly continued. "I've never had an issue with clinical depression but when doing 'Mind Matters,' I have a chance to talk to people who struggle differently than I do with suicidal ideation or depression, and I'm in such awe of the bravery of people."

RELATED:Carson Daly Opens Up About His 'Debilitating' Anxiety and Helping Others with Mental Illness

Daly first opened up about his anxiety in 2018 after hearing NBA player Kevin Love share his own experience.

"I've suffered for over 20 years with, at times, debilitating anxiety and panic, and never knew it. I never knew how to define it," he revealed at the time. "After finally opening up to friends, one of them had a history of anxiety, and looked at me and was like, 'You have anxiety.' "

The father of four underwent a 14-week cognitive therapy course and began to educate himself about his mental illness, eventually learning how to manage it.

"It felt so good to get that diagnosis, because for so long I would be driving in my car and start to get nervous and wonder if I should pull over. And now I know, 'Oh, this is happening, and wait 10 seconds and it will go away.' Being diagnosed and then talking about it just feels good," Daly added.

"It bothers me that anybody could feel that they're less than normal if they also have something about them that they're unsure about as it pertains to their mental health. It doesn't have to be anxiety. It can be depression, it could be PTSD, or any number of things. I want to hold their hand and go, 'It's okay to not be okay.' "

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Carson Daly Recalls Having Panic Attacks on The Voice , Says He's in 'Better Place' Now with His Anxiety - Yahoo Entertainment

Physiology

After you swipe right, read this – Green Prophet

A loving relationship can be predicted by the first date. You want sustainable love and a sustainable planet? Read on.

Looking for a sustainable romantic relationship? One that will last till the end of days? Then youll know how important that first date can be. When falling in love, what makes us attracted to some people, and not to others?

The answer will be surprising to most of us but it wasnt to the team of researchers led by Shir Atzil of the Department of Psychology at the Hebrew University in Jerusalem.

Connecting with a partner depends on how well we can synchronize our bodies. We specialize in studying parent-infant bonding and we had already seen the same thing there, she explained.

The researchers looked at how a heterosexual couples physiology and behavior adapt to each other during that first encounter.

The study was based on a speed-date experiment consisting of forty-six dates. Each date lasted 5 minutes during which the levels of physiological regulation of each partner were recorded with a band worn on the wrist. Behavioral movements, such as nodding, moving an arm, shifting a leg were also recorded in each partner during the date.

After the encounter, the couple assessed the romantic interest and sexual attraction they felt for each other. The study clearly showed that when couples synchronize their physiology with one another and adapt their behavioral movements to their partner during the date, they are romantically attracted to one another. This research was recently published inScientific Reports.

Intriguingly, the study also showed that the degree of synchrony affected men and women differently.

Although for both genders synchrony predicted attraction, women were more sexually attracted to men who showed a high level of synchrony super-synchronizers; these men were highly desirable to female partners.

Our research, said Atzil, demonstrates that behavioral and physiological synchrony can be a useful mechanism to attract a romantic partner. However, we still dont know whether synchrony raises attraction or does the feeling of attraction generate the motivation to synchronize? An area of research that Atzil is planning to investigate.

And for pan, by, trans and everything on the spectrum? The jury is out.

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Physiology

Understanding gut response to high-fat meals key to effective IBD treatments, says study – NutraIngredients.com

This apparent link between diet, gut microbiota, and gene expression could be used to develop prognostic or therapeutic treatments for IBDs, such as Crohns disease and ulcerative colitis, according to study authors.

The study focused on a transcription factor called hepatocyte nuclear factor 4 alpha (HNF4A), known to regulate genes involved in lipid metabolism and genes that respond to microbes.

Genetic variants at human HNF4A are associated with both Crohns disease and ulcerative colitis, the authors explain, but the underlying reason for the overlap between microbial and HNF4A-regulated genes, and how microbes alter HNF4A occupancy, host metabolism and acquisition of nutrients, remain unknown.

Therefore, understanding how the intestine perceives and responds to the major stimuli of nutritional and microbial signals remains a fundamental challenge.

Lead author, Dr Colin Lickwar said: We thought that it might represent an interface or a crossroads between interpreting information that comes from either microbial sources or from dietary fat.

