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Can microRNAs in the Bloodstream Signal Cognitive Decline?

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In a cohort of pre-diagnosed, cognitively “normal” men, a recent Aging study compares expression levels of circulating miRNAs and their association with cognitive function and decline.

miRNAs, microRNAs, RNA illustration
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Can factors in our bloodstream tell us about our cognitive abilities or predict cognitive decline later in life? Among individuals with dementias, including Alzheimer’s disease (AD), studies have identified extracellular microRNAs (miRNAs) as potential biomarkers of cognitive impairment. In cognitively normal individuals, however, this association has not yet been fully investigated. 

“Understanding the functions of miRNAs in the earliest stages of cognitive decline will expand our knowledge on the biology of prodromal AD and the roles of circulating miRNAs in neurodegenerative diseases and could result in identification of therapeutic targets to guide drug development [17].”

In a new research paper, published on the cover of Volume 14, Issue 17, of Aging (listed as “Aging (Albany NY)” by Medline/PubMed and “Aging-US” by Web of Science), researchers Nicole Comfort, Haotian Wu, Peter De Hoff, Aishwarya Vuppala, Pantel S. Vokonas, Avron Spiro, Marc Weisskopf, Brent A. Coull, Louise C. Laurent, Andrea A. Baccarelli, and Joel Schwartz from Columbia University Mailman School of Public Health, University of California San Diego, VA Boston Healthcare System, Boston University School of Medicine, and Harvard TH Chan School of Public Health assessed the expression levels of extracellular miRNAs circulating in blood plasma taken from 530 cognitively normal men and investigated the association between these miRNAs and cognitive function. Their secondary goal was to investigate the genes and biological pathways associated with miRNAs linked to cognitive function or decline. The research paper was published on September 6, 2022, and entitled, “Extracellular microRNA and cognitive function in a prospective cohort of older men: The Veterans Affairs Normative Aging Study.”

The NAS Cohort

The Normative Aging Study (NAS) is a large longitudinal study that was established by the United States Department of Veterans Affairs in 1963. Since this study began, researchers have been diligently following-up with a cohort of 2,280 men from Massachusetts, United States. (Most of these men served in World War II and the Korean War.) Participants in NAS have comprehensive baseline examinations every three to five years to record their aging patterns, including global cognitive function assessments using the Mini-Mental State Examination (MMSE). The average age of this veteran cohort is currently 72 years old.

The Study

In the present study, blood samples were collected from 530 NAS participants between the years 1996 and 2013—totaling 1,331 in-person visits; equal to 2,471 years of follow-up. Plasma miRNAs were profiled using small RNA sequencing (RNA-seq). Linear regression and linear mixed models were used to assess the expression of 381 miRNAs and their association with current cognitive function and rate of change in cognitive function.

Of the 381 plasma miRNAs detected in at least 70% of the samples collected, two miRNAs were associated with higher baseline MMSE scores. Thirty-three miRNAs were associated with the rate of change in MMSE over time. KEGG enrichment analysis and repeated measures analyses were used to explore potential regulatory targets of the significant plasma miRNAs. The genes targeted by the significant miRNAs were primarily associated with prion diseases, fatty acid biosynthesis, Hippo signaling, ECM-receptor interactions, and TGF-β signaling pathways. 

“Taken together, our results suggest that various plasma extracellular miRNAs are associated with global cognitive function among cognitively ‘normal’ men. If they were to play a causal role in cognitive decline, it would likely be through pathways that regulate synaptic plasticity, cell death, the response to injury, and energy homeostasis. Extracellular miRNAs may also contribute to greater rates of cognitive decline possibly through involvement in the prion-like propagation of AD lesions or in hindering their neuroprotective role of curbing AD-like pathology.”

Conclusion

These findings suggest that plasma miRNA levels are associated both with global cognition and the rate of change in global cognition among cognitively normal older men. The researchers were forthcoming about the limitations of this study, especially in regard to the study population and the MMSE scoring.  Still, this study highlights the potential of miRNAs as biomarkers for cognitive function and decline in older men and underscores the importance of elucidating the mechanisms by which extracellular miRNAs influence cognition.

