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Untreated or undertreated pain is well established as a significant problem, but unidentified pain is a distinct construct that still needs to be clearly modeled or fully described. This paper aims to develop a conceptual model of unidentified pain in humans with the goal of future development of an unidentified pain risk tool. A multi-phase process was employed consisting sequentially of 1) brainstorming followed by consensus building, 2) peer-review and publication of an integrative theoretical review protocol for "unidentified pain," 3) conduct of the integrative review, and 4) a repeated brainstorming session to identify areas of risk for unidentified pain to produce a conceptual model. Brainstorming led to a consensus on "unidentified pain" as the concept of interest, followed by developing a review protocol. Twenty-four abstracts were reviewed after database searches, and four articles were included for full-text review. Three pain risk areas (hazards) were identified: cognition/communication problems, being alone or in the absence of a surrogate/proxy report, and the presence of known painful conditions or treatments and a conceptual model was developed. The hazards are posited to have the potential to both interact and be cumulative, increasing the risk for unidentified pain. There is currently no risk tool for assessing unidentified pain. The development of this conceptual model will be used for future development and psychometric testing of a tool to recognize the risk for unidentified pain in humans. PERSPECTIVE: This focus article describes the development a conceptual model for the concept of unidentified pain in humans. This pain may occur in individuals who experience one or more interactive and cumulative hazards: cognition/communication problems, being alone, absence of a surrogate/proxy report, or presence of known painful conditions or treatments., Competing Interests: Declaration of Competing Interest Jeffrey Boon reports funding from the Vanderbilt Institute for Clinical and Translational Research and the Sigma Theta Tau International Nursing Honor Society (Iota); support for attending meetings from the American Society for Pain Management Nursing. Stephen Bruehl reports funding from the National Institutes of Health; consulting fees from Akigai; and a leadership role in the Reflex Sympathetic Dystrophy Syndrome Association. Michael Carter reports a leadership role (chair, Board of Directors) for Frontier Nursing University. Michelle Failla reports funding from the National Institute of Neurological Disorders and Stroke, the National Institute on Aging; honoraria from the University of Pittsburgh; and an unpaid leadership role (special interest group) in the International Association for the Study of Pain. Todd Monroe reports funding from the National Institute on Aging; support for attending meetings from the National Institute on Aging. Ulrike Muench reports funding from the National Institute on Aging, University of California San Francisco Clinical and Translational Science Institute, California Health Care Foundation, and the Department of Health Care Access and Information; consulting fees from Brown University and the University of California San Francisco School of Medicine Technology Services. Diane Von Ah reports funding from the National Cancer Institute; honoraria from the Oncology Nursing Society; support for attending meetings from the Oncology Nursing Society, the Multinational Association of Supportive Care in Cancer, the Midwest Nursing Research Society, and the NIH NCI PDQ Supportive Care; leadership role in the Midwest Nursing Research Society. Other authors report no relationships or conflicts of interests., (Copyright © 2024 United States Association for the Study of Pain, Inc. Published by Elsevier Inc. All rights reserved.)

Lipid enals are electrophilic products of lipid peroxidation that induce genotoxic and proteotoxic stress by covalent modification of DNA and proteins, respectively. As lipid enals accumulate to substantial amounts in visceral adipose during obesity and aging, we hypothesized that biogenic lipid enals may represent an endogenously generated, and therefore physiologically relevant, senescence inducers. To that end, we identified that 4-hydroxynonenal (4-HNE), 4-hydroxyhexenal (4-HHE) or 4-oxo-2-nonenal (4-ONE) initiate the cellular senescence program of IMR90 fibroblasts and murine adipose stem cells. In such cells, lipid enals induced accumulation of γH2AX foci, increased p53 signaling, enhanced expression of p21 Cip1 , and upregulated the expression and secretion of numerous cytokines, chemokines, and regulatory factors independently from NF-κB activation. Concomitantly, lipid enal treatment resulted in covalent modification of mitochondrial proteins, reduced mitochondrial spare respiratory capacity, altered nucleotide pools, and increased the phosphorylation of AMP kinase. Lipid-induced senescent cells upregulated BCL2L1 (Bcl-xL) and BCL2L2 (Bcl-w). and were resistant to apoptosis while pharmacologic inhibition of BAX/BAK macropores attenuated lipid-induced senescence. In situ, the 4-HNE scavenger L-carnosine ameliorated the development of the cellular senescence, while in visceral fat of obese C57BL/6J mice, L-carnosine reduced the abundance of 4-HNE-modified proteins and blunted the expression of senescence biomarkers CDKN1A (p21 Cip1 ), PLAUR, BCL2L1, and BCL2L2. Taken together, the results suggest that lipid enals are endogenous regulators of cellular senescence and that biogenic lipid-induced senescence (BLIS) may represent a mechanistic link between oxidative stress and age-dependent pathologies., (© 2024 The Author(s). Aging Cell published by the Anatomical Society and John Wiley & Sons Ltd.)

Objectives: While chemotherapy is the primary contributor to cancer-related cognitive impairment (CRCI), interindividual differences in CRCI are not well-understood. Studies suggest that breast cancer (BC) survivors who are in pain are more likely to experience depression, which in turn contributes to CRCI, although this hypothesis is not yet tested. Therefore, this study aimed to investigate the relationship between pain and CRCI among BC survivors and the mediation effect of depression on this relationship., Methods: As a secondary analysis of a descriptive cross-sectional study investigating fatigue and preferred types of fatigue self-management in BC survivors recruited from five tertiary hospitals in South Korea; of the 229 participants, data on 186 who received chemotherapy were analyzed. Study participants were aged between 20 and 69 years, diagnosed with stage I to III, and treated with chemotherapy and/or radiation therapy. Measurement was done with Korean versions of the Cognitive Failure Questionnaire (to assess CRCI), Brief Pain Inventory (for pain severity and interference on daily functioning), and C-ESD (for depression). To assess bivariate relationships between pain, depression, and CRCI, Pearson correlation was used. A mediation analysis was used to examine the effect of depression on CRCI., Results: Significant associations were found among pain, depression, and CRCI (all P < 0.01). Furthermore, a mediation effect of depression was found on the association between pain and CRCI (severity, β = 1.26, SE = 0.38, 95% confidence intervals [0.60, 2.08]; interference, β = 1.53, SE = 0.32, 95% confidence intervals [0.95, 2.20])., Conclusion: Findings indicate that among BC survivors, those with higher pain tend to show higher depression and consequently had lower cognitive function., Implication for Nursing Practice: Oncology nurses may need to identify BC survivors with higher pain, and screening those survivors could be a strategy to identify those at higher risk for CRCI. Also, nurses should focus on managing depression to prevent and/or treat CRCI in BC survivors., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this article., (Copyright © 2024 Elsevier Inc. All rights reserved.)

The neurobiological underpinnings of gender differences in pain perception, and how these differences may be modified by age, are incompletely understood, placing patients at risk of suboptimal pain management. Using functional magnetic resonance imaging, we examined brain responses in the descending pain modulatory system (DPMS, specifically, dorsolateral prefrontal cortex, anterior cingulate cortex, insula, hypothalamus, amygdala, and periaqueductal gray, during an evoked pain task. We investigated the interaction of age and gender in our sample of healthy adults (27 females, 32 males, 30-86 years) on DPMS response. In a perceptually matched thermal pain paradigm, we investigated pain unpleasantness and neural responses for 3 heat pain percepts: just noticeable pain, weak pain, and moderate pain (MP). Females reported just noticeable pain at a lower temperature, but reported less unpleasantness at weak pain and MP percepts, compared to males. There was a significant age-by-gender interaction during moderate pain in the right anterior cingulate cortex and bilateral insula, such that, males had a stronger positive relationship between DPMS response and age compared to females in these regions. Our results indicate that differences in DPMS responses may explain some gender differences in pain perception and that this effect may change across the adult lifespan. PERSPECTIVE: Gender differences in pain have been well-documented but the brain mechanisms for these differences are still unclear. This article describes potential differences in brain functioning during different levels of pain that could explain differences in pain responses between men and women across the adult lifespan., (Copyright © 2024 United States Association for the Study of Pain, Inc. Published by Elsevier Inc. All rights reserved.)

