Early life exposure to air pollution and psychotic-like experiences, emotional symptoms, and conduct problems in middle childhood.

BACKGROUND: Air pollution has been linked to a variety of childhood mental health problems, but results are inconsistent across studies and the effect of exposure timing is unclear. We examined the associations between air pollution exposure at two time-points in early development and psychotic-like experiences (PLEs), and emotional and conduct symptoms, assessed in middle childhood (mean age 11.5 years). METHODS: Participants were 19,932 children selected from the NSW Child Development Study (NSW-CDS) with available linked multi-agency data from birth, and self-reported psychotic-like experiences (PLEs) and psychopathology at age 11-12 years (middle childhood). We used binomial logistic regression to examine associations between exposure to nitrogen dioxide (NO2) and particulate matter less than 2.5 µm (PM2.5) at two time-points (birth and middle childhood) and middle childhood PLEs, and emotional and conduct symptoms, with consideration of socioeconomic status and other potential confounding factors in adjusted models. RESULTS: In fully adjusted models, NO2 exposure in middle childhood was associated with concurrent PLEs (OR = 1.10, 95% CI = 1.02-1.20). Similar associations with PLEs were found for middle childhood exposure to PM2.5 (OR = 1.05, 95% CI = 1.01-1.09). Neither NO2 nor PM2.5 exposure was associated with emotional symptoms or conduct problems in this study. CONCLUSIONS: This study highlights the need for a better understanding of potential mechanisms of action of NO2 in the brain during childhood.

5-MeO-DMT: An atypical psychedelic with unique pharmacology, phenomenology & risk?

5-MeO-DMT is a tryptamine being developed as a potential antidepressant that may display a distinct therapeutic mechanism due to its unique pharmacology and subjective effects compared to typical psychedelics. In this article, we parallel the relatively distinct phenomenology and behavioral effects of the acute and post-acute effects of 5-MeO-DMT to those induced by epileptiform activity, particularly in instances within epileptogenic zones of the temporal lobes. This is done by reviewing aberrant 5-HT1A receptor functioning in epilepsy, noting that 5-MeO-DMT has notable 5-HT1A receptor agonist properties-and then comparing the acute behavioral and subjective effects induced by 5-MeO-DMT to those that occur in seizures. It might be that 5-MeO-DMT's therapeutic mechanism is partly mediated by evoking temporary epileptiform activity, suggesting a similarity to electroconvulsive therapy. It is also noted that "reactivations," the sudden re-experiencing of drug effects common after 5-MeO-DMT but not after typical psychedelics, may suggest that 5-MeO-DMT produces recurrent epileptiform activity. Overall, this review indicates that further evaluation of 5-MeO-DMT's unique mechanisms in research settings and among naturalistic users are warranted.

Control Conditions in Randomized Trials of Psychedelics: An ACTTION Systematic Review.

Objective: To systematically review control conditions of all available randomized psychedelic trials.Data Sources: We searched PubMed, PsycINFO, and EMBASE for randomized trials of psychedelics in humans from 1940 through May 2020 with no language restrictions. PRISMA guidelines were followed. (PROSPERO registration number: PROSPERO-CRD42020205341.).Study Selection: All randomized trials of psychedelics in humans from 1940 through May 2020 were included.Data Extraction: Two independent reviewers performed extraction. Extracted data included study design, demographics, blinding type, whether and how blind integrity was assessed, psychedelic used and dose, drug control condition and dose, type of non-drug control condition, number of dosing sessions, and recruitment source. Outcome data were not collected.Results: In total, 126 articles were included, encompassing 86 unique studies. Of studies with a drug control condition (80), 49 (61.2%) used an inert placebo control, 16 (20.0%) used active comparators, 12 (15.0%) used both, and 3 (3.8%) used only different active psychedelic doses as a control. Only 3 of 21 therapeutic trials compared the use of psychological support to a minimally supportive condition. The majority (81/86; 94%) of studies were blinded, though only 14 (17.3%) included blind assessment; only 8 of these 14 studies assessed participants' blinding. Blinding success, assessed in highly varied ways, was generally poor.Conclusions: Randomized psychedelic trials underutilize elements that would improve quality or provide important information: blind assessment, active drug controls, and testing psychological support against minimal-support conditions. Several queried categories, including blind integrity assessment and details of non-drug control conditions, were insufficiently reported by many reviewed studies. Recommendations are provided to improve trial methods.