Its certainly complicated, but we do appear to identify that HNF4-Alpha is important in simultaneously integrating multiple signals within the intestine.

There is plenty of evidence to suggest a high-fat diet and microbiota interactively influence host physiology but there is limited intelligence on integrative host reponses, say researchers.

In their report, published in Cellular and Molecular Gastroenterology and Hepatology, they write: Chronic high-fat diet feeding leads to adaptive physiological responses that can make it difficult to distinguish primary impacts of microbiota on host response, those impacts can be more easily discerned in the postprandial response to a single high-fat meal.

In the current study, scientists focused on a single, early postprandial period after consumption of a HFM consisting of chicken egg yolk emulsion. The time point was chosen to capture initial responses prior to cell-division and cell-type changes.

Adult mice were split among four groups: germ-free (GF); GF plus HFM; ex-GF colonised (CV) with conventional microbiota, and CV plus HFM.

Multiple functional genomic assays were applied to evaluate the interaction between HFM and microbiota colonisation in mouse small IECs.

There were significant differences in gene transcriptions for each of the four groups, and blocks of genes were impacted by either microbial or nutritional status.

Both germ-free and normal mice were able to metabolise fatty acids in a high-fat diet, although the germ-free group used a different set of genes to metabolise the HFM.

Professor of Molecular Genomics and Microbiology, John Rawls, commented: We were surprised to find that the gene playbook that the gut epithelium uses to respond to dietary fat is different depending on whether or not microbes are there.

Researchers note that microbes assisted with gut absorption of fatty acids. They observed increased activity of genes involved in fatty acid oxidation in germ-free mice, which literally burned off fatty acids to provide fuel for the guts cells.

Professor Rawls added: Typically we think about the gut just doing its job absorbing dietary nutrients across the epithelium to share with the rest of the body, but the gut has to eat too. So, what we think is going on in germ-free animals, is that the gut is consuming more of the fat than it would if the microbes were there.

Overall findings suggest that gut microbes may promote lipid accumulation and weight gain, while suppressing gene activity designed to regulate beneficial intestinal and metabolic activity, including gut inflammation.

Source: Cellular and Molecular Gastroenterology and Hepatology

Published online: https://doi.org/10.1016/j.jcmgh.2022.04.013

Transcriptional Integration of Distinct Microbial and Nutritional Signals by the Small Intestinal Epithelium

Colin R. Lickwar, James M. Davison, Cecelia Kelly, Gilberto Padilla Mercado, Jia Wen, Briana R. Davis, Matthew C. Tillman, Ivana Semova, Sarah F. Andres, Goncalo Vale, Jeffrey G. McDonald, and John F. Rawls

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Physiology

An APS fellowship helps to complete the transition from machine gunner to researcher – news.wm.edu

In 2019, Jacob Stechmann was a U.S. Marine deployed to Syria.

I was a machine gunner, he said, adding that circumstances of combat meant that he was occasionally pressed into service by Army and Navy Special Forces medics to help treat casualties among the Kurdish population.

They would bring some of us over if they needed help, Stechmann said. Not anything serious, but we got to do some of the little things.

Those little things included treating a gunshot wound to the arm and replacing bandages of people who had suffered shrapnel wounds to the stomach.

That was my last year in the Corps, Stechmann said. That was the deployment that kind of opened my eyes up to medicine: getting to see Army doctors and surgeons work on Kurdish allies coming in after certain incidents.

In 2022, Stechmann is a student-researcher at William & Mary, studying the function of blood vessels in Robin Looft-Wilsons lab. He was one a dozen students awarded a Summer Undergraduate Research Fellowship (SURF) by the American Physiological Society (APS).

The SURF fellowships supports students conducting research in the laboratory of an APS member. Looft-Wilson, a professor in William & Marys Department of Kinesiology, studies artery function and its role in cardiovascular health. She says Stechmann is a good addition to her lab and is well deserving of the SURF fellowship.

I loved that he had a military background. Im from a military family, and I know the work ethic, so that that was certainly a plus, Looft-Wilson said. He expressed a strong interest in research and said he wanted to go into medicine.