Oral consumption of histidyl dipeptides such as l-carnosine has been suggested to promote cardiometabolic health, although therapeutic mechanisms remain incompletely understood. We recently reported that oral consumption of a carnosine analog suppressed markers of fibrosis in liver of obese mice, but whether antifibrotic effects of carnosine extend to the heart is not known, nor are the mechanisms by which carnosine is acting. Here, we investigated whether oral carnosine was able to mitigate the adverse cardiac remodeling associated with diet induced obesity in a mouse model of enhanced lipid peroxidation (i.e., glutathione peroxidase 4 deficient mice, GPx4 +/- ), a model which mimics many of the pathophysiological aspects of metabolic syndrome and T2 diabetes in humans. Wild-type (WT) and GPx4 +/- male mice were randomly fed a standard (CNTL) or high fat high sucrose diet (HFHS) for 16 weeks. Seven weeks after starting the diet, a subset of the HFHS mice received carnosine (80 mM) in their drinking water for duration of the study. Carnosine treatment led to a moderate improvement in glycemic control in WT and GPx4 +/- mice on HFHS diet, although insulin sensitivity was not significantly affected. Interestingly, while our transcriptomic analysis revealed that carnosine therapy had only modest impact on global gene expression in the heart, carnosine substantially upregulated cardiac GPx4 expression in both WT and GPx4 +/- mice on HFHS diet. Carnosine also significantly reduced protein carbonyls and iron levels in myocardial tissue from both genotypes on HFHS diet. Importantly, we observed a robust antifibrotic effect of carnosine therapy in hearts from mice on HFHS diet , which further in vitro experiments suggest is due to carnosine's ability to suppress collagen-cross-linking. Collectively, this study reveals antifibrotic potential of carnosine in the heart with obesity and illustrates key mechanisms by which it may be acting., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Berdaweel, Monroe, Alowaisi, Mahoney, Liang, Berns, Gao, McLendon and Anderson.)

Background: Vulnerable older adults living with Alzheimer's disease or Alzheimer's disease and related dementia (AD/ADRD) and chronic pain generally receive fewer pain medications than individuals without AD/ADRD, especially in nursing homes. Little is known about pain management in older adults with AD/ADRD in the community. The aim of the study was to examine opioid prescribing patterns in individuals with chronic pain by levels of cognitive ability in ambulatory care., Methods: We used the Medical Expenditure Panel Survey (MEPS), years 2002-2017, and identified three levels of cognitive impairment: no cognitive impairment (NCI), individuals reporting cognitive impairment (CI) without an AD/ADRD diagnosis, and individuals with a diagnosis of AD/ADRD. We examined any receipt of an opioid prescription and the number of opioid prescriptions using a logistic and negative binomial regression adjusting for sociodemographic and health characteristics and stratifying by three types of chronic pain (any chronic pain, severe chronic pain, and chronic pain identified through ICD 9/10 chronic pain diagnoses)., Results: Among people with any chronic pain, adjusted odds of receiving an opioid for people with CI (OR 1.41, 95% confidence interval 1.31-1.52) and AD/ADRD (OR 1.23, 95% confidence interval 1.04-1.45) were higher compared to NCI. Among people with chronic pain ICD 9/10 conditions, the odds of receiving an opioid were also higher for those with CI (OR 1.43, 95% confidence interval 1.34-1.56) and AD/ADRD (OR 1.48, 95% confidence interval 1.23-1.78) compared to NCI. Among those with severe chronic pain, people with CI were more likely to receive an opioid (OR 1.17, 95% confidence interval 1.07-1.27) relative to NCI (OR 0.89, 95% confidence interval 0.75-1.06). People with AD/ADRD experiencing severe chronic pain were not more likely to receive an opioid compared to the NCI group. Adjusted predicted counts of opioid prescriptions showed more opioids in CI and AD/ADRD in all chronic pain cohorts, with the largest numbers of opioid prescriptions in the severe chronic pain and ICD 9/10 diagnoses groups., Conclusions: The results suggest increased opioid use in people living with CI and AD/ADRD in the ambulatory care setting and potentially indicate that these individuals either require more analgesics or that opioids may be overprescribed. Further research is needed to examine pain management in this vulnerable population., (© 2023. The Author(s).)

Background: At-home self-collection of specimens has become more commonplace because of measures taken in response to the coronavirus pandemic. Self-collection of hair cortisol is important because chronic stress is present in many populations, such as older adults living with Alzheimer's disease and their family caregivers. For the evaluation of chronic stress, scalp hair can be used as a predictive biomarker because it examines the cumulative, retrospective stress from previous months., Objectives: The aim of the paper is to provide a study procedure for at-home, scalp hair self-collection for cortisol concentration analysis from dyads consisting of a person living with Alzheimer's disease and their family caregiver., Methods: After informed electronic consent is obtained, a package containing the necessary tools for self-collection of hair samples from the dyad is mailed to the participant's home. Participants are provided detailed print and video multimedia guides outlining how to obtain the hair samples. Ideally, the hair samples are obtained during the virtual data collection meeting with research personnel. Participants mail back the hair sample in a prepaid package to the biomedical laboratory for analysis., Discussion: At-home, self-collection of hair provides potential advantages such as reduced participant burden, especially for vulnerable populations where transportation and different environments are challenging. At-home sample collection options may increase research participation and can be applied to multiple research foci. Research considerations for dyads, such as people living with Alzheimer's disease and their caregivers, are discussed., Competing Interests: The authors have no conflicts of interest to report., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

For over 100 years, psychophysics ..÷ the scientific study between physical stimuli and sensation ... has been successfully employed in numerous scientific and healthcare disciplines, as an objective measure of sensory phenomena. This manuscript provides an overview of fundamental psychophysical concepts, emphasizing pain and research application..÷defining common terms, methods, and procedures.Psychophysics can provide systematic and objective measures of sensory perception that can be used by nursing scientists to explore complex, subjective phenomena..÷such as pain perception. While there needs to be improved standardization of terms and techniques, psychophysical approaches are diverse and may be tailored to address or augment current research paradigms. The interdisciplinary nature of psychophysics..÷like nursing..÷provides a unique lens for understanding how our perceptions are influenced by measurable sensations. While the quest to understand human perception is far from complete, nursing science has an opportunity to contribute to pain research by using the techniques and methods available through psychophysical procedures., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 American Society for Pain Management Nursing. Published by Elsevier Inc. All rights reserved.)

Introduction: Most definitions of pain require individuals experiencing pain to report their pain. There are three groups who may not always report pain including those who: (1) lack the cognitive ability to verbally communicate their pain and also lack a proxy/surrogate to report pain for them; (2) lack the cognitive ability to verbally communicate their pain but have a proxy to report the pain; and (3) have the cognitive ability to verbally report pain but are unable or unwilling to do so. Clinicians may not be able to determine which patients are at risk for unidentified pain. Therefore, in this study, we present a protocol for an integrative review with the aim of identifying existing theoretical approaches to understanding unidentified pain., Methods and Analysis: We propose a systematic overview of the existing theoretical approaches to understanding 'unidentified pain'. We will use Campbell and colleagues' criteria for systematic reviews of theory and the Preferred Reporting Items for Systematic Review and Meta-Analysis Protocols guidelines. Our search will be broad to cover theoretical approaches to 'unidentified pain' using MEDLINE, CINAHL, Embase and Google Scholar. Covidence systematic review software will be used for data extraction and analysis. Then, qualitative content analysis will take place. The content analysis will be presented as a narrative., Ethics and Dissemination: No human or animal subjects will be involved. The results are to be published in peer-reviewed journals and presented at conferences in the USA and internationally., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Cultural stereotypes that equate aging with decreased competence and increased forgetfulness have persisted for decades. Stereotype threat (ST) refers to the psychological discomfort people experience when confronted by a negative, self-relevant stereotype in a situation where their behavior could be construed as confirming that belief. The purpose of this study was to examine the relationships of ST on memory performance in older adults over 24 months. The ST levels on average significantly declined, or improved in the memory training, but not the health training group. Although not significant at the .01 level, the bivariate correlation indicated that change in ST was moderately related to change in verbal memory, suggesting the possibility that improvements (or reductions) in ST may be related to increases in verbal memory scores. We discovered that the unique contribution of ST into the memory performance of healthy older adults offers a possible malleable trait.

