Long-term follow-up of participants in ketamine clinical trials for mood disorders.

BACKGROUND: Participants who received ketamine at the NIMH were among the first to receive ketamine for depression in controlled clinical trials, providing a unique opportunity to assess long-term outcomes. This analysis evaluated the relationship between participating in a ketamine clinical trial and subsequent ketamine/esketamine use after leaving the research setting. METHODS: Participants seen within the NIMH Experimental Therapeutics and Pathophysiology Branch from 2002 to 2022 (n = 1000) were contacted for follow-up assessment. Participants reported whether they had used ketamine/esketamine, sought non-prescribed ketamine, attempted suicide, or been psychiatrically hospitalized since discharge. Information regarding their recent depressive symptoms, dissociative symptoms, and hallucinations was also collected. RESULTS: Of the 203 participants in follow-up assessments (55 % female, average time since leaving NIMH = 9.04 years), 52 (25.6 %) had originally received ketamine at the NIMH, and the rest had participated in non-ketamine studies. Individuals who had received ketamine at the NIMH were more likely to have received ketamine/esketamine post-discharge than those who did not receive ketamine at the NIMH (OR = 0.25, p < .001). Participants who reported using ketamine/esketamine post-discharge reported more depressive symptoms than those who had not (p < .001). Receiving ketamine at the NIMH was not associated with differences in suicide attempts, psychiatric hospitalizations, dissociation, hallucinations, or attempt to obtain non-prescribed ketamine. LIMITATIONS: Low follow-up study participation rate; varying time since discharge. CONCLUSIONS: Participants who received ketamine in an NIMH clinical trial were more likely to receive ketamine/esketamine post-discharge, but none reported symptoms indicating abuse. Results underscore the critical need for long-term follow-up of individuals receiving these and other rapid-acting antidepressants. CLINICAL TRIALS IDENTIFIER: NCT04877977.

Emergency services utilization by patients with alcohol-associated hepatitis: An analysis of national trends.

BACKGROUND: Hospitalization and mortality in patients with alcohol-associated hepatitis (AH), a severe form of liver disease, continue to increase over time. Given the severity of the illness, most hospitalized patients with AH are admitted from the emergency department (ED). However, there are no data on ED utilization by patients with AH. Thus, the Nationwide Emergency Department Sample (NEDS) dataset was analyzed to determine the ED utilization for AH. METHODS: Temporal trends (2016-2019) and outcomes of ED visits for AH were determined. Primary or secondary AH diagnoses were based on coding priority. Numbers of patients evaluated in the ED, severity of disease, complications of liver disease, and discharge disposition were analyzed. Crude and adjusted rates were examined, and temporal trends evaluated using logistic regression with orthogonal polynomial contrasts for each year. RESULTS: There were 466,014,370 ED visits during 2016-2019, of which 448,984 (0.096%) were for AH, 85.0% of which required hospitalization. The rate of visits for AH (primary and secondary) between 2016 and 2019 increased from 85 to 106.8/100,000 ED visits. The rate of secondary AH increased more than the rate of primary AH (from 68.6 to 86.5 vs. from 16.4 to 20.3/100,000 ED visits). Patients aged 45-64 years had the highest rate of ED visits for AH, which decreased during the study period, while the rate of ED visits for AH increased in those aged 25-44 years (from 38.5% to 42.9%). The severity of disease (ascites, hepatic encephalopathy, and acute kidney injury) also increased over time. Medicaid and private insurance were the most common payors for patients seeking care in the ED for AH. CONCLUSIONS: Temporal trends show an overall increase in ED utilization rates for AH, more patients requiring hospitalization, and an increase in the proportion of younger patients presenting to the ED with AH.

Phencyclidine Positivity on Urine Drug Screening in Patients Treated for Alcohol Withdrawal on a Dual-diagnosis Medically Assisted Withdrawal Unit.