Stechmann transferred into William & Mary from J. Sergeant Reynolds Community College. He expects to get his bachelors degree in 2024 and is already considering his post-William & Mary options. Depending on how he wants to balance research and patient care, he will choose among programs leading to an M.D., a Ph.D. or an M.D./Ph.D. combination.

I know that many M.D.s will do research and they dont have the Ph.D. attached, Stechmann said. I dont think Ive talked to enough M.D.-Ph.D.s and M.D.s-only yet. But yeah, if I want research to be a big part of my career, then maybe M.D.-Ph.D. is something that I want to look at.

Hes getting plenty of opportunity to see how he likes conducting research in Looft-Wilsons lab. Theyre studying constriction in very small blood vessels. Lately, Stechmann has been cannulating mesenteric arteries, those vessels that supply blood from the aorta to the intestines.

This is a microsurgery, so Jacob does all of this under the microscope, Looft-Wilson explained. The cannula are teeny-tiny. And as you can imagine, youve got these very fine tipped forceps and youre in this tiny little dish, the dish is about this big, making a thumb-forefinger circle.

Each cannula Stechmann uses is roughly twice the diameter of a human hair. Working in the tiny little dish, peering through the microscope, Stechmann slips the artery over the teeny-tiny glass cannula (Kind of like putting a sock on a foot, Looft-Wilson says) and ties it down. Stechmann explained that once he has an artery cannulated, the lab adds a chemical to stimulate constriction of the artery.

We study artery function at the molecular level, and also at the tissue level, Looft-Wilson explained. We look at contraction and relaxation of the artery, which is very important for controlling blood both blood pressure in the body, and blood flow to individual tissues.

She went on to say that her lab is researching the molecular signaling in the sympathetic nerve stimulation pathway.

You know: your fight or flight response, Looft-Wilson said. When youre stressed or when you exercise, your sympathetic nervous system is activated. And one of the things that happens is sympathetic nerves release a neurotransmitter that causes the blood vessels to constrict.

The APS SURF fellowship carries a stipend to support his summer research in the Looft-Wilson lab. It also provides for Stechmann to attend the APS international meeting, the Physiology Summit, in April 2023.

Thousands of scientists will be there, Looft-Wilson said. Jacob will be presenting a poster, probably in a couple of different forums, including one highlighting undergraduates.

Mingling with the M.D.s, Ph.D.s and M.D.-Ph.D.s at the Physiology Summit will give Stechmann the opportunity to hear different points of view on the research-patient care professional spectrum. Its another of the many advantages the SURF fellowship offers.

At a very basic level, the fellowship allows me to really dive deep and research and understand the process that is backbone of science to understand how it actually works and how these results are determined and presented and shared among colleagues, Stechmann said. I think it just really opens me up to the experience in general. And as for my future, Im sort of debating as how much I want research to be a part of my career, and I think this will be perfect for seeing how I enjoy it.

Joseph McClain, Research Writer

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An APS fellowship helps to complete the transition from machine gunner to researcher - news.wm.edu

Physiology

Trevena Announces Results from Respiratory Physiology Study of Head-to-Head Comparison of OLINVYK and IV Morphine in Elderly/Overweight Subjects -…

Trevena Inc.

OLINVYK showed a statistically significant reduced impact on respiratory function compared to IV morphine, among elderly/overweight subjects

Data replicate observations previously seen in a comparative study of respiratory physiology in younger subjects with OLINVYK and IV morphine

CHESTERBROOK, Pa., April 20, 2022 (GLOBE NEWSWIRE) -- Trevena, Inc. (Nasdaq: TRVN), a biopharmaceutical company focused on the development and commercialization of novel medicines for patients with central nervous system (CNS) disorders, today announced results from its double blinded, crossover study evaluating OLINVYK (oliceridine) injection for the management of acute pain, in elderly/overweight. This study builds on the collaborative work with Dr. Albert Dahan and his research team at Leiden University Medical Center (LUMC).

We are very pleased with the results of our study, which replicate earlier results reported in younger subjects, said Dr. Albert Dahan, Professor of Anesthesiology at Leiden University Medical Center, These data suggest that OLINVYK, a new chemical entity, may offer a more favorable respiratory safety profile when compared to IV morphine.

