Goal 2: Reduce Human Disease

Clinical Trials in Pediatric Sleep Disorders - Effect of adenotonsillectomy

Effect of adenotonsillectomy on behavioral and cardiovascular outcomes in children with primary snoring

Submitted by (@nhlbiforumadministrator)

Is this idea a Compelling Question (CQ) or Critical Challenge (CC)? : Compelling Question (CQ)

Details on the impact of addressing this CQ or CC :

The recent NHLBI Childhood Adenotonsillectomy (CHAT) study showed highly significant behavioral improvements in children with obstructive sleep apnea syndrome . This study included children with an apnea hypopnea index as low as 2/hr. Many small or suboptimally controlled studies suggest that even primary snoring can affect behavior. If large randomized controlled trials confirm this finding, it will radically affect the treatment of the estimated 10% of children who snore.

Name of idea submitter and other team members who worked on this idea : ATS Member

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Goal 2: Reduce Human Disease

Elucidate the different causes of circadian disorders, and tailor the treatment to the cause

There are several possible physiological causes of Circadian Rhythm Sleep-Wake Disorders (CRSWDs), including lack of sensitivity to light, over-sensitivity to light, deficiencies in the ipRGC cells of the retina, lack of melatonin production, long elimination time of melatonin, long intrinsic circadian period, differences in timing of sleep relative to internal circadian rhythms, differences in tolerance to phase mismatch, ...more »

Submitted by (@peter0)

Is this idea a Compelling Question (CQ) or Critical Challenge (CC)? : Compelling Question (CQ)

Details on the impact of addressing this CQ or CC :

By analogy, a patient may complain of abdominal pain. This could be due to infection, food poisoning, ulcers, gall bladder, cancer, etc. Imagine if we treated all these patients by removing their gall bladder. There would be some successes, and many failures. Surveys of the literature would be unable to conclude that there's a well established successful treatment. That's the state of treatment of CRSWDs today.

 

CRSWDs such as Delayed Sleep-Wake Phase Disorder and Non-24-Hour Sleep-Wake Disorder cause suffering and inability to work normal hours, and often result in otherwise productive individuals being unable to find jobs and having to seek disability support. Those who force themselves into a conventional schedule often end up with chronic health problems, resulting in further cost to themselves and to society.

Feasibility and challenges of addressing this CQ or CC :

A major challenge is to diagnose not only a CRSWD but also its underlying cause. Improved biomarkers are essential to this effort, and are the subject of other Questions/Challenges. So too are a better understanding of the effects of light and melatonin on patients with these disorders, with the differing underlying impairments studied separately. With improvements in genetic testing and analysis, and improved sensor technology and automated data analysis, we are at the threshold of being able to study these underlying causes of CRSWDs.

Name of idea submitter and other team members who worked on this idea : Peter Mansbach

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Goal 2: Reduce Human Disease

Can Psychological Science Improve Weight Loss?

Will sensitivity to the psychological aspects of obesity, including lifestyle priorities and motivations, improve the efficacy of long-term effectiveness of weight loss and obesity prevention interventions?

Submitted by (@nhlbiforumadministrator)

Is this idea a Compelling Question (CQ) or Critical Challenge (CC)? : Compelling Question (CQ)

Details on the impact of addressing this CQ or CC :

A primary focus on principles of psychology may result in significantly improved control of the obesity epidemic. Effective interventions could reduce the risk of diabetes, sleep apnea, and hypertension. This research could also affect clinical practice guidelines for weight loss and obesity treatment.

Feasibility and challenges of addressing this CQ or CC :

Psychological science has been successful in developing effective treatments for a number of conditions, including sleep disorders, depressive symptoms, anxiety and phobias. Many of the behavioral principles employed in such interventions (e.g., cognitive restructuring, motivational methods) could be translated for the prevention and treatment of obesity within a reasonable time frame. Additional attention should be directed to the needs of population subgroups in which obesity is most prevalent.

In their Viewpoint article on weight loss intervention research, Pagoto and Appelhans (JAMA, 2013, see attachment) question whether a continued focus on dietary factors in research on weight loss and obesity is warranted. Their commentary raises the importance of attention to the individual psychological characteristics that influence adherence to weight loss interventions rather than dietary composition.

Name of idea submitter and other team members who worked on this idea : NHLBI Staff

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Goal 2: Reduce Human Disease

Sleep Apnea - Trial of Treatment vs No Treatment of Snoring

Randomized trial of the treatment of snoring vs. no treatment.