Background: Pain continues to be underrecognized and undertreated in people with Alzheimer's disease (AD). The periaqueductal gray (PAG) is essential to pain processing and modulation yet is damaged by AD. While evidence exists of altered neural processing of pain in AD, there has not been a focused investigation of the PAG during pain in people with AD., Purpose: To investigate the role of the PAG in sensory and affective pain processing for people living with AD., Methods: Participants from a larger study completed pain psychophysics assessments and then a perceptually-matched heat pain task (warmth, mild, and moderate pain) during a functional MRI scan. In this cross-sectional study, we examined blood oxygenation level-dependent (BOLD) responses in the PAG and other pain-related regions in participants with AD ( n  = 18) and cognitively intact older adults (age- and sex-matched, n  = 18). Associations of BOLD percent signal change and psychophysics were also examined., Results: There were significant main effects of AD status on the temperature needed to reach each perception of warmth or pain, where people with AD reached higher temperatures. Furthermore, participants with AD rated mild and moderate pain as more unpleasant than controls. PAG BOLD activation was greater in AD relative to controls during warmth and mild pain percepts. No significant differences were found for moderate pain or in other regions of interest. Greater PAG activation during mild pain was associated with higher affective/unpleasantness ratings of mild pain in participants with AD but not in controls., Conclusion: Results suggest a role for the PAG in altered pain responses in people with AD. The PAG is the primary source of endogenous opioid pain inhibition in the neuroaxis, thus, altered PAG function in AD suggests possible changes in descending pain inhibitory circuits. People with AD may have a greater risk of suffering from pain compared to cognitively intact older adults., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (© 2022 Anderson, Monroe, Dietrich, Bruehl, Iversen, Cowan and Failla.)

Recruitment and retention of participants for pain-related neuroimaging research is challenging and becomes increasingly so when research participants have a diagnosis of Alzheimer's disease and related dementias (ADRD). This article shares the authors' recommendations from several years of successful recruitment and completion of pain-related neuroimaging studies of people living with ADRD and includes supportive literature. While not an exhaustive list, this review covers several topics related to recruitment and retention of participants living with ADRD, including community engagement, capacity to consent, dementia diagnostic criteria, pain medication and other study exclusion criteria, participant and caregiver burden, communication concerns, and relationships with neuroimaging facilities. Threaded throughout the paper are important cultural considerations. Additionally, we discuss implications of the coronavirus (COVID-19) pandemic for recruitment. Once tailored to specific research study protocols, these proven strategies may assist researchers with successfully recruiting and retaining participants living with ADRD for pain-related neuroimaging research studies toward improving overall health outcomes., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Iversen, Monroe, Atalla, Anderson, Cowan, Wright, Failla and Moss.)

Objective: Advanced age is associated with a higher risk of both pain and dementia, with many studies finding that dementia often heightens sensitivity to pain. Vascular dementia (VaD) is the second most common type of dementia. Only a few observational or retrospective studies have examined pain responsiveness in VaD, suggesting that it could increase pain unpleasantness (i.e., pain affect). This study compared thermal pain psychophysics between a cohort of patients with VaD and healthy control (HC) subjects., Design: Single-center, cross-sectional, between-subjects design., Subjects: Verbally communicative patients with probable VaD (n = 23) and age- and sex-matched HCs (n = 23)., Methods: A thermal psychophysics protocol assessed "mild pain" and "moderate pain" thresholds (temperature in degrees Celsius) and associated unpleasantness ratings (0-20 scale) in both the VaD and HC groups. Psychophysics were compared between groups by way of a mixed-effects analysis, controlling for depressive symptoms., Results: There were no significant differences between groups for pain thresholds (main effect P = 0.086, Cohen's d: mild = 0.55, moderate = 0.27). However, unpleasantness ratings were higher in the VaD group than in the HC group (main effect P = 0.003; mild pain P = 0.022, Cohen's d = 0.79; moderate pain P = 0.057, Cohen's d = 0.6)., Conclusions: These results are consistent with prior observational findings suggesting that VaD could make patients more susceptible to pain, particularly its affective component., (© The Author(s) 2021. Published by Oxford University Press on behalf of the American Academy of Pain Medicine. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

(1) Background: African Americans experience high rates of psychological stress and hypertension, which increases their risk of cardiovascular disease with age. Easy-to-collect psychological and biological stress data are valuable to investigations of this association. Hair cortisol concentration (HCC), as a proxy biomarker of chronic stress exposure, provides such advantages in contrast to collection of multiple daily samples of saliva. Objective: To examine the relationships among HCC, perceived stress, mental well-being, and cardiovascular health (systolic blood pressure (SBP), diastolic blood pressure (DBP), and mean arterial pressure (MAP)). (2) Methods: Cross-sectional secondary data ( N = 25) were used from a mind-body intervention study in hypertensive African Americans ages 65 and older. Data included HCC, a four-item perceived stress scale, SF-36 mental components summary, and SBP/DBP. SBP + 2 (DBP)/3 was used to calculate MAP. (3) Results: The relationship between mental well-being and perceived stress (r = -0.497, p ≤ 0.01) and mental well-being and DBP (r = -0.458, p = 0.02) were significant. HCC change was not significant. In a regression model, every unit increase in well-being predicted a 0.42 decrease in DBP (β = -0.42, 95% CI (-0.69-0.15)) and a 1.10 unit decrease in MAP (β = -1.10, 95% CI (-1.99-0.20)). (4) Conclusions: This study contributes to the knowledge of physiologic data regarding the relationship between MAP and well-being. Findings from this study may aid in the development of interventions that address mental well-being and cardiovascular health in African American older adults with hypertension.

Aim: The purpose of this manuscript is to summarize research on how experimental pain is experienced by adults with Alzheimer's disease (AD) and to translate results into implications for nurses., Design: This discursive review synthesizes the results of three previous research studies exploring experimental pain in adults with AD., Methods: Using a series of fictional clinical vignettes, the authors discuss how the results from three previous papers using acute experimental pain can potentially be translated into clinical practice. The authors also introduce the reader to the concept of research-related psychophysics using introductory definitions and concepts with the impetus to encourage other nurses to consider this research methodology., Results: Pain characteristics in AD that differ from cognitively intact controls must be explored to properly address pain in this population. Nurses are well positioned to address these issues in order to provide a high quality of care to adults with AD., (© 2021 The Authors. Nursing Open published by John Wiley & Sons Ltd.)

Background: Pain management is important to post-acute functional recovery, yet older persons with Alzheimer's disease and related dementias (ADRD) are often undertreated for pain. The main objectives were (1) to examine the relationship between ADRD and analgesic use among Medicare home health care (HHC) recipients with daily interfering pain, and (2) to examine the impact of analgesic use on functional outcome in patients with and without ADRD., Methods: We analyzed longitudinal data from the Outcome and Assessment Information Set, Medicare HHC claims, and HHC electronic medical records during a 60-day HHC episode. The sample included 6048 Medicare beneficiaries ≥65 years receiving care from an HHC agency in New York in 2019 who reported daily interfering pain. Analgesic use was assessed during HHC medication reconciliation and included any analgesic, non-opioid analgesic, and opioid. ADRD was identified from ICD-10 codes (HHC claims) and cognitive impairment symptoms (Outcome and Assessment Information Set [OASIS]). Functional outcome was measured as change in the composite Activity of Daily Living (ADL) limitation score in the HHC episode., Results: ADRD was related to a lower likelihood of using any analgesic (odds ratio [OR] = 0.66, 95% confidence interval [CI]: 0.49, 0.90, p = 0.008) and opioids (OR = 0.54, 95% CI: 0.47, 0.62, p < 0.001), but not related to non-opioid analgesic use (OR = 0.94, 95% CI: 0.74, 1.18, p = 0.58). Stratified analyses showed that any analgesic use (β = -0.43, 95% CI: -0.73, -0.13, p = 0.004) and non-opioid analgesic use (β = -0.31, 95% CI: -0.56, -0.06, p = 0.016) were associated with greater ADL improvement in patients with ADRD, but not in patients without ADRD. Opioid use was not significantly related to ADL improvement regardless of ADRD status., Conclusions: HHC patients with ADRD may be undertreated for pain, yet pain treatment is essential for functional improvement in HHC. HHC clinicians and policymakers should ensure adequate pain management for older persons with ADRD for improved functional outcomes., (© 2021 The American Geriatrics Society.)