OBJECTIVES: Little contemporary research has explored phencyclidine (PCP) use in people with alcohol use disorder. Therefore, we sought to determine the prevalence of PCP positivity on urine toxicology screening among patients admitted for alcohol withdrawal, identify correlates of PCP positivity, and investigate PCP positivity's relationship to length of stay (LOS) and risk of facility readmission. METHODS: This was a retrospective study of patients admitted to a dual-diagnosis medically assisted withdrawal unit for alcohol withdrawal from 2014 to 2019. Univariate tests and logistic regression were used to investigate potential correlates of PCP positivity on admission toxicology screening (primary outcome). Multivariable linear regression models and survival analyses analyzing LOS and risk of readmission (secondary outcomes) were also developed. RESULTS: Ninety of 3731 patients (2.4%) screened positive for PCP. There were significant associations on univariate testing between PCP positivity and age, race, homeless status, and urine toxicology positivity for amphetamines, benzodiazepines, barbiturates, cocaine, tetrahydrocannabinol, and oxycodone. On multivariate logistic regression, only tetrahydrocannabinol, barbiturates, and cocaine positivity were associated with PCP positivity. Multivariate logistic regression and survival analysis found no statistically significant associations between PCP positivity and LOS or risk of readmission. CONCLUSIONS: This study provides rare analysis of contemporary data on PCP use among patients undergoing medically assisted alcohol withdrawal. Phencyclidine positivity was uncommon, but use appears considerably higher among this patient population than the general population. There was no significant association between PCP positivity and LOS or readmission risk.

Emergency department evaluation of nurse triage questions about safe-at-home and abuse or neglect in traumatic ocular injuries.

OBJECTIVES: Approximately 10 million Americans experience acts of physical violence by an intimate partner (IPV). Ocular injuries can present as a symptom of IPV in the emergency department, but IPV remains underreported in the literature. Understanding the incidence and trends in IPV-associated ocular injuries in the emergency department could increase the detection of at-risk patients otherwise overlooked. DESIGN: Retrospective chart review. PARTICIPANTS: Emergency department patients evaluated for traumatic ocular injuries between January 2018 and April 2023 at a large tertiary care health system. METHODS: The study population was identified by ICD-10 code and their responses to being screened at triage for home safety and any nursing concerns for abuse or neglect. Patient screening consisted of a 2-part questionnaire inquiring first about whether the patient feels safe at home ("Yes" or "No") and second regarding nurses' concerns for abuse, neglect, domestic violence, sexual assault, or human trafficking. RESULTS: There were 2,653,993 emergency department visits and 16,737 traumatic ocular injuries in the study period. Of them, 1.1% of patients (154 of 14,457) responded "No" to feeling safe at home. In only 0.6% of patients (82 of 14,457), a nursing concern was documented. Patients responding "No" to feeling safe at home presented with more severe ocular injuries such as maxillary fractures. On regression analysis, married, divorced, and widowed patients as well as patients on private insurance were less likely to report feeling unsafe at home than single patients on public insurance (p < 0.05). CONCLUSION: Traumatic ocular injuries in emergency departments should raise concerns about IPV. Opportunity exists to improve education, screening, and management of these patients.

Participants' Engagement With and Results From a Web-Based Integrative Population Mental Wellness Program (CHAMindWell) During the COVID-19 Pandemic: Program Evaluation Study.

BACKGROUND: The COVID-19 pandemic involved a prolonged period of collective trauma and stress during which substantial increases in mental health concerns, like depression and anxiety, were observed across the population. In this context, CHAMindWell was developed as a web-based intervention to improve resilience and reduce symptom severity among a public health care system's patient population. OBJECTIVE: This program evaluation was conducted to explore participants' engagement with and outcomes from CHAMindWell by retrospectively examining demographic information and mental health symptom severity scores throughout program participation. METHODS: We examined participants' symptom severity scores from repeated, web-based symptom screenings through Computerized Adaptive Testing for Mental Health (CAT-MH) surveys, and categorized participants into symptom severity-based tiers (tier 1=asymptomatic to mild; tier 2=moderate; and tier 3=severe). Participants were provided tier-based mindfulness resources, treatment recommendations, and referrals. Logistic regressions were conducted to evaluate associations between demographic variables and survey completion. The McNemar exact test and paired sample t tests were performed to evaluate changes in the numbers of participants in tier 1 versus tier 2 or 3 and changes in depression, anxiety, and posttraumatic stress disorder severity scores between baseline and follow-up. RESULTS: The program enrolled 903 participants (664/903, 73.5% female; 556/903, 61.6% White; 113/903, 12.5% Black; 84/903, 9.3% Asian; 7/903, 0.8% Native; 36/903, 4% other; and 227/903, 25.1% Hispanic) between December 16, 2020, and March 17, 2022. Of those, 623 (69%) completed a baseline CAT-MH survey, and 196 completed at least one follow-up survey 3 to 6 months after baseline. White racial identity was associated with completing baseline CAT-MH (odds ratio [OR] 1.80, 95% CI 1.14-2.84; P=.01). Participants' odds of having symptom severity below the clinical threshold (ie, tier 1) were significantly greater at follow-up (OR 2.60, 95% CI 1.40-5.08; P=.001), and significant reductions were observed across symptom domains over time. CONCLUSIONS: CHAMindWell is associated with reduced severity of mental health symptoms. Future work should aim to address program engagement inequities and attrition and compare the impacts of CHAMindWell to a control condition to better characterize its effects.