“Additional research is needed to identify the biological pathways influenced by expression of these extracellular miRNAs, investigate relationships with CNS miRNA expression, and examine the potential impacts of circulating miRNAs on other neurological outcomes.”

Click here to read the full research paper published by Aging.

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Aging is an open-access journal that publishes research papers bi-monthly in all fields of aging research. These papers are available at no cost to readers on Aging-us.com. Open-access journals have the power to benefit humanity from the inside out by rapidly disseminating information that may be freely shared with researchers, colleagues, family, and friends around the world.

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Trending With Impact: Neuromodulation in Alzheimer’s Disease Treatment

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Dr. Fabrizio Vecchio wrote about the potential synergistic effects of neuromodulation combined with cognitive training to treat Alzheimer’s disease.

Neuromodulation in Alzheimer’s Disease Treatment

The Trending With Impact series highlights Aging (Aging-US) publications that attract higher visibility among readers around the world online, in the news, and on social media—beyond normal readership levels. Look for future science news about the latest trending publications here, and at Aging-US.com.

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Many neurodegenerative disorders among elderly populations share some common characteristics. In dementias, for example, neurons and glial cells undergo a progressive loss of structure or function in the brain and spinal cord. Alzheimer’s disease (AD) is the most common form of dementia and the main cause of cognitive impairment. Studies have confirmed that cognitive treatments, such as cognitive stimulation, training and rehabilitation, can improve brain function by increasing brain plasticity.

Recently, researcher Fabrizio Vecchio, from IRCCS San Raffaele Roma‘s Brain Connectivity Laboratory, discussed innovative treatment options for Alzheimer’s disease. On April 27, 2022, Dr. Vecchio published his new editorial paper in Volume 14, Issue 9, of Aging (Aging-US), entitled, “Cognitive training and neuromodulation for Alzheimer treatment.”

“Neuromodulation techniques are having a growing consensus as a therapeutic approach of incipient and mild to moderate dementia because of their capability to be modulated both in space, i.e. in different cortical and subcortical areas of the brain, and time.”

Neuromodulation

Neuromodulation is a considerably recent development in the medical field. This promising treatment option therapeutically alters nerve activity within specific neurological sites of the body using the targeted delivery of electrical stimulation or chemical agents. Neuromodulation can be used not only for patients with dementia but also for those with a number of other disorders, including chronic pain, epilepsy and psychiatric disorders. However, the demonstrated value of cognitive treatments has not been discounted by Dr. Vecchio. In his editorial paper, he discussed the potential synergistic effects of neuromodulation combined with cognitive training (COG). 

“Together with cognitive treatments one of the possible innovative strategies to be undertaken is the neuromodulation that involves non-invasive brain stimulation techniques (NIBS) such as transcranial magnetic stimulation (TMS), transcranial direct current stimulation (tDCS) and transcranial alternating current stimulation (tACS).”

Dr. Vecchio described his recent study on repetitive transcranial magnetic stimulation (rTMS) combined with cognitive training. In this randomized, double-blind, sham-controlled trial, researchers evaluated the efficacy of rTMS-COG treatment in Alzheimer’s patients. Before, immediately after and 40 weeks after rTMS-COG treatment, patients were assessed using neuropsychological and electroencephalography (EEG) examinations. The researchers evaluated six regions of the brain and analyzed neuropsychological and neurophysiological data derived from EEG. After six weeks of intensive daily treatment, immediate results showed an improvement in cognitive scales. At the 40-week follow-up evaluation, improvements in brain connectivity emerged.

“Based on these assumptions and promising results, particularly of rTMS and COG, some researchers hypothesized that a treatment combining rTMS and COG may result in synergic effects more effective [in] respect to applying the two therapies separately.”