E-cigarette Price Impacts legal and Black-Market Cigarette Purchasing Under a Hypothetical Reduced-Nicotine Cigarette Standard.

INTRODUCTION: The Tobacco Control Act gives the U.S. Food and Drug Administration authority to establish a reduced-nicotine content standard in combusted cigarettes. This future potential regulation may pose a significant public health benefit; however, black markets may arise to meet demand for normal-nicotine content cigarettes among smokers unwilling to transition to or use an alternative product. AIMS AND METHODS: We determined the behavioral-economic substitutability of illicit normal-nicotine content cigarettes and e-cigarettes for reduced-nicotine content cigarettes in a hypothetical reduced-nicotine regulatory market. Adult cigarette smokers were recruited online to complete hypothetical cigarette purchasing tasks for usual-brand cigarettes, reduced-nicotine content cigarettes, and illicit normal-nicotine content cigarettes, as well as a cross-commodity task in which reduced-nicotine content cigarettes were available across multiple prices and illicit cigarettes were concurrently available for $12/pack. Participants completed two three-item cross-commodity purchasing tasks in which e-cigarettes were available for $4/pod or $12/pod alongside reduced-nicotine content cigarettes and illicit cigarettes. RESULTS: Usual-brand cigarette purchasing was greater than illicit normal-nicotine content cigarettes and less than reduced-nicotine content cigarettes. In the cross-commodity purchasing tasks, illicit cigarettes and e-cigarettes both served as economic substitutes for reduced-nicotine content cigarettes; however, when e-cigarettes were available for $4/pod, they were purchased at greater levels than illicit cigarettes and resulted in greater reductions in reduced-nicotine content cigarettes purchasing than when available for $12/pod. CONCLUSIONS: These data suggest that some smokers are willing to engage in illicit cigarette purchasing in a reduced-nicotine regulatory environment, but e-cigarette availability at lower prices may reduce black-market engagement and shift behavior away from combusted cigarette use. IMPLICATIONS: E-cigarettes available at low, but not high, prices were stronger substitutes for legal, reduced-nicotine content cigarettes than illegal, normal-nicotine content cigarettes in a hypothetical reduced-nicotine tobacco market. Our findings suggest the availability of relatively inexpensive e-cigarettes may reduce illicit cigarette purchasing and combusted cigarette use under a reduced-nicotine cigarette standard.

Association of Hospice Profit Status With Family Caregivers' Reported Care Experiences.

Importance: Expansive growth in the US hospice market has been driven almost exclusively by an increase in for-profit hospices. Prior research found that, in contrast to not-for-profit hospices, for-profit hospices focus on delivering care to patients in nursing homes, provide fewer nursing visits, and use less skilled staff. However, prior studies have not reported on the associations of these differences in care patterns with hospice care quality. Patient- and family-centeredness is a core element of hospice care quality that is measured through surveys of care experiences. Objective: To examine whether differences in profit status are associated with family caregivers' reports of hospice care experiences and assess factors that may be associated with observed differences in care experiences by profit status. Design, Setting, and Participants: Consumer Assessment of Healthcare Providers and Systems (CAHPS) Hospice Survey data from 653 208 caregiver respondents, reflecting care received from 3107 hospices between April 2017 and March 2019, were used for a cross-sectional examination of hospice care experiences by profit status. Data analysis was performed from January 2020 to November 2022. Main Outcomes and Measures: Outcomes were case-mix-adjusted and mode-adjusted top-box scores for 8 measures of hospice care experiences, including communication, timely care, symptom management, and emotional and religious support, as well as a summary score averaging across measures. Linear regression examined the association between profit status and hospice-level scores, adjusting for other organizational and structural hospice characteristics. Results: There were 906 not-for-profit and 1761 for-profit hospices with mean (SD) time in operation of 25.7 (7.8) years and 13.8 (8.0) years, respectively. Mean (SD) decedent age at death was 82.8 (2.3) years, similar for not-for-profit and for-profit hospices. The mean proportion of patients who were Black, Hispanic, and White was 4.9%, 0.9%, and 91.4% for not-for-profit hospices and 9.0%, 2.2%, and 85.4% for for-profit hospices, respectively. Family caregivers reported worse care experiences at for-profit hospices than at not-for-profit hospices for all measures. Significant differences in average hospice performance by profit status remained after adjusting for hospice characteristics. However, for-profit hospice performance varied, with 548 of 1761 (31.1%) for-profit hospices scoring 3 or more points below the national hospice average of overall performance and 386 of 1761 (21.9%) scoring 3 or more points above the average. In contrast, only 113 of 906 (12.5%) not-for-profit hospices scored 3 or more points below the average, and 305 of 906 (33.7%) scored 3 or more points above the average. Conclusions and Relevance: In this cross-sectional study of CAHPS Hospice Survey data, caregivers of patients receiving hospice care reported substantially worse care experiences in for-profit than in not-for-profit hospices; however, there was variation in reported experiences among both types of hospices. Public reporting of hospice quality is important.