An Open-Label Study of Adjunctive Dextromethorphan/Quinidine in Treatment-Resistant Depression.

BACKGROUND: Approximately one third of individuals with major depressive disorder have treatment-resistant depression (TRD). Glutamatergic modulators such as the N -methyl- d -aspartate receptor antagonist ketamine have rapid and robust antidepressant effects, but their use has been limited by accessibility and route of administration. This open-label pilot study assessed the adjunctive antidepressant efficacy of dextromethorphan/quinidine (DM/Q) in TRD. METHODS: Inpatients with TRD (n = 17, 40.8 ± 12.3 years; 9 females/8 males) received adjunctive open-label DM/Q (20 mg/10 mg) up to 3 times daily. The study had no set endpoint; participants were followed until they discontinued DM/Q or were discharged. Montgomery-Asberg Depression Rating Scale (MADRS) scores were obtained at baseline (before DM/Q administration) and regularly during hospitalization. Full response was defined as a ≥50% reduction in baseline MADRS score, partial response as a 25% to 50% decrease in baseline MADRS score, and nonresponse as a <25% reduction or an increase in baseline MADRS score. RESULTS: The 17 inpatients received open-label DM/Q for 5.1 ± 2.7 weeks. Forty-seven percent of participants responded to DM/Q-12% achieved a full response and 35% achieved a partial response. The largest MADRS difference observed at any time point was -6.4 ± 8.4 (-21.0% ± 29.9%), and the MADRS difference observed at time of DM/Q discontinuation or hospital discharge was -4.8 ± 8.4 (-15.9% ± 29.7%). Twenty-four percent of participants experienced a nonserious adverse event; none experienced a serious adverse event. CONCLUSIONS: In this open-label pilot study, 47% of participants responded to adjunctive DM/Q, which was well tolerated. Larger placebo-controlled trials are needed to determine the real-world efficacy of DM/Q.

Care Management of Comorbid Medical and Psychiatric Illness: A Conceptual Framework for Improving Equity of Care.

Psychiatric and medical comorbidities are common among adults in the United States. Due to the complex interplay between medical and psychiatric illness, comorbidities result in substantial disparities in morbidity, mortality, and health care costs. There is, thus, both an ethical and fiscal imperative to develop care management programs to address the needs of individuals with comorbid conditions. Although there is substantial evidence supporting the use of care management for improving health outcomes for patients with chronic diseases, the majority of interventions described in the literature are condition-specific. Given the prevalence of comorbidities, the authors of this article reviewed the literature and drew on their clinical expertise to guide the development of future multimorbidity care management programs. Their review yielded one study of multimorbidity care management and two studies of multimorbidity collaborative care. The authors supplemented their findings by describing three key pillars of effective care management, as well as specific interventions to offer patients based on their psychiatric diagnoses and illness severity. The authors proposed short-, medium-, and long-term indicators to measure and track the impact of care management programs on disparities in care. Future studies are needed to identify which elements of existing multimorbidity collaborative care models are active ingredients, as well as which of the suggested supplemental interventions offer the greatest value.

Characterization of ophthalmic presentations to emergency departments in the United States: 2010-2018.