Conclusion

Although more research must be conducted to confirm the clinical efficacy of neuromodulation for the treatment of Alzheimer’s disease, initial results are promising. Cognitive treatments should not be discounted either, as they have been shown to improve brain function. Dr. Vecchio suggests a potentially efficacious combination of neuromodulation and cognitive training that may offer significant benefits for patients with Alzheimer’s disease.

“In conclusion, rTMS combined with cognitive training, can be regarded as a potentially useful treatment for AD, not modifying the neuropathological changes, but slowing down their effects on brain networks and providing important groundwork for future studies to build upon. Derived EEG parameters can be awarded the role of diagnostic and predictive biomarkers of AD progression.”

Click here to read the full editorial paper published by Aging (Aging-US).

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Aging (Aging-US) is an open-access journal that publishes research papers bi-monthly in all fields of aging research. These papers are available at no cost to readers on Aging-us.com. Open-access journals have the power to benefit humanity from the inside out by rapidly disseminating information that may be freely shared with researchers, colleagues, family, and friends around the world.

For media inquiries, please contact [email protected].

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Trending With Impact: Cognitive Decline Predicted from Middle-Age

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Researchers investigated epigenetic and brain aging markers in middle-age for their potential to predict cognitive decline.

Trending With Impact: Cognitive Decline Predicted from Middle-Age

The Trending With Impact series highlights Aging (Aging-US) publications that attract higher visibility among readers around the world online, in the news, and on social media—beyond normal readership levels. Look for future science news about the latest trending publications here, and at Aging-US.com.

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Aging seems nearly synonymous with brewing cognitive decline, but does it have to be? There are interventions that may help preserve cognitive function with age, however, the first order of business is identifying early biological aging markers that present before symptoms begin emerging. Mid-life biomarkers that can indicate accelerated aging and predict age-related cognitive decline (including Alzheimer’s disease and dementia) may provide humans with enough time to course-correct and improve our quality of life in old age.

The latest to endeavor in search of these early aging markers are researchers from Northwestern University Feinberg School of Medicine, University of Texas Health Science Center at San Antonio, University of Pennsylvania, Boston University School of Medicine, National Institute on Aging from the National Institutes of Health, University of Minnesota, Columbia University Mailman School of Public Health, Kaiser Permanente Division of Research, University of Texas at Austin, University of California San Francisco, and the San Francisco Veterans Affairs Medical Center. Their new research study was published in Aging (Aging-US) as the cover paper in Volume 14, Issue 4, on February 27, 2022. The paper is entitled, “Mid-life epigenetic age, neuroimaging brain age, and cognitive function: coronary artery risk development in young adults (CARDIA) study.”

The Study

In this study, the researchers looked at the associations between cognitive function, epigenetic age and age acceleration measures (using DNA methylation), and brain imaging data in a biracial cohort involving 1,676 healthy human participants. These participants were derived from the Coronary Artery Risk Development in Young Adults (CARDIA) study. The CARDIA study began in 1985 with the aim of tracking changes in cardiovascular disease risk factors among thousands of young-adult to middle-age participants. The average age of participants in this current study was 40 years old.

Participants were evaluated for cognitive function using three tests: the Rey Auditory Verbal Learning Test (RAVLT), Trail Making Test B-A (TMTB-A) and the Digit Symbol Coding Test (DSCT). The researchers assessed and re-analyzed the cohort twice (up to 15 years apart). Data were generated for two separate sub-studies. The first sub-study looked specifically at DNA methylation (DNAm) data using GrimAge, PhenoAge, Hannum’s DNAm Age, and Horvath’s DNAm Age. The second sub-study collected neuroimaging data from participants using magnetic resonance imaging (MRI) scans.

“While blood-derived epigenetic aging markers have shown predictive value years before age-related diseases occur [21–23], biological aging rates can differ across organ systems, so predictors derived directly from the brain may hold unique information for cognition [24, 25].”