Dr. Dahans team compared the analgesic and respiratory effects of two doses of OLINVYK (0.5mg and 2.0mg) and morphine (2.0mg and 8.0mg) administered intravenously in a population of elderly individuals (age range 56 to 87 years, mean age = 71.2) across a range of body weight (BMI range from 20 to 34 kg/m2, mean BMI= 26.3). Subjects were tested on 4 occasions and randomized by drug and dose. On each visit, the ventilatory response to inhaled carbon dioxide was measured to evaluate the potential effect of the drug on the brain respiratory centers. Elderly and overweight patients are known to be at higher risk of respiratory depression with the use of opioid medications. This study hypothesized that, at similar levels of analgesia, there would be a reduced impact on respiratory function with OLINVYK compared to IV morphine. The primary endpoint of the study was ventilatory rate at an extrapolated PCO2 of 55 mmHg (VE55).

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Key Findings

Both OLINVYK and IV morphine achieved comparable levels of pain relief. However, a statistically significantly reduced impact on respiratory function was observed in patients treated with OLINVYK compared to IV morphine, as measured by the mean respiratory ventilation profiles over time (P < 0.0001).

In contrast to the lower dose of IV morphine, very little impact on respiratory function was observed with the lower dose of OLINVYK.

At the higher dose of both drugs studied, less respiratory depression over the 6 h measurement period was observed with OLINVYK. The peak level was lower for OLINVYK compared to morphine, though this difference was not statistically significant (P > 0.05). In addition, in contrast to morphine, respiratory function at the higher dose of OLINVYK rapidly returned toward baseline from 3 hours onward (all time points P < 0.05 in pairwise comparison).

The data replicate the results from a previously reported study in younger subjects.

Comparing the sensitivity of the impact on respiratory function from the earlier study and the results from the current study suggests that there is a nearly identical impact on respiratory function with OLINVYK in the younger and elderly age groups, while IV morphine data suggests an increase in impact in the elderly compared to the younger subjects.

We believe these data from Dr. Dahans study team are important. They replicate the results from an earlier study reported by Trevena in younger subjects using a similar methodology, and they extend our knowledge to patients who are at higher risk for the development of respiratory depression with the use of opioids, namely elderly and overweight patients, said Mark A. Demitrack, M.D., Senior Vice President and Chief Medical Officer of Trevena. As with all opioids, serious, life-threatening, or fatal respiratory depression may occur in patients treated with OLINVYK. We look forward to seeing further analysis of this data by Dr. Dahans team and working with him to see these results reported to the wider scientific community and submitted for publication in the near future.

About OLINVYK (oliceridine) injection

OLINVYK is a new chemical entity approved by the FDA in August 2020. OLINVYK contains oliceridine, an opioid, which is a Schedule II controlled substance with a high potential for abuse similar to other opioids. It is indicated in adults for the management of acute pain severe enough to require an intravenous opioid analgesic and for whom alternative treatments are inadequate. OLINVYK is available in 1 mg/1 mL and 2 mg/2 mL single-dose vials, and a 30 mg/30 mL single-patient-use vial for patient-controlled analgesia (PCA). Approved PCA doses are 0.35 mg and 0.5 mg and doses greater than 3 mg should not be administered. The cumulative daily dose should not exceed 27 mg. Please see Important Safety Information, including the BOXED WARNING, and full prescribing information at http://www.OLINVYK.com.

IMPORTANT SAFETY INFORMATIONWARNING: ADDICTION, ABUSE, AND MISUSE; LIFE-THREATENING RESPIRATORY DEPRESSION; NEONATAL OPIOID WITHDRAWAL SYNDROME; and RISKS FROM CONCOMITANT USE WITH BENZODIAZEPINES OR OTHER CENTRAL NERVOUS SYSTEM (CNS) DEPRESSANTS

ADDICTION, ABUSE, AND MISUSE OLINVYK exposes patients and other users to the risks of opioid addiction, abuse, and misuse, which can lead to overdose and death. Assess each patients risk before prescribing OLINVYK, and monitor all patients regularly for the development of behaviors or conditions.