This brief report details a pilot analysis conducted to explore racial differences in pain sensitivity and unpleasantness between cognitively healthy Black and White adults, stratified by sex. A total of 24 cognitively healthy adults (12 Black and 12 White) from two completed studies were matched by age and sex, and divided into two groups based on race. Stratified analyses by sex demonstrated that Black females reported experiencing pain intensity ratings of all three intensity sensations at lower temperatures than White females. These findings will inform future research studies to determine if these results hold true in a fully-powered sample and should include mixed methodologies, incorporating neuroimaging data to further assess this phenomenon. Improving pain assessment and management across racial/ethnic groups will help healthcare providers such as nurses and physicians to ensure optimal quality of life for all., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Moss, Wright, Tan, Rose, Scharre, Gure, Cowan, Failla and Monroe.)

The purpose of this consensus paper was to convene leaders and scholars from eight Expert Panels of the American Academy of Nursing and provide recommendations to advance nursing's roles and responsibility to ensure universal access to palliative care. Part I of this consensus paper herein provides the rationale and background to support the policy, education, research, and clinical practice recommendations put forward in Part II. On behalf of the Academy, the evidence-based recommendations will guide nurses, policy makers, government representatives, professional associations, and interdisciplinary and community partners to integrate palliative nursing services across health and social care settings. The consensus paper's 43 authors represent eight countries (Australia, Canada, England, Kenya, Lebanon, Liberia, South Africa, United States of America) and extensive international health experience, thus providing a global context for the subject matter. The authors recommend greater investments in palliative nursing education and nurse-led research, nurse engagement in policy making, enhanced intersectoral partnerships with nursing, and an increased profile and visibility of palliative nurses worldwide. By enacting these recommendations, nurses working in all settings can assume leading roles in delivering high-quality palliative care globally, particularly for minoritized, marginalized, and other at-risk populations., (Crown Copyright © 2021. Published by Elsevier Inc. All rights reserved.)

Monoamine oxidase (MAO) is rapidly gaining appreciation for its pathophysiologic role in cardiac injury and failure. Oxidative deamination of norepinephrine by MAO generates H 2 O 2 and the catecholaldehyde 3,4-dihydroxyphenylglycolaldehyde (DOPEGAL), the latter of which is a highly potent and reactive electrophile that has been linked to cardiotoxicity. However, many questions remain as to whether catecholaldehydes regulate basic physiological processes in the myocardium and the pathways involved. Here, we examined the role of MAO-derived oxidative metabolites in mediating the activation of cardiac fibroblasts in response to norepinephrine. In neonatal murine cardiac fibroblasts, norepinephrine increased reactive oxygen species (ROS), accumulation of catechol-modified protein adducts, expression and secretion of collagens I/III, and other markers of profibrotic activation including STAT3 phosphorylation. These effects were attenuated with MAO inhibitors, the aldehyde-scavenging dipeptide l-carnosine, and FPS-ZM1, an antagonist for the receptor for advanced glycation endproducts (RAGE). Interestingly, treatment of cardiac fibroblasts with a low dose (1 μM) of DOPEGAL-modified albumin phenocopied many of the effects of norepinephrine and also induced an increase in RAGE expression. Higher doses (>10 μM) of DOPEGAL-modified albumin were determined to be toxic to cardiac fibroblasts in a RAGE-dependent manner, which was mitigated by l-carnosine. Collectively, these findings suggest that norepinephrine may influence extracellular matrix remodeling via an adrenergic-independent redox pathway in cardiac fibroblasts involving the MAO-mediated generation of ROS, catecholaldehydes, and RAGE. Furthermore, since elevations in the catecholaminergic tone and oxidative stress in heart disease are linked with cardiac fibrosis, this study illustrates novel drug targets that could potentially mitigate this serious disorder.

Monoamine oxidase (MAO) catalyzes the oxidative deamination of dopamine and norepinephrine to produce 3,4-dihydroxyphenylacetaldehyde (DOPAL) and 3,4-dihydroxyphenylglycolaldehyde (DOPEGAL), respectively. Both of these aldehydes are potently cytotoxic and have been implicated in pathogenesis of neurodegenerative and cardiometabolic disorders. Previous work has demonstrated that both the catechol and aldehyde moieties of DOPAL are reactive and cytotoxic via their propensity to cause macromolecular cross-linking. With certain amines, DOPAL likely reacts via a Schiff base before oxidative activation of the catechol and rearrangement to a stable indole product. Our current work expands on this reactivity and includes the less-studied DOPEGAL. Although we confirmed that antioxidants mediated DOPAL's reactivity with carnosine and N -acetyl-l-lysine, antioxidants had no effect on reactivity with l-cysteine. Therefore, we propose a non-oxidative mechanism where, following Schiff base formation, the thiol of l-cysteine reacts to form a thiazolidine. Similarly, we demonstrate that DOPEGAL forms a putative thiazolidine conjugate with l-cysteine. We identified and characterized both l-cysteine conjugates via HPLC-MS and additionally identified a DOPEGAL adduct with carnosine, which is likely an Amadori product. Furthermore, we were able to demonstrate that these conjugates are produced in biological systems via MAO after treatment of the cell lysate with norepinephrine or dopamine along with the corresponding nucleophiles (i.e., l-cysteine and carnosine). As it has been established that metabolic and oxidative stress leads to increased MAO activity and accumulation of DOPAL and DOPEGAL, it is conceivable that conjugation of these aldehydes to carnosine or l-cysteine is a newly identified detoxification pathway. Furthermore, the ability to characterize these adducts via analytical techniques reveals their potential for use as biomarkers of dopamine or norepinephrine metabolic disruption.

Aims: Catecholamine metabolism via monoamine oxidase (MAO) contributes to cardiac injury in models of ischemia and diabetes, but the pathogenic mechanisms involved are unclear. MAO deaminates norepinephrine (NE) and dopamine to produce H 2 O 2 and highly reactive "catecholaldehydes," which may be toxic to mitochondria due to the localization of MAO to the outer mitochondrial membrane. We performed a comprehensive analysis of catecholamine metabolism and its impact on mitochondrial energetics in atrial myocardium obtained from patients with and without type 2 diabetes. Results: Content and maximal activity of MAO-A and MAO-B were higher in the myocardium of patients with diabetes and they were associated with body mass index. Metabolomic analysis of atrial tissue from these patients showed decreased catecholamine levels in the myocardium, supporting an increased flux through MAOs. Catecholaldehyde-modified protein adducts were more abundant in myocardial tissue extracts from patients with diabetes and were confirmed to be MAO dependent. NE treatment suppressed mitochondrial ATP production in permeabilized myofibers from patients with diabetes in an MAO-dependent manner. Aldehyde dehydrogenase (ALDH) activity was substantially decreased in atrial myocardium from these patients, and metabolomics confirmed lower levels of ALDH-catalyzed catecholamine metabolites. Proteomic analysis of catechol-modified proteins in isolated cardiac mitochondria from these patients identified >300 mitochondrial proteins to be potential targets of these unique carbonyls. Innovation and Conclusion: These findings illustrate a unique form of carbonyl toxicity driven by MAO-mediated metabolism of catecholamines, and they reveal pathogenic factors underlying cardiometabolic disease. Importantly, they suggest that pharmacotherapies targeting aldehyde stress and catecholamine metabolism in heart may be beneficial in patients with diabetes and cardiac disease. Antioxid. Redox Signal. 35, 235-251.