The researchers note that aging-related brain atrophy occurs in a predictable manner across the human lifespan. Therefore, brain atrophy is the measure of brain aging identified by MRI scans in this study. To translate the atrophy of brain structures into a biomarker of aging, the team leveraged machine-learning algorithms to generate a composite age-related morphological index called the Spatial Pattern of Atrophy for Recognition (SPARE) of Brain Age (SPARE-BA).

“The goal of the present study was to quantify the associations of epigenetic age acceleration and SPARE-BA acceleration with subsequent cognitive performance in a biracial cohort (~40% Black participants and ~60% White participants) of middle-aged adults with 5 to 15 years of follow up.”

The Results

Out of the four epigenetic aging markers examined, the researchers found that GrimAA was uniquely capable of closely predicting worse cognitive outcomes in this middle-aged CARDIA population. In the long term, biomarkers of epigenetic aging were more stable predictors of cognitive decline than the brain aging biomarker. However, changes in SPARE-BA and the SPARE-BA acceleration (SPARE-BAA) index showed stronger associations with cognition over time than any of the epigenetic aging markers. The researchers believe this is because the brain age/aging biomarkers may be more temporally dynamic in association with cognitive decline. When the researchers compared each biomarker’s association with cognition, they found that a combined model of GrimAA and SPARE-BAA demonstrated an improved ability to predict lower cognitive performance.

“GrimAA and SPARE-BAA were not correlated with one another, indicating that they capture distinct facets of biological aging.”

Conclusion

The researchers were forthcoming about limitations in this study. The epigenetic and brain imaging markers were mostly derived from different participants within the study, therefore, other unmeasured factors may have contributed to the study results. Baseline cognitive data was not recorded at younger ages and epigenetic markers were collected at different time points than cognitive and neuroimaging outcomes. These differences inhibited cross-sectional analysis of epigenetic and brain aging. In addition, predictions may be better validated with extended follow-up periods. Nonetheless, this research may have identified two profoundly useful indicators of cognitive decline that could be put to use as early as middle-age—a potential “tipping point” in the human lifespan; when interventions may still prevent irreversible cognitive impairment.

“With further validation, epigenetic and brain aging markers may help aid timely identification of individuals at risk for accelerated cognitive decline and promote the development of interventions to preserve optimal functioning across the lifespan.”

Click here to read the full research paper published by Aging (Aging-US).

AGING (AGING-US) VIDEOS: YouTube | LabTube | Aging-US.com

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Aging (Aging-US) is an open-access journal that publishes research papers bi-monthly in all fields of aging research. These papers are available to read at no cost to readers on Aging-us.com. Open-access journals offer information that has the potential to benefit our societies from the inside out and may be shared with friends, neighbors, colleagues, and other researchers, far and wide.

For media inquiries, please contact [email protected].

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Trending With Impact: Can Singing Improve Aging?

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In a two-year study, researchers compared the effects of choral singing with the effects of health education in an elderly cohort.

Couple singing

The Trending With Impact series highlights Aging (Aging-US) publications that attract higher visibility among readers around the world online, in the news, and on social media—beyond normal readership levels. Look for future science news about the latest trending publications here, and at Aging-US.com.

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There may be many paths that lead to the cessation of aging, or there may only be one—this mystery has yet to reveal itself. However, there is a wide array of evidenced methods capable of preserving youth by slowing down the aging process, and even mildly reversing it. Some known natural interventions are healthy diets, consistent exercise and avoiding aging-related risk factors, including carcinogens such as alcohol, cigarettes and excess sun exposure. Researchers have also studied less intuitive repetitive behaviors that appear to improve the cognitive decline associated with aging. For example, in a study published in 2015, researchers found that active singing led to cognitive improvements in participants with dementia. 

“People engaging in lifelong music-making have been found to have better cognitive outcomes later in life.”