Submitted by (@nhlbiforumadministrator)

Is this idea a Compelling Question (CQ) or Critical Challenge (CC)? : Compelling Question (CQ)

Details on the impact of addressing this CQ or CC :

Snoring is increasingly implicated as potential disruptor of carotid artery intima and function. Repetitive vibratory trauma has been hypothesized as cause of this. Intermediate markers of cardiovascular risk such as intimal thickening have been linked to snoring as independent from sleep apnea. This field is ready for a larger scale trial in which snoring is intervened upon and IMT is measured as one of several endpoints. Other endpoints could be QOL measures, sleepiness, etc. Another reason this field is ready to be addressed is we now have inexpensive nasal resistors, which treat snoring without the need for surgery, oral appliances, or CPAP. These would allow the sleep medicine field to do a trial of such therapy vs. a sham therapy.

Name of idea submitter and other team members who worked on this idea : ATS Member

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Goal 2: Reduce Human Disease

Role of sleep quality in critical care

Would improving sleep and circadian rhythms in the critical care setting result in improved patient outcomes (e.g., reduce severity of infection, duration of intubation, length of hospital stay)?

Submitted by (@nhlbiforumadministrator)

Is this idea a Compelling Question (CQ) or Critical Challenge (CC)? : Compelling Question (CQ)

Name of idea submitter and other team members who worked on this idea : NHLBI Staff

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Goal 2: Reduce Human Disease

Sleep Apnea

Does alteration of sleep duration improve patient outcomes in sleep apnea?

Submitted by (@nhlbiforumadministrator)

Is this idea a Compelling Question (CQ) or Critical Challenge (CC)? : Compelling Question (CQ)

Name of idea submitter and other team members who worked on this idea : ATS Member

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Goal 2: Reduce Human Disease

What are the biological consequences of sleep loss or disruption and how can they best be avoided?

Arousals in obstructive sleep apena (OSA) are life saving, but the associated disruption of sleep is now thought to cause cognitive impairment, increased risk of high blood pressure and atherosclerosis, as well as glucose intolerance and metabolic syndrome. The mechanisms for these downstream effects, however, are not well understood. Can these specific pathophysiological mechanisms be identified, and can ways for mitigating ...more »

Submitted by (@csaper)

Is this idea a Compelling Question (CQ) or Critical Challenge (CC)? : Critical Challenge (CC)

Details on the impact of addressing this CQ or CC :

By identifying the mechanisms by which sleep loss or disruption affects cognitive, cardiovascular, and metabolic function, we hope to find key regulatory points for which interventions may be developed. For example, if we can allow respiratory reflex responses to reopen the airway without EEG activation during OSA, we may be able to forestall some of the cognitive consequences of inadequate sleep. If we can prevent the autonomic responses associated with the EEG arousals and increases in respiratory drive, we may be able to block the repetiive elevations of blood pressure that lead to long term hypertension and accelerated atherosclerosis. If we can identify the reason for metabolic derangement associated with OSA, we may find, for example, that it is due to circadian misalignment and find ways to realign the sequence of metabolic events with the actual wake-sleep patterns of the patients. Finally, if we can potentiate the respiratory reflexes that re-establish the airway in OSA, without triggering the other components of arousals, we may be able to minimize or prevent the apneas. While current methods for treating OSA (e.g., CPAP and dental appliances) help many people, many others cannot tolerate these devices, and we require additional modes of therapy to mitigate the consequences of OSA.

Feasibility and challenges of addressing this CQ or CC :

The methods are currently available to address the questions that are raised above. The revolution in methods for evaluating the functions of neural circuits, using optogenetics and chemogenetics, for example, should allow us to identify brain circuits that are involved in the various components of the reflex responses to apnea. We can examine their neurotransmitters and receptors, and design new therapies based on manipulating CNS circuitry. Methods for assessing ongoing autonomic, respiratory, and metabolic responses in genetically mutated mouse modesl may require further miniaturization of various physiological methods, but this field is also rapidly advancing. Finally, methods for examining ongoing changes in neuronal activity in the living brain of awake mice are rapidly advancing.

Name of idea submitter and other team members who worked on this idea : Clifford B Saper, MD, PhD

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Goal 2: Reduce Human Disease

Sleep and obesity

What characteristics of sleep relate to obesity and does improving sleep using medication help with changes linked to obesity and in the end with weight?