MACRA Palliative Care Quality Measure Development-Testing Summary Report: Measure Name: Receiving Desired Help for Pain.

Palliative care has expanded rapidly in the past 20 years, especially in the ambulatory (office) setting, and there is growing consensus regarding the need to systematically measure and incentivize high-quality care. The Centers for Medicare & Medicaid Services entered a cooperative agreement with the American Academy of Hospice and Palliative Medicine (AAHPM) as part of the Medicare Access and CHIP Reauthorization Act of 2015 to develop two patient-reported measures of ambulatory palliative care experience: Feeling Heard and Understood and Receiving Desired Help for Pain. Under contract to AAHPM, RAND Health Care researchers developed and tested both measures over a three-year project period. Researcher efforts included identifying, developing, testing, and validating appropriate patient-reported data elements for each measure; developing and fielding a survey instrument to collect necessary data in a national beta field test with 44 ambulatory palliative care programs; and collecting and analyzing data about measure reliability and validity to establish measure performance and final specifications. Further, the authors elicited provider and program perspectives on the use and value of the performance measures and their implementation and elicited the perspectives of patients from racial and ethnic minorities to understand their experience of ambulatory palliative care and optimal approaches to measurement. In this study, the authors present results from their test of the Receiving Desired Help for Pain performance measure, which they demonstrate to be a reliable and valid measure that is ready for use in quality improvement and quality payment programs.

MACRA Palliative Care Quality Measure Development-Testing Summary Report: Measure Name: Feeling Heard and Understood.

Palliative care has expanded rapidly in the past 20 years, especially in the ambulatory (office) setting, and there is growing consensus regarding the need to systematically measure and incentivize high-quality care. The Centers for Medicare & Medicaid Services entered a cooperative agreement with the American Academy of Hospice and Palliative Medicine (AAHPM) as part of the Medicare Access and CHIP Reauthorization Act of 2015 to develop two patient-reported measures of ambulatory palliative care experience: Feeling Heard and Understood and Receiving Desired Help for Pain. Under contract to AAHPM, RAND Health Care researchers developed and tested both measures over a three-year project period. Researcher efforts included identifying, developing, testing, and validating appropriate patient-reported data elements for each measure; developing and fielding a survey instrument to collect necessary data in a national beta field test with 44 ambulatory palliative care programs; and collecting and analyzing data about measure reliability and validity to establish measure performance and final specifications. Further, the authors elicited provider and program perspectives on the use and value of the performance measures and their implementation and elicited the perspectives of patients from racial and ethnic minorities to understand their experience of ambulatory palliative care and optimal approaches to measurement. In this study, the authors present results from their test of the Feeling Heard and Understood performance measure, which they demonstrate to be a reliable and valid measure that is ready for use in quality improvement and quality payment programs.

Adjusting for Patient Characteristics to Compare Quality of Care Provided by Serious Illness Programs.

Background: To compare serious illness programs (SIPs) using recently developed patient experience measures, adjustment must be made for patient characteristics not under control of the programs. Objectives: To develop a case-mix adjustment model to enable fair comparison of patient experience between SIPs by investigating the roles of patient characteristics, proxy response, and mode of survey administration (mail-only vs. mail with telephone follow-up) in survey responses. Methods: Using survey data from 2263 patients from 32 home-based SIPs across the United States, we fit regression models to assess the association between patient-level variables and scores for seven quality measures (Communication, Care Coordination, Help for Symptoms, Planning for Care, Support for Family and Friends, and two global assessments of care). Characteristics that are not consequences of the care the program delivered were considered as adjustors. Results: Final recommended case-mix adjustors are age, education, primary diagnosis, self-reported functional status, self-rated physical health, self-rated mental health, proxy respondent use, and response percentile (a measure of how soon a person responded compared with others in the same program and mode). Age, primary diagnosis, self-rated mental health, and proxy respondent use had the most impact on program-level scores. We also recommend adjusting for mode of survey administration. We find that up to 12 percent of pairs of programs would have their rankings reversed by adjustment. Conclusions: To ensure fair comparison of programs, scores should be case-mix adjusted for variables that influence patients' reports about care quality, but are not under the control of the program administering care.