In a research study published in 2020, 30 researchers—from National University of Singapore, Singapore Institute for Clinical Sciences, National University Health System, University of Cambridge, University of London, Singapore Immunology Network, Maurine Tsakok Inc, Voices of Singapore Choral Society, Presbyterian Community Services, NTUC Health Co-operative Limited, Beijing Chui Yang Liu Hospital, Fudan University, Massachusetts General Hospital, Harvard Medical School, Nanyang Technological University, Imperial College London, and Genome Institute of Singapore—conducted the world’s first study designed to compare the impact of choral singing versus health education on cognitive function and aging in a randomized controlled trial (RCT). Their trending research paper was published by Aging (Aging-US) in 2020 and entitled, “Effects of choral singing versus health education on cognitive decline and aging: a randomized controlled trial”.

“In this RCT, we hypothesized that choral singing would improve cognitive health and/or reduce cognitive decline in elderly with high risk of dementia.”

The Study

This study, based out of Singapore, was designed for half of the subjects to participate in a choral singing program for one hour every week, over the course of two years. This program was conducted at the National University of Singapore’s Yong Siew Toh Conservatory of Music. In these sessions, professional musicians taught the fundamental concepts and mechanics of “good” singing, including breathing techniques, harmonies, memorization and listening skills. Participants also prepared to sing in public performances to promote motivation, purpose, pride and accomplishment.

“Each session incorporated the musical, social, and physical aspects of choral singing.”

Forty-seven participants were randomly assigned to the choral singing intervention (CSI) arm, and 46 were assigned to the health education program (HEP) arm. Parallel to the CSI participants, HEP participants completed a weekly one-hour health education session at the Training and Research Academy at Jurong Point for two years. Family physicians, specialist clinicians and community nurses facilitated these sessions, which included short talks on health-related topics, group activities, memory work, and physical activities (not including singing).

At baseline, the researchers collected demographic and clinical characteristics from each participant. Characteristics included: age, gender, education, marital status, living situation, status of hypertension, diabetes mellitus, heart diseases, average composite cognitive test score, Singapore Modified Mini-Mental State Examination (SM-MMSE) score, and Geriatric Depression Scale (GDS). Follow-up assessments were conducted at two additional times throughout the study—after year one and year two of the programs. Researchers assessed the effects of both these programs on brain imaging, immune system and oxidative damage markers.

“Our study is the first randomized trial in the world that systematically assessed the effects of singing on cognitive decline in aging and the potential effects on brain imaging, immune system and oxidative damage markers.”

Results and Conclusion

The researchers were forthcoming about limitations in this study. The cohort was small and they did not include a non-intervention control arm; researchers were only able to compare the effects of choral singing to the effects seen in the health education cohort. The team did, however, observe an increase in the mean composite cognitive test scores among participants in the singing group, and a decrease in the mean composite cognitive test scores among participants in the health education group. They did not observe differences in brain aging, oxidative damage or immunosenescence.

“Our findings from the very first RCT on this topic suggest that choral singing is a potentially useful intervention for the promotion of cognitive health in aging. Choral singing is a safe and enjoyable activity, and is likely to be embraced by the community. Policy makers may consider promoting choral singing for healthy and active aging of seniors in the community. This is especially relevant for countries where existing resources are available.”

Click here to read the full research paper published by Aging (Aging-US).

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Aging (Aging-US) is an open-access journal that publishes research papers monthly in all fields of aging research and other topics. These papers are available to read at no cost to readers on Aging-us.com. Open-access journals offer information that has the potential to benefit our societies from the inside out and may be shared with friends, neighbors, colleagues, and other researchers, far and wide.

For media inquiries, please contact [email protected].

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Risks for Dementia and Mortality: Sleep Disturbance and Deficiency

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Researchers used nationally representative data to examine the relationship between sleep disturbance and deficiency and their risk for incident dementia and all-cause mortality among older adults.

Person sleeping in bed and alarm clock in the foreground
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Are serious health consequences looming for those with trouble sleeping? Based on a large sum of available research, the answer appears to be yes—poor sleep poses an increased risk of dementia and all-cause mortality. But what defines poor sleep? Conflicting results have been reported by researchers regarding the characteristics of sleep when examining incident dementia and all-cause mortality. For instance, one meta-analysis suggests that sleeping fewer than five hours (short sleep) and longer than nine hours (long sleep) per night is associated with greater risk of mortality. Another meta-analysis finds that only longer than nine hours is associated with greater risk of mortality.