LIFE-THREATENING RESPIRATORY DEPRESSION Serious, life-threatening, or fatal respiratory depression may occur with use of OLINVYK. Monitor for respiratory depression, especially during initiation of OLINVYK or following a dose increase.

NEONATAL OPIOID WITHDRAWAL SYNDROME Prolonged use of OLINVYK during pregnancy can result in neonatal opioid withdrawal syndrome, which may be life-threatening if not recognized and treated, and requires management according to protocols developed by neonatology experts. If opioid use is required for a prolonged period in a pregnant woman, advise the patient of the risk of neonatal opioid withdrawal syndrome and ensure that appropriate treatment will be available.

RISK FROM CONCOMITANT USE WITH BENZODIAZEPINES OR OTHER CNS DEPRESSANTS Concomitant use of opioids with benzodiazepines or other CNS depressants, including alcohol, may result in profound sedation, respiratory depression, coma, and death. Reserve concomitant prescribing for use in patients for whom alternative treatment options are inadequate; limit dosages and durations to the minimum required; and follow patients for signs and symptoms of respiratory depression and sedation.

INDICATIONS AND USAGEOLINVYK is an opioid agonist indicated in adults for the management of acute pain severe enough to require an intravenous opioid analgesic and for whom alternative treatments are inadequate.Limitations of UseBecause of the risks of addiction, abuse, and misuse with opioids, even at recommended doses, reserve OLINVYK for use in patients for whom alternative treatment options [e.g., non-opioid analgesics or opioid combination products]:

Have not been tolerated, or are not expected to be tolerated

Have not provided adequate analgesia, or are not expected to provide adequate analgesia.

The cumulative total daily dose should not exceed 27 mg, as total daily doses greater than 27 mg may increase the risk for QTc interval prolongation.CONTRAINDICATIONSOLINVYK is contraindicated in patients with:

Significant respiratory depression

Acute or severe bronchial asthma in an unmonitored setting or in the absence of resuscitative equipment

Known or suspected gastrointestinal obstruction, including paralytic ileus

Known hypersensitivity to oliceridine (e.g., anaphylaxis)

WARNINGS AND PRECAUTIONS

OLINVYK contains oliceridine, a Schedule II controlled substance, that exposes users to the risks of addiction, abuse, and misuse. Although the risk of addiction in any individual is unknown, it can occur in patients appropriately prescribed OLINVYK. Assess risk, counsel, and monitor all patients receiving opioids.

Serious, life-threatening respiratory depression has been reported with the use of opioids, even when used as recommended, especially in patients with chronic pulmonary disease, or in elderly, cachectic and debilitated patients. The risk is greatest during initiation of OLINVYK therapy, following a dose increase, or when used with other drugs that depress respiration. Proper dosing of OLINVYK is essential, especially when converting patients from another opioid product to avoid overdose. Management of respiratory depression may include close observation, supportive measures, and use of opioid antagonists, depending on the patients clinical status.

Opioids can cause sleep-related breathing disorders including central sleep apnea (CSA) and sleep-related hypoxemia with risk increasing in a dose-dependent fashion. In patients who present with CSA, consider decreasing the dose of opioid using best practices for opioid taper.

Prolonged use of opioids during pregnancy can result in withdrawal in the neonate that may be life-threatening. Observe newborns for signs of neonatal opioid withdrawal syndrome and manage accordingly. Advise pregnant women using OLINVYK for a prolonged period of the risk of neonatal opioid withdrawal syndrome and ensure that appropriate treatment will be available.

Profound sedation, respiratory depression, coma, and death may result from the concomitant use of OLINVYK with benzodiazepines or other CNS depressants (e.g., non-benzodiazepine sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, other opioids, or alcohol). Because of these risks, reserve concomitant prescribing of these drugs for use in patients for whom alternative treatment options are inadequate, prescribe the lowest effective dose, and minimize the duration.

OLINVYK was shown to have mild QTc interval prolongation in thorough QT studies where patients were dosed up to 27 mg. Total cumulative daily doses exceeding 27 mg per day were not studied and may increase the risk for QTc interval prolongation. Therefore, the cumulative total daily dose of OLINVYK should not exceed 27 mg.