Purpose: In this secondary analysis we tested whether 12 h of Senior WISE (Wisdom Is Simply Exploration) memory or health training with older adults would produce better outcomes by gender in perceptions of anxiety and bodily pain and whether the effects of the Senior WISE training on pain were mediated by anxiety., Design: An implemented Phase III randomized clinical trial with follow up for 24 months in Central Texas. The sample was mostly female (79%), 71% Caucasian, 17% Hispanic, and 12% African American with an average age of 75 and 13 years of education., Results: The effects of the memory intervention on anxiety were consistent across time, with effects present for males but not females at post-treatment and end-of-study. Although males had more anxiety in the health promotion group, the memory training reduced males' anxiety such that no gender difference was present in this group. The Senior WISE intervention reduced pain for both males and females at post-intervention but not at end-of-study. Although gender differences did not depend on the treatment group for pain, females reported somewhat, but not significantly, less pain at post-treatment and end-of-study. Mediation analysis indicated that, for males, the memory intervention indirectly affected pain at post-treatment, in part, by reducing anxiety, which lowered pain. However, at end-of-study, no indirect effect was present. Males responded to memory training. Training tailored to gender may increase the efficacy of the programs and "buy-in" from male participants, especially if tailored to anxiety and pain., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Background: Neoplasm-related pain is often suboptimally treated, contributing to avoidable suffering and increased medical resource use and costs. We hypothesized that dementia may contribute to increased resource use and costs in patients hospitalized for neoplasm-related pain in the United States., Aims: To examine how persons with cancer and dementia use medical resources and expenditures in US hospitals compared to ondividuals without dementia., Design: This study examined a retrospective cohort., Setting: Admissions to US hospitals for neoplasm-related pain from 2012-2016 PARTICIPANTS/SUBJECTS: METHODS: Data were obtained from the 2012-2016 National Inpatient Sample (NIS). The sample included hospital admissions of individuals aged 60 or older with a primary diagnosis of neoplasm-related pain. Dementia was defined using the International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM), and ICD-10-CM diagnosis codes. Primary outcomes were number of admissions, costs, and length of stay (LOS). Descriptive statistics and multivariable regression models were used to examine the relationships among dementia, costs, and LOS., Results: Of 12,034 admissions for neoplasm-related pain, 136 (1.1%) included a diagnosis of dementia and 11,898 (98.9%) did not. Constipation was present in 13.2% and 24.5% of dementia and nondementia admissions, respectively. The median LOS was 4 days in persons with dementia and three in those without. Mean costs per admission were higher in persons without dementia ($10,736 vs. $9,022, p = .0304). In adjusted regression results, increased costs were associated with nonelective admissions and longer LOS, and decreased costs with age above the mean. In contrast, decreased LOS was associated with age above the mean and nonelective admissions. Dementia was associated with neither endpoint., Conclusion: This study provides nurses and other health care professionals with data to further explore opportunities for improvement in cancer pain management in patients with and without dementia that may optimize use of medical resources., Competing Interests: Declaration of Competing Interest None., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Early recognition of Alzheimer's disease (AD) in the prodromal period has not been robust yet will be necessary if effective disease-modifying drugs are to be useful in preventing or delaying the condition. The objective of this narrative review was to describe the current, evidenced based understanding of alterations in sensory data as potential biomarkers for AD. Review of empirical studies that tested senses as biomarkers for AD and were published in English within the past 50 years was completed. Eighteen empirical studies were identified that met the strict criteria for inclusion, with 12 of these studies being related to the olfactory system. Two studies examined auditory, two examined vision, one examined proprioception, and one examined taste. Thus, only olfaction has been studied to any extent, leaving a clear gap in the literature for the use of other senses. A promising area of research has begun to be reported concerning differences in responses to pain stimuli in AD relative to cognitively normal subjects. Pain is not a single sense like the others but integrates several senses and may allow for use as an early biomarker for AD, as it integrates several brain areas and pathways. Unlike the other senses, simple devices can be used to measure changes in pain perception in cognitively normal adults with genetic predispositions for possible AD, making this potentially useful for clinicians in the future.

Background: Pain continues to be underrecognized and undertreated in Alzheimer's disease (AD) while existing guidance about pain assessment and management in dementia is not widespread. Brain regions involved in pain processing and modulation are damaged during AD, and the pain experience in AD is not well understood. Experimental pain studies using psychophysics can further our understanding of the pain experience in AD, which may lead to improved assessment and management of pain in people living with AD., Objective: A systematic review was conducted to explicate the current understanding of experimentally evoked pain in AD from primary research using psychophysical methods., Data Sources: Peer-reviewed publications were found via PubMed, CINAHL, and PsycINFO. A total of 18 primary research, peer-reviewed full articles that met inclusion criteria were included, representing 929 total participants., Conclusions: Experimentally evoked pain in people with AD demonstrates that despite cognitive impairment and a reduced ability to effectively communicate, individuals with AD experience pain similar to or more unpleasant than cognitively intact older adults. This may mean amplified pain unpleasantness in people with AD., Implications for Practice: Our current best practices need to be widely disseminated and put into clinical practice. Self-report of pain continues to be the gold standard, but it is ineffective for noncommunicative patients and those unable to understand pain scales or instructions because of memory/cognitive impairment. Instead, pain treatment should be ethically initiated based on patient reports and behaviors, caregiver/surrogate reports, review of the medical record for painful conditions, analgesic trials, and regular reassessments., Competing Interests: Competing interests: The authors report no conflicts of interest., (Copyright © 2021 American Association of Nurse Practitioners.)

Aims: Determine sex- and age-associated psychophysical and neurophysiological differences in the processing of pain across the adult lifespan., Design: Preliminary, exploratory, cross-sectional study., Methods: Using psychophysics (to measure intensity and unpleasantness) and functional magnetic resonance imaging blood oxygenation level dependent methods (to measure stimulus-evoked brain activation), we will examine sex- and age-associated differences in thermal pain processing and their underlying neurophysiology in a broad range of healthy adults (ages 30-89). We will acquire resting state functional connectivity data for secondary analyses exploring whether resting state connectivity predicts psychophysical and neurophysiological responses to thermal pain. To examine the effects of altered blood flow, we will acquire resting-state arterial spin labeling magnetic resonance imaging data to quantify resting cerebral blood flow. We will interpret findings in the context of a proposed neural model of pain, ageing, and sex. Study funding was received in June of 2014. Ethical approval was obtained from the Vanderbilt University IRB prior to study initiation., Conclusion: Exploring the biological reasons for age- and sex-associated differences in pain processing will increase our understanding of pain in older adults. The paucity of neurobiological evidence to support best practice pain management in older adults places these individuals at risk for poor pain management., Impact: Poorly treated pain in older adults is a critical public health problem associated with a poor quality of life and increased healthcare costs. Understanding how age and sex have an impact on central processing of pain across the lifespan is a critical step toward improving personalized pain medicine., (© 2021 The Authors. Journal of Advanced Nursing published by John Wiley & Sons Ltd.)

Objectives: Hypertension increases the risk of developing Alzheimer's disease or related dementias. This pilot study's purpose was to examine the feasibility and acceptability of a novel intervention, Mindfulness in Motion (MIM) and Dietary Approaches to Stop Hypertension DASH (MIM DASH), to improve diet, mindfulness, stress, and systolic blood pressure (BP) in older African Americans with mild cognitive impairment (MCI) and hypertension., Design: Cluster randomized controlled trial., Setting: Intergenerational community center in a large metropolitan area., Participants: African Americans with MCI and hypertension. Participants were divided into six groups randomized 1:1:1 to the MIM DASH group, attention only (non-hypertensive education) group, or true control group. The MIM DASH and attention only interventions were delivered in 8-weekly 2 hour group sessions. MIM included mindful movements from chair/standing, breathing exercises, and guided meditation. The DASH component used a critical thinking approach of problem solving, goal setting, reflection, and self-efficacy. The true control group received a DASH pamphlet at the end., Measurements: Feasibility was tracked through enrollment and attendance records; acceptability was assessed through interviews. Blood pressure was measured using the Omron HEM-907XL Monitor. Dietary intake was measured by DASH-Q. Mindfulness was measured by the Cognitive and Affective Mindfulness Scale. Stress was measured by the Perceived Stress Scale. MCI was determined using the Self-Administered Gerocognitive Examination. Data were collected at baseline and 3-months., Results: Median session attendance was six for the MIM DASH group and six for the attention only group. There were no changes in diet, mindfulness, or stress. There was a clinically significant reduction in systolic BP in the MIM DASH group (-7.2 mmHg) relative to the attention only group (-.7), and no change between the MIM DASH and true control groups., Conclusion: Results indicate that the MIM DASH intervention was feasible and culturally acceptable in African Americans with hypertension and MCI., (© 2021 The American Geriatrics Society.)