Submitted by (@helenahillmanlaroche)

Is this idea a Compelling Question (CQ) or Critical Challenge (CC)? : Compelling Question (CQ)

Details on the impact of addressing this CQ or CC :

We are getting more information that sleep is linked to obesity. Those of us treating obesity also try to address sleep but often need to try medication in those with chronic insomnia. Whether this will help with weight or perhaps make it worse and whether one medication might be better to choose over another are questions that impact medical practice.

Name of idea submitter and other team members who worked on this idea : Helena Laroche

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Goal 2: Reduce Human Disease

Understanding of chronobiological systems

We know that all life functions are based on circadian and other rhythms; chronobiological systems are interdependent in intricate ways. Disturbances and disorders in one part of a system may affect other vital systems in unexpected but far-reaching ways. Many aspects of circadian rhythms and sleep-wake regulation in normal, healthy humans have been charted. Much of the knowledge thus gained is assumed to be valid also ...more »

Submitted by (@nma120)

Is this idea a Compelling Question (CQ) or Critical Challenge (CC)? : Critical Challenge (CC)

Details on the impact of addressing this CQ or CC :

As research on the extrinsic Shift Work Disorder shows, disturbances of the normal person’s sleep-wake cycle have consequences. These may include excessive daytime sleepiness, increased risk of traffic and other accidents, dysregulation of metabolic and other systems, obesity, increased risk of cancer, cardiovascular diseases, mood disorders and other diseases. Normal people trying to function on an abnormal schedule may develop conditions that lead to disability or death. Intrinsic CSWD patients suffer many of the same conditions as well as others.

 

These patients desperately need answers: Why am I like this, Do I dare have children, Will it get worse as I age, Can anything be done in addition to light boxes, scototherapy and melatonin, What is really the best timing in use of these treatments, Will I get disability?

 

Research on these patients will likely lead to discoveries that could be the target for future studies, thus impacting the modern fields of sleep and circadian rhythms research.

Feasibility and challenges of addressing this CQ or CC :

The intrinsic CSWDs are:

 

1) Lifelong DSWPD, delayed sleep-wake phase disorder

2) Adolescent DSWPD

3) ASWPD, advanced sleep-wake phase disorder

4) ISWRD, irregular sleep-wake rhythm disorder

5) Blind Non-24, N24SWRD, non-24-hour sleep-wake rhythm disorder in the blind

6) Sighted Non-24, N24SWRD in the non-blind.

 

I have listed 6 disorders; the usual number is 4. The first 2 on my list are usually combined, as are the last 2.

 

Some of the challenges, for different age groups and degrees of severity, are to:

--Find the causes of the disorders that are not yet explained

--Examine genetics and heritability

--Differentiate teens’ DSWPD as adolescent or persistent type

--Discover why adult DSWPD often precedes the development of Non-24 in sighted people

--Validate the use of light therapy, dark therapy and melatonin, including detailed recommendations for the timing and dosage of each of them

--Find other, more reliable, treatments

--Develop simple tests for determining persistent internal circadian desynchronization in an individual.

 

 

Some of the disorders have been explained, in whole or in part. There is great need for work with, at least, the following groups of patients:

-Adult DSWPS

-Pre-puberty children w/ DSWPS

-Adult sighted N24

-Pre-puberty sighted children w/ Non-24

 

Of these, adults with DSWPD are, of course, the most numerous. Research on that disorder may lead to results of interest for N24, these disorders being closely related.

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Goal 2: Reduce Human Disease

What causes the structural abnormalities that cause sleep apnea, and how can they be prevented?

It is estimated that up to 28% of the population suffer from sleep apnea, which impairs functioning and reduces quality of life, while increasing risk of accidents and a variety of cardiovascular, metabolic, and neuropsychiatric diseases. A large portion of sleep apnea cases are caused by abnormal oro-nasal-maxillo-mandibular features that result in crowding of the upper airway, making it vulnerable to collapsing or ...more »

Submitted by (@bmdixon)

Is this idea a Compelling Question (CQ) or Critical Challenge (CC)? : Compelling Question (CQ)

Details on the impact of addressing this CQ or CC :