Reliable and Valid Survey-Based Measures to Assess Quality of Care in Home-Based Serious Illness Programs.

Background: There is a pressing need for standardized measures to assess the quality of home-based serious illness care. Currently, there are no validated quality measures that are specific to home-based serious illness programs (SIPs) and the unique needs of their patients. Objective: To develop and evaluate standardized survey-based measures of serious illness care experiences for assessing and comparing quality of home-based serious illness care programs. Methods: From October 2019 through January 2020, we administered a survey to patients who received care from 32 home-based SIPs across the United States. Using the 2263 survey responses, we assessed item performance and constructed composite measures via factor analysis, evaluated item-scale correlations, estimated reliability, and examined validity by regressing overall ratings and willingness to recommend care on each composite. Results: The overall survey response rate was 36%. Confirmatory factor analyses supported five composite quality measures: Communication, Care Coordination, Help for Symptoms, Planning for Care, and Support for Family and Friends. Cronbach's alpha estimates for the composite measures ranged from 0.69 to 0.85, indicating adequate internal consistency in assessing their underlying constructs. Interprogram reliability ranged from 0.67 to 0.80 at 100 completed surveys per measure, meeting common standards for distinguishing between programs' performance. Together, the composites explained 45% of the variance in patients' overall care ratings. Communication, Care Coordination, and Planning for Care were the strongest predictors of overall ratings. Conclusion: Our analyses provide evidence of the feasibility, reliability, and validity of proposed survey-based measures to assess the quality of home-based serious illness care from the perspective of patients and their families.

Genome sequencing for detection of pathogenic deep intronic variation: A clinical case report illustrating opportunities and challenges.

Variants in JAM3 have been reported in four families manifesting a severe autosomal recessive disorder characterized by hemorrhagic destruction of the brain, subependymal calcification, and cataracts. We describe a 7-year-old male with a similar presentation found by research-based quad genome sequencing to have two novel splicing variants in trans in JAM3, including one deep intronic variant (NM_032801.4: c.256+1260G>C) not detectable by standard exome sequencing. Targeted sequencing of RNA isolated from transformed lymphoblastoid cell lines confirmed that each of the two variants has a deleterious effect on JAM3 mRNA splicing. The role for genome sequencing as a clinical diagnostic test extends to those patients with phenotypes strongly suggestive of a specific Mendelian disorder, especially when the causal genetic variant(s) are not found by a more targeted approach. Barriers to diagnosis via identification of pathogenic deep intronic variation include lack of laboratory consensus regarding in silico splicing prediction tools and limited access to clinically validated confirmatory RNA experiments.

"If We Turned Our Backs, They Would Ignore Our Wishes": Bereaved Family Perceptions of Concordance of Care at the End of Life.

Background: The key to high-quality care at the end of life is goal-concordant care, defined as care that is consistent with patient wishes. Objectives: To characterize decedent wishes for care at the end of life and to examine next of kin narratives of their loved ones' perceptions of whether wishes were honored. Design: Mortality follow-back survey and in-depth interviews. Setting/Subjects: Survey responses (n = 601) were from next of kin of decedents who died in the San Francisco Bay area of the United States. Interviews were conducted with 51 next of kin, of whom 14 indicated that the decedent received care that was inconsistent with their wishes. Measurements: The survey asked if the decedent had wishes or plans for care and if care provided ever went against those wishes. In-depth interviews focused on aspects of care at the end of life that were not consistent with the decedent's wishes. Results: Approximately 10% of next of kin who reported on the survey that the decedent had specific wishes for medical care at the end of life also reported that the decedent received care that went against their wishes in the last month of life. The main theme of the in-depth interviews with next of kin who reported care that went against wishes was that discordant care was inconsistent with wishes for comfort-focused care and a lack of symptom palliation. Conclusions: Despite decades of work to improve quality of end-of-life care, poor pain and symptom management that result in lack of comfort remain the main reason that next of kin state wishes were not honored.

Bereaved Family More Likely to Report "Too Little" Care than "Too Much" Care at the End of Life.