The increasing appearance of engineered nanomaterials in broad biomedical and industrial sectors poses an escalating health concern from unintended exposure with unknown consequences. Routine in vitro assessments of nanomaterial toxicity are a vital component to addressing these mounting health concerns; however, despite the known role of cell-cell and cell-matrix contacts in governing cell survival, these physical interactions are generally ignored. Herein, we demonstrate that exposure to amorphous silica particles destabilizes mitochondrial membrane potential, stimulates reactive oxygen species (ROS) production and promotes cytotoxicity in SH-SY5Y human neuroblastoma through mechanisms that are potently matrix dependent, with SH-SY5Y cells plated on the softest matrix displaying a near complete recovery in viability compared to dose-matched cells plated on tissue-culture plastic. Cells on the softest matrix (3 kPa) further displayed a 50% reduction in ROS production and preserved mitochondrial membrane potential. The actin cytoskeleton is mechanosensitive and closely related to ROS production. SH-SY5Y cells exposed to a 100 μg/mL dose of 50 nm silica particles displayed distinct cytoskeletal aberrations and a 70% increase in cell stiffness. Overall, this study establishes that the mechanical environment can significantly impact silica nanoparticle toxicity in SH-SY5Y cells. The mechanobiochemical mechanisms behind this regulation, which are initiated at the cell-matrix interface to adjust cytoskeletal structure and intracellular tension, demand specific attention for a comprehensive understanding of nanotoxicity., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Background: Pain is common yet under-studied among older Medicare home health (HH) patients with Alzheimer's disease and related dementias (ADRD)., Aims: Examine (1) the association between ADRD and severe pain in Medicare HH patients; and (2) the impact of severe pain and ADRD on unplanned facility admissions in this population., Design: Analysis of the Outcome and Assessment Information Set (OASIS) and Medicare claims data., Settings/participants: 6,153 patients ≥65 years receiving care from a nonprofit HH agency in 2017., Methods: Study outcomes included presence of severe pain and time-to-event measures of unplanned facility admissions (hospital, nursing home, or rehabilitation facilities). ADRD was identified using ICD-10 diagnosis codes and cognitive impairment symptoms. Logistic regression and Cox proportional hazard models were used to examine, respectively, the association between ADRD and severe pain, and the independent and interaction effects of severe pain and ADRD on unplanned facility admission., Results: Patients with ADRD (n = 1,525, 24.8%) were less likely to have recorded severe pain than others (16.4% vs. 23.6%, p < .001). Adjusting for demographics, comorbidities, mental and physical functional status, and use of HH services, having severe pain was related to a 35% increase (hazard ratio [HR] = 1.35, p = .002) in the risk of unplanned facility admission, but the increase in such risk was the same whether or not the patient had ADRD., Conclusions: HH patients with ADRD may have under-recognized pain. Severe pain is a significant independent predictor of unplanned facility admissions among HH patients., (Copyright © 2021 American Society for Pain Management Nursing. Published by Elsevier Inc. All rights reserved.)

Background: This study evaluated whether the apolipoprotein ɛ4 (APOE4) allele, a genetic marker associated with increased risk of developing late-onset Alzheimer's disease (AD), was associated with differences in evoked pain responsiveness in cognitively healthy subjects., Objective: The aim was to determine whether individuals at increased risk of late-onset AD based on APOE allele genotype differ phenotypically in their response to experimentally-induced painful stimuli compared to those who do not have at least one copy of the ɛ4 allele., Methods: Forty-nine cognitively healthy subjects aged 30-89 years old with the APOE4 allele (n = 12) and without (n = 37) were assessed for group differences in pain thresholds and affective (unpleasantness) responses to experimentally-induced thermal pain stimuli., Results: Statistically significant main effects of APOE4 status were observed for both the temperature at which three different pain intensity percepts were reached (p = 0.040) and the level of unpleasantness associated with each (p = 0.014). APOE4 positive participants displayed lower overall pain sensitivity than those who were APOE4 negative and also greater overall levels of pain unpleasantness regardless of intensity level., Conclusion: Cognitively healthy APOE4 carriers at increased risk of late-onset AD demonstrated reduced thermal pain sensitivity but greater unpleasantness to thermal pain stimuli relative to individuals at lower risk of late-onset AD. These results suggest that altered evoked pain perception could potentially be used as a phenotypic biomarker of late-onset AD risk prior to disease onset. Additional studies of this issue may be warranted.

Background: There is currently no gold standard instrument for assessing pain in severely cognitively impaired adults who are unable to provide self-report., Aims: To determine interrater reliability of the PACSLAC and PAINAD in assessing pain behaviors in patients with the same pain stimulus, determine the consistency of the reliable changes between and within the instruments and assess nurse preference for either instrument., Design: A single-group, within-subjects repeated-measures design was implemented., Setting: The study took place in a small suburban hospital., Participants/subjects: Pain levels were observed at 24, 48, and 72 hours postsurgery using two instruments: Pain Assessment Checklist for Seniors with Limited Ability to Communicate (PACSLAC) and Pain Assessment in Advanced Dementia Scale (PAINAD). These instruments were selected because they are among the most commonly recommended tools for clinical use. Interrater reliability was analyzed along with reliable changes in pain for each period, and the study concluded with the nurse raters completing a preference survey., Methods: A convenience sample of 30 patients was used with a diagnosis of severe dementia rendering the patient unable to reliably express pain, 60+ years of age, recovering from hip fracture surgery., Results: Greater interrater reliability was found for the PACSLAC, with reliable change potentially affected by the type and level of pain medication. The nurses' preference for the tool was split., Conclusions: The results of this study indicate that the PACSLAC may be the more reliable tool over the PAINAD; however, rater training and familiarity with the tool is critical., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)

Objective: To examine psychophysical and brain activation patterns to innocuous and painful thermal stimulation along a continuum of healthy older adults., Design: Single center, cross-sectional, within-subjects design., Methods: Thermal perceptual psychophysics (warmth, mild, and moderate pain) were tested in 37 healthy older adults (65-97 years, median = 73 years). Percept thresholds (oC) and unpleasantness ratings (0-20 scale) were obtained and then applied during functional magnetic resonance imaging scanning. General linear modeling assessed effects of age on psychophysical results. Multiple linear regressions were used to test the main and interaction effects of brain activation against age and psychophysical reports. Specifically, differential age effects were examined by comparing percent-signal change slopes between those above/below age 73 (a median split)., Results: Advancing age was associated with greater thresholds for thermal perception (z = 2.09, P = 0.037), which was driven by age and warmth detection correlation (r = 0.33, P = 0.048). Greater warmth detection thresholds were associated with reduced hippocampal activation in "older" vs "younger" individuals (>/<73 years; beta < 0.40, P < 0.01). Advancing age, in general, was correlated with greater activation of the middle cingulate gyrus (beta > 0.44, P < 0.01) during mild pain. Differential age effects were found for prefrontal activation during moderate pain. In "older" individuals, higher moderate pain thresholds and greater degrees of moderate pain unpleasantness correlated with lesser prefrontal activation (anterolateral prefrontal cortex and middle-frontal operculum; beta < -0.39, P < 0.009); the opposite pattern was found in "younger" individuals., Conclusions: Advancing age may lead to altered thermal sensation and (in some circumstances) altered pain perception secondary to age-related changes in attention/novelty detection and cognitive functions., (© 2019 American Academy of Pain Medicine.)

Background: Since the inception of magnetic resonance imaging, thousands of studies have appeared in the literature reporting on multiple imaging techniques. However, there is a paucity of neuroimaging research programs developed by nurse scientists., Objectives: The purpose of this article is to introduce the nurse scientist to complex neuroimaging methods with the ultimate goal of creating impetus for future use of brain imaging in nursing research., Methods: This article reviews common neuroimaging methods, presents vocabulary frequently used in neuroimaging work, provides information on access to resources in neuroimaging education, and discusses considerations for use of neuroimaging in research., Results: Ten imaging modalities are reviewed, including structural and functional magnetic resonance imaging, computed tomography, positron emission tomography, and encephalography., Discussion: Choosing an imaging modality for research depends on the nature of the research question, needs of the patient population of interest, and resources available to the novice and seasoned nurse scientist. Neuroimaging has the potential to innovate the study of symptom science and encourage interdisciplinary collaboration in research.