Obstructive sleep apnea (OSA) is a common condition, which causes chronic fatigue and daytime sleepiness, as well as cognitive impairments affecting learning, concentration, and memory. Over the long term, it increases many health risks, including accidents, cardiovascular disease, and depression. OSA is characterized by partial, or complete, blockage of the airway during sleep, so that breathing repeatedly pauses or airflow is limited, causing repeated arousals from sleep. It is usually secondary to a narrow, or collapsible, airway due to either 1) obesity or overweight, or 2) abnormal morphology of the mandible or maxilla bones, which crowds facial structures, such as the tongue and nose, narrowing the pharynx. The causes of obesity are already being well studied, but there is relatively little research on the etiology of the structural abnormalities involved in OSA. Abnormalities of facial structure are widespread in the population causing, not only OSA, but also orthodontic problems that require many to get braces or have wisdom teeth extracted, and widespread temporomandibular joint (TMJ) problems. However, multiple studies have documented that these abnormalities are almost completely absent from populations living a preindustrial, agrarian or forager, lifestyle, making them a “disease of civilization”. In particular, the abnormalities are associated with consumption of a modern diet of processed foods during prenatal, infant, and early childhood development.

Feasibility and challenges of addressing this CQ or CC :

Current evidence implicates three factors in the development of these structural abnormalities: prenatal maternal nutrition (especially vitamin K2 status), breastfeeding vs. bottle-feeding, and frequency of consumption of tough foods after weaning (which provides exercise to the jaw). We need to form a large cohort and study orthodontic development prospectively from fetal development through mid-childhood, with data on diet, feeding practices, and physiological measures of nutrient status. Measurement methods are available using existing technologies to collect the necessary data on each of these measures. Determining the causes responsible for these structural abnormalities will enable further research to demonstrate effective methods of preventing them. Given that many patients with OSA are rendered so miserable by it that they undergo maxillomandibular advancement surgery to correct it, an expensive procedure with a lengthy recovery period, prevention would be a far better solution. This research will move us a big step closer to a future without sleep apnea and its formidable collection of negative effects on health and functioning.

Name of idea submitter and other team members who worked on this idea : Bonnie Dixon

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Goal 3: Advance Translational Research

NEW INFRASTRUCTURE FOR CLINICAL RESEARCH IN SLEEP AND CIRCADIAN DISORDERS

Much of the current clinical research on sleep and circadian research depends on cohorts designed for other purposes. While this has been helpful, such studies have limitations. These limitations are related to availability of in-depth phenotyping data and questions as to whether individuals identified in population studies are equivalent to those who present clinically with specific disorders. These concerns could ...more »

Submitted by (@jnoel0)

Is this idea a Compelling Question (CQ) or Critical Challenge (CC)? : Critical Challenge (CC)

Details on the impact of addressing this CQ or CC :

Sleep and circadian disorders are extremely common. For many of these we know little about the natural history, whether different subgroups exist and effects of current therapies. Thus, developing specific registries for common sleep and circadian disorders would provide a basis for addressing these questions.

 

For some aspects, e.g., studies of inadequate sleep, impact of snoring and circadian disruption, would be facilitated by developing a specific sleep/circadian cohort with in-depth phenotyping. This strategy has worked extremely well in other areas, e.g., cardiovascular disease. The lack of this type of cohort for sleep and circadian disorders is a barrier to progress in this area. The high prevalence of these disorders and their known public health significance argue that development of such a cohort would be a game changer and accelerate progress in this new area of medicine.

 

Such a cohort could address several compelling questions:

 

a. What is the natural history of short sleep across the lifespan?

b. What is the impact of snoring? Does it lead, as has been proposed, to vibration injury to carotid arteries with accelerated vessel wall damage?

c. Are there different subtypes of individuals with the different sleep and circadian disorders?

d. What is the natural history of shift-workers and what types of shifts lead to increased risk for cardiovascular disease?

Feasibility and challenges of addressing this CQ or CC :

Problems with sleep and circadian rhythm and the relevant disorders are common. There are multiple accredited sleep centers for clinical purposes in the United Sates. They use common phenotyping platforms that could be the basis of some aspects of addressing this critical challenge. Moreover, most CTSA programs have a sleep study component. There are patient support groups for sleep apnea, insomnia, restless legs syndrome and narcolepsy. Thus, these groups could be marshaled to help in this effort. There is already a Sleep Research Network that was founded by the field itself. It is currently based on volunteer effort and there are no resources to support it. It could be the basis for future activities in this area.

Name of idea submitter and other team members who worked on this idea : Sleep Research Society

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