Background: An often-stated concern is that dying persons receive too much aggressive medical care. Objective: Examine next-of-kin perceptions of the amount of medical care received in the last month of life. Design: Mixed-methods study with 623 survey responses and in-depth interviews with a subsample of 17 respondents. Subjects: Nontraumatic deaths 18 years and older in San Francisco Bay area. Measure: The survey asked: "During the last month of your family member's life, did he or she receive too little, the right amount, or too much medical care?" Additionally, surveys examined 18 measures of quality of care in the last month of life, reporting concerns or unmet needs with staff communication, symptom management, emotional support, physician communication, treating the patient with dignity, respecting a person's culture, spiritual support, and providing timely help after hours. Results: Of the 623 survey respondents, 16.9% reported their loved one received "too little" care while only 1.4% reported "too much." Likelihood of reporting too little medical care did not differ by age, gender, or being insured by Medicaid only. Respondents who reported "too little" compared with those that stated the "right amount" reported higher unmet needs for symptom palliation, physician communication concerns, with other important opportunities to improve the quality of care. Among the 17 in-depth interviews of those indicating "too little" care on the structured survey, the predominant concern (n = 10) was inadequate symptom management. Conclusion: While the majority of respondents indicated their loved one received the right amount of medical care at the end of life, a notable minority (one in six) indicated that their loved one received too little care.

Racial Differences in End-of-Life Care Quality between Asian Americans and Non-Hispanic Whites in San Francisco Bay Area.

Background: Little is known about end-of-life care experiences of Asian Americans and gaps in end-of-life care quality between Asians and non-Hispanic whites. Objective: Compare the perceptions of next-of-kin of Asian and non-Hispanic white decedents on end-of-life care quality. Design: Mortality follow-back survey. Setting/Subjects: Population-based sample of 108 Asian and 414 non-Hispanic white bereaved family members or close friends of adult, nontraumatic deaths in the San Francisco Bay area in 2018. Measurements: Survey items examined whether health care professionals treated the dying person with respect and dignity, respected their cultural traditions, respected their religious or spiritual beliefs, provided enough information about what to expect during the last month of life, provided emotional support to the family after the patient's death, and whether the dying person and the family received the needed help after work hours. Results: Of the 623 surveys (weighted n = 6513), 108 (weighted percentage = 17.6%) were from caregivers of Asian decedents. Almost half of these respondents indicated that they did not always experience respect for their cultural traditions (45.9% vs. 21.8%, p = 0.00) or respect for their religious and spiritual beliefs (42.2% vs. 24.5%, p = 0.01). With the exception of two outcomes, worse caregiver-reported care quality for Asian decedents persisted after adjustment for cause of death, site of death, type of health insurance, respondent's relationship to decedent, decedent age, and respondent education. Conclusions: Compared with caregivers of non-Hispanic whites, caregivers of Asian decedents reported unmet needs for caregiver support and lack of respect for cultural traditions and religious/spiritual beliefs.

Association between Receipt of Emotional Support and Caregivers' Overall Hospice Rating.

Background: A major goal of hospice care is to provide individually tailored emotional and spiritual support to caregivers of hospice patients. Objectives: Examine the association between reported emotional support and caregivers' overall rating of hospice care, overall and by race/ethnicity/language. Subjects: We analyzed survey data corresponding to 657,805 decedents/caregivers who received care from 3160 hospice programs during January 2017-December 2018. Measurements: Linear regression models examined the association between caregiver-reported receipt of emotional and spiritual support ("too little" vs. "right amount" vs. "too much") and overall rating of the hospice (0 vs. 100 rating). Interaction terms assessed variation in this association by race/ethnicity/language. Results: "Too much" emotional support was less common than "too little," except for caregivers of Hispanic decedents responding in Spanish. "Too little" support was strongly associated with lower hospice ratings for all groups (compared to "right amount" of support, p < 0.001). In contrast, the negative association between "too much" support and hospice rating was much smaller (p < 0.001) among caregivers of white and black decedents. "Too much" support was associated with more positive ratings among caregivers of Hispanic decedents (p < 0.001). Conclusions: Receipt of "too much" support is a less common and much weaker driver of poor hospice ratings than receipt of "too little" support for all groups, and is not always viewed negatively. This suggests that for hospice evaluation, "too much" support should not be scored equivalently to "too little" support and that providing enough support should be a hospice priority.

Characteristics of Hospices Providing High-Quality Care.