Background and Purpose: The incidence of Alzheimer disease (AD) is increasing in the United States, yet more than half of the people with AD are diagnosed late in the course of the disease. Most are identified outside primary care. New approaches to prevention and treatment mean that early detection of AD may improve the quality of life of those affected by the disease. Nurse practitioners (NPs) have an important role in increasing early diagnosis of AD.The purpose of this systematic literature review is to identify health care system factors that contribute to missed or delayed diagnosis of dementia by primary care providers., Methods: Articles were identified through a systematic electronic search of the following databases: MEDLINE, the Cochrane Central Register of Controlled Trials, CINAHL, and PsycINFO., Conclusions and Implications for Practice: Results indicate considerable variation in the diagnostic accuracy of dementia by primary care providers. Missed or underdiagnosis of dementia results from organizational, provider, and patient factors. New treatments are under investigation that may slow the progression of AD much better than current therapy, emphasizing the need to improve early detection by clinicians, especially primary care NPs.

Oxidative stress is associated with numerous diseases, and markers of oxidative stress in biological material are becoming a mainstay of both experimental and clinical/epidemiological research. Lipid peroxidation is a major form of oxidative stress, but due to their rapid degradation and instability, lipid peroxides are notoriously difficult to measure, particularly in biological specimens where their production and removal are continuously occuring. Thus, a commonly used surrogate marker of lipid peroxidation is protein adducts of 4-Hydroxynonenal (HNE), an α, β-unsaturated hydroxyalkenal ( i.e. , a reactive aldehyde) formed via degradation of oxidized polyunsaturated fatty acids (PUFAs). HNE adducts can be measured via commercially-available immunosorbent assays, but these have their limitations due to excessive costs, and reproducibility among laboratories is challenging due to variability in assay sensitivity, procedure, and reagents. Here we present a reproducible, facile, and economically conservative protocol for quantifying HNE protein adducts. The key to this protocol is to generate HNE-adduct standards by incubating bovine serum albumin (BSA) with HNE. These standards are then adsorbed to immunsorbent plastic in a multi-well plate format alongside biological samples. An enzyme-linked immunosorbent assay (ELISA) is then performed on the multi-well plate using commercially-available primary and secondary antibodies, and a peroxide-based fluorescent developing reagent. This protocol is highly sensitive and offers advantages to commercial sources in that it allows for reproducible, high-throughput quantitation of HNE adducts in a large number of samples. As such, it may be useful as a biomarker of chronic oxidative stress for experimental and clinical studies., Competing Interests: Competing interestsAuthors have no conflicts of interest to disclose., (Copyright © 2019 The Authors; exclusive licensee Bio-protocol LLC.)

Delirium is a serious complication of acute illness. Little is known, however, regarding the neurobiology of delirium, largely due to challenges in studying the complex inpatient population. Neuroimaging is one noninvasive method that can be used to study structural and functional brain abnormalities associated with delirium. The purpose of this integrative literature review was to examine the content and quality of current structural neuroimaging evidence in delirium. After meeting inclusion criteria, 11 articles were included in the review. Commonly noted structural abnormalities were impaired white matter integrity, brain atrophy, ischemic lesions, edema, and inflammation. Findings demonstrated widespread alterations in several brain structures. Limitations of the studies in this review included small sample sizes, inappropriate or questionable delirium measurements, and failure to consider confounding variables. This review provides insight into possible structural changes responsible for the signs and symptoms seen in patients with delirium, but more high-quality studies are needed.

The comorbidity of chronic pain and opioid addiction is a serious problem that has been growing with the practice of prescribing opioids for chronic pain. Neuroimaging research has shown that chronic pain and opioid dependence both affect brain structure and function, but this is the first study to evaluate the neurophysiological alterations in patients with comorbid chronic pain and addiction. Eighteen participants with chronic low back pain and opioid addiction were compared with eighteen age- and sex-matched healthy individuals in a pain-induction fMRI task. Unified structural equation modeling (SEM) with Lagrange multiplier (LM) testing yielded a network model of pain processing for patient and control groups based on 19 a priori defined regions. Tests of differences between groups on specific regression parameters were determined on a path-by-path basis using z -tests corrected for the number of comparisons. Patients with the chronic pain and addiction comorbidity had increased connection strengths; many of these connections were interhemispheric and spanned regions involved in sensory, affective, and cognitive processes. The affected regions included those that are commonly altered in chronic pain or addiction alone, indicating that this comorbidity manifests with neurological symptoms of both disorders. Understanding the neural mechanisms involved in the comorbidity is crucial to finding a comprehensive treatment, rather than treating the symptoms individually.

Background: Sex differences in pain have been shown to exist in older adults with normal cognition and people with Alzheimer's disease. It is unknown if sex differences in pain in older adults exist in a range of communicative older adults with varying cognitive ability from no impairment to moderately severe cognitive impairment., Objective: This study proposes to compare the association between psychophysical responses to experimental thermal pain between males and females to determine if sex differences in pain exist across the cognitive spectrum., Methods: We conducted a secondary analysis of data from an age- and sex-matched between-groups cross-sectional study examining the psychophysical response to contact heat in people with and without dementia., Results: Median age of males (n = 38) and females (n = 38) was 73 (range: 68-87) with similar distributions of Mini-Mental State Examination (MMSE) scores (range: 11-30). Findings revealed inverse statistically significant associations with the threshold temperature of warmth (females: r = -0.41, p = 0.010; males: r = -0.33, p = 0.044). There was an apparent divergent pattern of MMSE associations with unpleasantness ratings between the groups. At the moderate pain threshold, that difference became statistically significant (p = 0.033). Females demonstrated a positive association of MMSE with unpleasantness (r = 0.30, p = 0.072), while males demonstrated an inverse association at that respective threshold (r = -0.20, p = 0.221)., Conclusions: Between-group findings suggest that patterns of responses to thermal stimulus intensity may differ between males and females with worsening cognition with females reporting significantly less unpleasantness with the percept of moderate pain and males reporting significantly higher unpleasantness with moderate pain perception.

Oxidative deamination of norepinephrine (NE) and dopamine (DA) by monoamine oxidase (MAO) generates the catecholaldehydes 3,4-dihydroxyphenylglycolaldehyde (DOPEGAL) and 3,4-dihydroxyphenylacetaldehyde (DOPAL), respectively, and H 2 O 2 . Catecholaldehydes are highly reactive electrophiles that have been implicated as causal factors in the etiology of neurodegenerative diseases and cardiac injury from ischemia and diabetes. The reactivity of both catechol and aldehyde groups enables the catecholaldehdyes to cross-link proteins and other biological molecules. Carnosine is a β-alanyl-histidine dipeptide found in millimolar concentrations in brain and myocardium. It is well known to detoxify aldehydes formed from oxidized lipids and sugars, yet the reactivity of carnosine with catecholaldehydes has never been reported. Here, we investigated the ability of carnosine to form conjugates with DOPAL and DOPEGAL. Both catecholaldehydes were highly reactive towards L-cysteine (L-Cys), as well as carnosine; however, glutathione (GSH) showed essentially no reactivity towards DOPAL. In contrast, GSH readily reacted with the lipid peroxidation product 4-hydroxy-2-nonenal (4HNE), while carnosine showed low reactivity to 4HNE by comparison. To determine whether carnosine mitigates catecholaldehyde toxicity, samples of atrial myocardium were collected from patients undergoing elective cardiac surgery. Using permeabilized myofibers prepared from this tissue, mitochondrial respiration analysis revealed a concentration-dependent decrease in ADP-stimulated respiration with DOPAL. Pre-incubation with carnosine, but not GSH or L-Cys, significantly reduced this effect (p < 0.05). Carnosine was also able to block formation of catecholaldehyde protein adducts in isolated human cardiac mitochondria treated with NE. These findings demonstrate the unique reactivity of carnosine towards catecholaldehydes and, therefore, suggest a novel and distinct biological role for histidine dipeptides in this detoxification reaction. The therapeutic potential of carnosine in diseases associated with catecholamine-related toxicity is worthy of further examination.