“Research on sleep disturbance and deficiency and all-cause mortality therefore has shown conflicting results. Further, few studies have included a comprehensive set of sleep characteristics in a single examination of incident dementia and all-cause mortality.” 

From Brigham and Women’s Hospital, Harvard Medical School, and Boston College, based out of Massachusetts, United States, a team of researchers saw the need to address the gaps in this research and developed a new study. They organized a single examination of the relationships between a comprehensive set of sleep characteristics and incident dementia and all-cause mortality. This paper was entitled, “Examining sleep deficiency and disturbance and their risk for incident dementia and all-cause mortality in older adults across 5 years in the United States,” and published in Aging’s Volume 13, Issue 3 in February 2021.

The Study

The researchers collected baseline data from the National Health and Aging Trends Study (NHATS). The NHATS is a nationally-representative longitudinal study of Medicare beneficiaries (65 years and older) in the United States. The data were collected from a randomly selected subset of 2,812 participants from the NHATS population that were administered sleep questionnaires in 2013 and 2014.

“Participants with dementia at baseline (year 2013) were excluded (n = 202) for a sample of 2,812 with sleep data in either 2013 or 2014.”

The sleep characteristics measured from the questionnaire were: sleep duration, sleep latency, difficulty maintaining alertness, sleep quality, napping frequency, and snoring. First, participants rated their memory and performed a memory-related activity to assess their cognitive capacity and screen for incident dementia. Body weight was reported by participants annually, and diagnosis of heart attack, heart disease, hypertension, arthritis, diabetes, stroke, and cancer were also self-reported. Annual interviews were conducted to record instances of participant mortality. The researchers used Cox proportional hazards modeling and controlled for confounders to examine each sleep characteristic and outcome.

Results

“Overall, our findings show a strong relationship between several sleep disturbance and deficiency variables and incident dementia over time.”

In the results adjusted for confounders, the team found that longer time to fall asleep and shorter sleep duration predicted incident dementia. They also found that short sleep duration, difficulty maintaining alertness, napping, and poor sleep quality predicted all-cause mortality. Given that short sleep duration was a strong predictor for both incident dementia and all-cause mortality, the researchers suggest that this may be the most important sleep characteristic related to adverse outcomes among older adults. 

“The association observed in our study between short sleep (5 hours or less) and incident dementia screening may be understood via the research drawing upon animal models to demonstrate brain toxin removal during sleep [24].”

Another fascinating finding from this study was the difference between unadjusted and adjusted results for long sleep. As mentioned, previous studies have shown that long sleep is associated with both incident dementia and all-cause mortality. However, after the researchers adjusted for confounders, such as age and chronic conditions, the association between long sleep and incident dementia and all-cause mortality disappeared. The relationship between short sleep and both incident dementia and all-cause mortality remained significant even after full adjustment. These findings stand in contrast to the meta-analyses initially mentioned that have found associations between both short and long sleep and all-cause mortality in adults. The researchers suggest the cause may be that long sleep is a reflection of underlying disease.

“The most parsimonious explanation for the disappearance of the effect of long sleep on dementia and mortality in adjusted models is that the deleterious impact of long sleep is a reflection of underlying disease.”

Conclusion

The researchers confirm that addressing the sleep disturbance and deficiency variables in this study may have a positive impact on risk for incident dementia and all-cause mortality among older adults.

“Also, future research may consider the development of novel behavioral interventions to improve sleep among older adults.”

Click here to read the full study, published on Aging-US.com.

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Aging is an online open-access journal that publishes research papers monthly in all fields of aging research and other topics. These papers are available to read at no cost to readers on Aging-us.com. Open-access journals offer information that has the potential to benefit our societies from the inside out and may be shared with friends, neighbors, colleagues, and other researchers, far and wide.

For media inquiries, please contact [email protected].

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