Background: The hospice market has changed substantially, shifting from predominately not-for-profit independent entities to for-profit national chains. Little is known about how hospice organizational characteristics are associated with quality of hospice care. Objective: To examine the association between hospice characteristics and care processes and performance on measures of hospice care quality. Design: Logistic regression models assessed the association between hospice characteristics and processes and hospices being in the top quartile of quality measure performance. Setting/Subjects: U.S. hospices with publicly reported measure scores in 2015-2017. Measurements: Summaries of hospice-level performance on Consumer Assessment of Healthcare Providers and Systems (CAHPS) Hospice Survey measures (including communication, timely care, symptom management, emotional and spiritual support, respect, training families, overall rating, and willingness to recommend) and Hospice Item Set (HIS) measures (including pain screening and assessment, dyspnea screening and treatment, bowel regimen for patients on opioids, discussion of treatment preferences, and beliefs/values addressed). Results: Of the 2746 hospices that met public reporting requirements, 5.6% were in the top quartile of both CAHPS and HIS performance. Characteristics associated with being in the top quartile for CAHPS included being a nonprofit and nonchain or government hospice, smaller size (<200 patients per year), and serving a rural area. Characteristics associated with being in the top quartile for HIS included being in a for-profit chain, larger size (91+ patients per year), and having <40% of patients in a nursing home. Providing professional staff visits in the last two days of life to a higher proportion of patients was associated with hospices being in the top quartile of HIS and in the top quartile of CAHPS. Conclusions: Hospice characteristics associated with strong performance on HIS measures differ from those associated with strong performance on CAHPS measures. Providing professional staff visits in the last two days of life is associated with high performance on both quality domains.

Development of Valid and Reliable Measures of Patient and Family Experiences of Hospice Care for Public Reporting.

BACKGROUND: Increasingly, dying patients and their families have a choice of hospice providers. Care quality varies considerably across providers; informing consumers of these differences may help to improve their selection of hospices. OBJECTIVE: To develop and evaluate standardized survey measures of hospice care experiences for the purpose of comparing and publicly reporting hospice performance. DESIGN: We assessed item performance and constructed composite measures by factor analysis, evaluating item-scale correlations and estimating reliability. To assess key drivers of overall experiences, we regressed overall rating and willingness to recommend the hospice on each composite. SETTING/SUBJECTS: Data submitted by 2500 hospices participating in national implementation of the Consumer Assessment of Healthcare Providers and Systems (CAHPS®) Hospice Survey for April through September 2015. MEASUREMENTS: Composite measures of Hospice Team Communication, Getting Timely Care, Treating Family Member with Respect, Getting Emotional and Religious Support, Getting Help for Symptoms, and Getting Hospice Care Training. RESULTS: Cronbach's alpha estimates for the composite measures range from 0.61 to 0.85; hospice-level reliability for the measures range from 0.67 to 0.81 assuming 200 completed surveys per hospice. Together, the composites are responsible for 48% of the variance in caregivers' overall ratings of hospices. Hospice Team Communication is the strongest predictor of overall rating of care. CONCLUSION: Our analyses provide evidence of the reliability and validity of CAHPS Hospice Survey measure scores. Results also highlight important opportunities to improve the quality of hospice care, particularly with regard to addressing symptoms of anxiety and sadness, discussing side effects of pain medicine, and keeping family informed of the patient's condition.

4-Hydroxyhexenal (HHE) impairs glutamate transport in astrocyte cultures.

Multiple studies show elevations of α,ß-unsaturated aldehydic by-products of lipid peroxidation including 4-hydroxynonenal and acrolein in vulnerable brain regions of subjects throughout the progression of Alzheimer's disease (AD). More recently 4-hydroxyhexenal (HHE), a diffusible α,ß-unsaturated aldehyde resulting from peroxidation of ω-3 polyunsaturated fatty acids, was shown to be elevated in the hippocampus/parahippocampal gyrus (HPG) of subjects with preclinical AD (PCAD) and in late stage AD (LAD). HHE treatment of primary rat cortical neuron cultures led to a time- and concentration-dependent decrease in survival and glucose uptake. To determine if HHE also impairs glutamate uptake, primary rat astrocyte cultures were exposed to HHE for 4 hours and glutamate transport measured. Results show subtoxic (2.5 µM) HHE concentrations significantly (p < 0.05) impair glutamate uptake in primary astrocytes. Immunoprecipitation of excitatory amino acid transporter-2 (EAAT-2), the primary glutamate transporter in brain, from normal control, mild cognitive impairment (MCI), PCAD, and LAD HPG followed by quantification of HHE immunolabeling showed a significant increase in HHE positive EAAT-2 in MCI and LAD HPG. Together these data suggest HHE can significantly impair glutamate uptake and may play a role in the pathogenesis of AD.