Increased plasma concentrations of OLINVYK may occur in patients with decreased Cytochrome P450 (CYP) 2D6 function or normal metabolizers taking moderate or strong CYP2D6 inhibitors; also in patients taking a moderate or strong CYP3A4 inhibitor, in patients with decreased CYP2D6 function who are also receiving a moderate or strong CYP3A4 inhibitor, or with discontinuation of a CYP3A4 inducer. These patients may require less frequent dosing and should be closely monitored for respiratory depression and sedation at frequent intervals. Concomitant use of OLINVYK with CYP3A4 inducers or discontinuation of a moderate or strong CYP3A4 inhibitor can lower the expected concentration, which may decrease efficacy, and may require supplemental doses.

Cases of adrenal insufficiency have been reported with opioid use (usually greater than one month). Presentation and symptoms may be nonspecific and include nausea, vomiting, anorexia, fatigue, weakness, dizziness, and low blood pressure. If confirmed, treat with physiologic replacement doses of corticosteroids and wean patient from the opioid.

OLINVYK may cause severe hypotension, including orthostatic hypotension and syncope in ambulatory patients. There is increased risk in patients whose ability to maintain blood pressure has already been compromised by a reduced blood volume or concurrent administration of certain CNS depressant drugs (e.g., phenothiazines or general anesthetics). Monitor these patients for signs of hypotension. In patients with circulatory shock, avoid the use of OLINVYK as it may cause vasodilation that can further reduce cardiac output and blood pressure.

Avoid the use of OLINVYK in patients with impaired consciousness or coma. OLINVYK should be used with caution in patients who may be susceptible to the intracranial effects of CO2 retention, such as those with evidence of increased intracranial pressure or brain tumors, as a reduction in respiratory drive and the resultant CO2 retention can further increase intracranial pressure. Monitor such patients for signs of sedation and respiratory depression, particularly when initiating therapy.

As with all opioids, OLINVYK may cause spasm of the sphincter of Oddi, and may cause increases in serum amylase. Monitor patients with biliary tract disease, including acute pancreatitis, for worsening symptoms.

OLINVYK may increase the frequency of seizures in patients with seizure disorders and may increase the risk of seizures in vulnerable patients. Monitor patients with a history of seizure disorders for worsened seizure control.

Do not abruptly discontinue OLINVYK in a patient physically dependent on opioids. Gradually taper the dosage to avoid a withdrawal syndrome and return of pain. Avoid the use of mixed agonist/antagonist (e.g., pentazocine, nalbuphine, and butorphanol) or partial agonist (e.g., buprenorphine) analgesics in patients who are receiving OLINVYK, as they may reduce the analgesic effect and/or precipitate withdrawal symptoms.

OLINVYK may impair the mental or physical abilities needed to perform potentially hazardous activities such as driving a car or operating machinery.

Although self-administration of opioids by patient-controlled analgesia (PCA) may allow each patient to individually titrate to an acceptable level of analgesia, PCA administration has resulted in adverse outcomes and episodes of respiratory depression. Health care providers and family members monitoring patients receiving PCA analgesia should be instructed in the need for appropriate monitoring for excessive sedation, respiratory depression, or other adverse effects of opioid medications.

ADVERSE REACTIONSAdverse reactions are described in greater detail in the Prescribing Information.The most common (incidence 10%) adverse reactions in Phase 3 controlled clinical trials were nausea, vomiting, dizziness, headache, constipation, pruritus, and hypoxia.MEDICAL INFORMATIONFor medical inquiries or to report an adverse event, other safety-related information or product complaints for a company product, please contact the Trevena Medical Information Contact Center at 1-844-465-4686 or email MedInfo@Trevena.com.You are encouraged to report suspected adverse events of prescription drugs to the FDA. Visit http://www.fda.gov/medwatch or call 1-800-FDA-1088.Please see Full Prescribing Information, including Boxed Warning.

About Trevena

Trevena, Inc. is a biopharmaceutical company focused on the development and commercialization of innovative medicines for patients with CNS disorders. The Company has one approved product in the United States, OLINVYK (oliceridine) injection, indicated in adults for the management of acute pain severe enough to require an intravenous opioid analgesic and for whom alternative treatments are inadequate. The Companys novel pipeline is based on Nobel Prize winning research and includes four differentiated investigational drug candidates: TRV045 for diabetic neuropathic pain and epilepsy, TRV027 for acute respiratory distress syndrome and abnormal blood clotting in COVID-19 patients, TRV250 for the acute treatment of migraine and TRV734 for maintenance treatment of opioid use disorder.