Sugar- and lipid-derived aldehydes are reactive carbonyl species (RCS) frequently used as surrogate markers of oxidative stress in obesity. A pathogenic role for RCS in metabolic diseases of obesity remains controversial, however, partly because of their highly diffuse and broad reactivity and the lack of specific RCS-scavenging therapies. Naturally occurring histidine dipeptides (e.g., anserine and carnosine) show RCS reactivity, but their therapeutic potential in humans is limited by serum carnosinases. Here, we present the rational design, characterization, and pharmacological evaluation of carnosinol, i.e., (2S)-2-(3-amino propanoylamino)-3-(1H-imidazol-5-yl)propanol, a derivative of carnosine with high oral bioavailability that is resistant to carnosinases. Carnosinol displayed a suitable ADMET (absorption, distribution, metabolism, excretion, and toxicity) profile and was determined to have the greatest potency and selectivity toward α,β-unsaturated aldehydes (e.g., 4-hydroxynonenal, HNE, ACR) among all others reported thus far. In rodent models of diet-induced obesity and metabolic syndrome, carnosinol dose-dependently attenuated HNE adduct formation in liver and skeletal muscle, while simultaneously mitigating inflammation, dyslipidemia, insulin resistance, and steatohepatitis. These improvements in metabolic parameters with carnosinol were not due to changes in energy expenditure, physical activity, adiposity, or body weight. Collectively, our findings illustrate a pathogenic role for RCS in obesity-related metabolic disorders and provide validation for a promising new class of carbonyl-scavenging therapeutic compounds rationally derived from carnosine.

Objective: A long-standing hypothesis is that when compared with males, females may be at increased risk of experiencing greater pain sensitivity and unpleasantness. The purpose of this study was to examine sex differences in pain psychophysics and resting state functional connectivity (RSFC) in core pain regions in an age- and sex-matched sample of healthy older adults., Design: Between groups, cross-sectional., Setting: Vanderbilt University and Medical Center., Subjects: The sample in the analyses reported here consisted of 19 cognitively intact males matched with 19 cognitively intact females of similar ages (median ages: females = 70 years, males = 68 years)., Methods: Psychophysical assessment of experimental thermal pain and RSFC., Results: There were no significant differences in perceptual thresholds or unpleasantness ratings in response to thermal stimuli. Older males showed greater RSFC between the affective and sensory networks and between affective and descending modulatory networks. Conversely, older females showed greater RSFC between the descending modulatory network and both sensory and affective networks. The strongest evidence for sex differences emerged in the associations of thermal pain with RSFC between the anterior cingulate cortex (ACC) and amygdala and between the ACC and periaqueductal gray matter in older females relative to older males., Conclusions: We found no differences in pain sensitivity or pain affect between older males and older females. Additionally, we found that older females exhibited a greater association between thermal pain sensitivity and RSFC signal between regions typically associated with pain affect and the descending modulatory system. One interpretation of these findings is that older females may better engage the descending pain modulatory system. This better engagement possibly translates into older females having similar perceptual thresholds for temperature sensitivity and unpleasantness associated with mild and moderate pain. These findings contrast with studies demonstrating that younger females find thermal pain more sensitive and more unpleasant.

Objectives: To examine pain interference in verbally communicative older adults with mild to moderate Alzheimer's disease (AD) and to examine the association of pain interference with cognitive function and depressive symptoms., Method: For this pilot study, we used a cross-sectional design to examine pain interference (Brief Pain Inventory-Short Form), cognitive function (Mini-Mental State Exam), and depressive symptoms (15-item Geriatric Depression Scale) in 52 older (≥65) communicative adults with AD who reported being free from chronic pain requiring daily analgesics., Results: Pain was reported to interfere with general activity (13.5%), mood (13.5%), walking ability (13.5%), normal work (11.5%), enjoyment of life (11.5%), relationships with other people (9.6%), and sleep (9.6%). Pain interference was significantly positively correlated with both cognitive function (r s = 0.46, p = 0.001) and depressive symptomology (r s = 0.45, p = 0.001), indicating that greater reported pain interference was associated with better cognitive function and more depressive symptoms., Conclusion: Among older people with AD who report being free from chronic pain requiring daily analgesics, 2 in 10 are at risk of pain interference and depressive symptoms. Those with better cognitive function reported more pain interference and depressive symptoms, meaning pain is likely to be under-reported as AD progresses. Clinicians should regularly assess pain interference and depressive symptoms in older persons with AD to identify pain that might be otherwise overlooked..

The risk of pain in adults with dementia worsens with advancing age. Painful comorbidities may be underassessed and inadequately treated. Receiving treatment in critical care settings may indicate greater occurrences of pain and complications. Pain may exacerbate behavioral and psychological symptoms of dementia (BPSD), such as agitation. Complementary and alternative medicine (CAM) therapies may alleviate pain and BPSD, and continuity of therapy may bolster these therapeutic effects. This review did not reveal an apparent benefit of aromatherapy; however, improvements in BPSD have been shown previously. Massage and human interaction did demonstrate efficacy in reducing BPSD and pain., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Background: It is currently unknown why people with Alzheimer's disease (AD) receive less pain medication and report pain less frequently., Objective: The purpose of this study was to determine the impact of AD on thermal psychophysics and resting-state functional connectivity (RSFC) among sensory, affective, descending modulatory, and default mode structures., Methods: Controls (n = 23, 13 = female) and age-matched people with AD (n = 23, 13 = females) underwent psychophysical testing to rate perceptions of warmth, mild, and moderate pain and then completed resting-state fMRI. Between groups analysis in psychophysics and RSFC were conducted among pre-defined regions of interest implicated in sensory and affective dimensions of pain, descending pain modulation, and the default mode network., Results: People with AD displayed higher thermal thresholds for warmth and mild pain but similar moderate pain thresholds to controls. No between-group differences were found for unpleasantness at any percept. Relative to controls, people with AD demonstrated reduced RSFC between the right posterior insula and left anterior cingulate and also between right amygdala and right secondary somatosensory cortex. Moderate pain unpleasantness reports were associated with increased RSFC between right dorsolateral prefrontal cortex and left ACC in controls only., Conclusions: While AD had little effect on unpleasantness, people with AD had increased thermal thresholds, altered RSFC, and no association of psychophysics with RSFC in pain regions. Findings begin to elucidate that in people with AD, altered integration of pain sensation, affect, and descending modulation may, in part, contribute to decreased verbal pain reports and thus decreased analgesic administration.

Background: People with Alzheimer's disease (AD) report pain less frequently and receive less pain medication than people without AD. Recent studies have begun to elucidate how pain may be altered in those with AD. However, potential sex differences in pain responsiveness have never been explored in these patients. It is unclear whether sex differences found in prior studies of healthy young and older individuals extend to people with AD., Objective: The purpose of this study was to examine sex differences in the psychophysical response to experimental thermal pain in people with AD., Methods: Cross-sectional analysis of 14 male and 14 female age-matched (≥65 years of age, median = 74) and AD severity-matched (Mini-Mental State Exam score <24, median = 16) communicative people who completed thermal psychophysics., Results: There was a statistically significant main effect of sex for both temperature and unpleasantness ratings that persisted after controlling for average and current pain (mixed-effects general liner model: temperature: p = 0.004, unpleasantness: p < 0.001). Females reported sensing mild pain and moderate pain percepts at markedly lower temperatures than did males (mild: Cohen's d = 0.72, p = 0.051, moderate: Cohen's d = 0.80, p = 0.036). By contrast, males rated mild and moderate thermal pain stimuli as more unpleasant than did females (mild: Cohen's d = 0.80, p = 0.072, moderate: Cohen's d = 1.32, p = 0.006). There were no statistically significant correlations of temperature with perceived unpleasantness for mild or moderate pain (rs = 0.29 and rs = 0.20 respectively, p > 0.05)., Conclusions: Results suggest experimental pain-related sex differences persist in older adults with AD in a different manner than those previously demonstrated in cognitively intact older adults. These findings could potentially aid in developing targeted pain management approaches in this vulnerable population. Further studies are warranted to replicate the findings from this pilot work.