For more information, please visit http://www.Trevena.com

Forward-Looking Statements

Any statements in this press release about future expectations, plans and prospects for the Company, including statements about the Companys strategy, future operations, clinical development and trials of its therapeutic candidates, plans for potential future product candidates and other statements containing the words anticipate, believe, estimate, expect, intend, may, plan, predict, project, suggest, target, potential, will, would, could, should, continue, and similar expressions, constitute forward-looking statements within the meaning of The Private Securities Litigation Reform Act of 1995. Actual results may differ materially from those indicated by such forward-looking statements as a result of various important factors, including: the status, timing, costs, results and interpretation of the Companys clinical trials or any future trials of any of the Companys investigational drug candidates; the uncertainties inherent in conducting clinical trials; expectations for regulatory interactions, submissions and approvals, including the Companys assessment of discussions with FDA; available funding; uncertainties related to the Companys intellectual property; uncertainties related to the ongoing COVID-19 pandemic, other matters that could affect the availability or commercial potential of the Companys therapeutic candidates and approved product; and other factors discussed in the Risk Factors set forth in the Companys Annual Report on Form 10-K and Quarterly Reports on Form 10-Q filed with the Securities and Exchange Commission (SEC) and in other filings the Company makes with the SEC from time to time. In addition, the forward-looking statements included in this press release represent the Companys views only as of the date hereof. The Company anticipates that subsequent events and developments may cause the Companys views to change. However, while the Company may elect to update these forward-looking statements at some point in the future, it specifically disclaims any obligation to do so, except as may be required by law.

For more information, please contact:

Investor Contact:

Dan FerryManaging DirectorLifeSci Advisors, LLCdaniel@lifesciadvisors.com(617) 430-7576

PR & Media Contact:

Sasha BennettAssociate Vice PresidentClyde GroupSasha.Bennett@clydegroup.com(239) 248-3409

Company Contact:

Bob YoderSVP and Chief Business OfficerTrevena, Inc.(610) 354-8840

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Trevena Announces Results from Respiratory Physiology Study of Head-to-Head Comparison of OLINVYK and IV Morphine in Elderly/Overweight Subjects -...

Physiology

PODCAST: Field Atlas Helps to Explore Career Options – Inside INdiana Business

Even though Hanover College senior Baylee Dwenger was in 4-H and FFA while growing up, her collegiate path steered her away from agriculture. Shes earning a degree in kinesiology and physiology, which seems far removed from the farm. Still, as an intern with AgriNovus Indianas Field Atlas ambassador program, she sees vast opportunities in the agbioscience sector.

During this weeks Ag+Bio+Science podcast presented by AgriNovus, Dwenger explained the correlation.

I just found the diversity within agbiosciences to be so surprising. And then how quickly its developing, Dwenger explained to Inside INdiana Business and podcast host Gerry Dick. Its crazy how, a few years ago, the technology we have now didnt even exist. So just thinking about how quickly its developing is great to me.

The Field Atlas is an online career exploration platform that enables students to explore agbioscience careers through online talent assessments, videos and profiles. The resource helps young job seekers and college students to identify jobs and companies that align with their personal and professional interests.

Sriya Nagubani, a sophomore studying pharmaceutical science at Purdue University, also served as an ambassador during the spring semester.

I didnt know much about the agbioscience sector at all. But once I started being an ambassador, I learned how up and coming it was, said Nagubani. I can see how fast its growing and how inclusive it is. There are many majors that can be a part of it.

Dwenger and Nagubani agree the Field Atlas is a perfect tool to help steer high school and college students towards the abundant job choices in Indianas agbioscience sector.

The new Ag+Bio+Science podcast comes out Monday morning. Click here to learn more. To access the full line-up of Inside INdiana Business podcasts, click here.

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PODCAST: Field Atlas Helps to Explore Career Options - Inside INdiana Business