BACKGROUND: Both traumatic and nontraumatic ocular issues often present to the emergency department. Understanding the epidemiology of ocular presentations to the emergency department not only informs current resource allocation, but also provides opportunities to evaluate the efficacy of prior healthcare access interventions. PURPOSE: To characterize emergency department utilization in the United States for ophthalmic encounters between 2010 and 2018. METHODS: Cross-sectional analysis of the National Hospital Ambulatory Medical Care Survey database, a nationally representative sample of United States emergency department visits. 4284 deidentified emergency department patient encounters with an ICD-10 ophthalmic diagnosis from 2010 to 2018 were analyzed. The main outcome measures were the composition and characteristics of ophthalmic emergency department encounters over time. MAIN FINDINGS: 4284 ophthalmic visits were identified which represented an estimated 23.1 million visits (95% CI, 20.8 million-25.5 million). 31.6% (95% CI, 29.6-33.8) of ophthalmic visits were traumatic. Conjunctivitis was the most common non-traumatic diagnosis (32.8%, 95% CI, 30.7-35.0), while superficial injury of the cornea was the most common traumatic diagnosis (13.9%, 95% CI, 12.5-15.3). A greater proportion of emergency department visits involving the sclera and cornea were made by men (58.7%, 95% CI, 53.7%-63.6%; P = 0.02), whereas more women visited for visual disturbances (57.8%, 95% CI, 51.3%-64.4%; P = 0.01). Longitudinal trends of ophthalmic visits revealed an increase in public insurance payers in 2014, which corresponds to Medicaid expansion and implementation of mandated coverage for pediatric vision care. After stratification, this increase continued to be present in nontraumatic visits, but not traumatic ones. CONCLUSIONS: Ophthalmic emergency department visits in the United States between 2010 and 2018 were typically for non-traumatic eye issues. Diagnoses varied greatly by patient demographics, such as age and gender. Understanding these variations is valuable for preparing emergency departments for ocular presentations and providing guidance for future practice.

Toward Population Health: Using a Learning Behavioral Health System and Measurement-Based Care to Improve Access, Care, Outcomes, and Disparities.

Achieving population behavioral health is urgently needed. The mental health system struggles with enormous challenges of providing access to mental health services, improving quality and equitability of care, and ensuring good health outcomes across subpopulations. Little data exists about increasing access within highly constrained resources, staging/sequencing treatment along care pathways, or personalizing treatments. The conceptual model of the learning healthcare system offers a potential paradigm shift for addressing these challenges. In this article we present an overview of how the three constructs of population health, learning health systems, and measurement-based care are inter-related, and we provide an example of how one academic, community-based, safety net health system is approaching integrating these paradigms into its service delivery system. Implementation outcomes will be described in a subsequent publication. We close by discussing how ultimately, to meaningfully improve population behavioral health, a learning healthcare system could expand into a learning health community in order to target critical points of prevention and intervention.

Remote Care Management for Older Adult Populations With Elevated Prevalence of Depression or Anxiety and Comorbid Chronic Medical Illness: A Systematic Review.

BACKGROUND: Comorbidity of psychiatric and medical illnesses among older adult populations is highly prevalent and associated with adverse outcomes. Care management is a common form of outpatient support for both psychiatric and medical conditions in which assessment, care planning, and care coordination are provided. Although care management is often remote and delivered by telephone, the evidence supporting this model of care is uncertain. OBJECTIVE: To perform a systematic review of the literature on remote care management programs for older adult populations with elevated prevalence of depression or anxiety and comorbid chronic medical illness. METHODS: A systematic review was performed in accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. A multidatabase search was performed. Articles were included for review if they studied fully remote care management for older adult populations with elevated prevalence of depression or anxiety and chronic medical illness or poor physical health. A narrative synthesis was performed. RESULTS: A total of 6 articles representing 6 unique studies met inclusion criteria. The 6 studies included 4 randomized controlled trials, 1 case-matched retrospective cohort study, and 1 pre-post analysis. Two studies focused on specific medical conditions. All interventions were entirely telephonic. Five of 6 studies involved an intervention that was 3 to 6 months in duration. Across the 6 studies, care management demonstrated mixed results in terms of impact on psychiatric outcomes and limited impact on medical outcomes. No studies demonstrated a statistically significant impact on health care utilization or cost. CONCLUSIONS: Among older adult populations with elevated prevalence of depression or anxiety and comorbid chronic medical illness, remote care management may have favorable impact on psychiatric symptoms, but impact on physical health and health care utilization is uncertain. Future research should focus on identifying effective models and elements of remote care management for this population, with a particular focus on optimizing medical outcomes.

Creating Matched In vivo/In vitro Patient-Derived Model Pairs of PDX and PDX-Derived Organoids for Cancer Pharmacology Research.

Patient-derived tumor xenografts (PDXs) are considered the most predictive preclinical models, largely believed to be driven by cancer stem cells (CSC) for conventional cancer drug evaluation. A large library of PDXs is reflective of the diversity of patient populations and thus enables population based preclinical trials ("Phase II-like mouse clinical trials"); however, PDX have practical limitations of low throughput, high costs and long duration. Tumor organoids, also being patient-derived CSC-driven models, can be considered as the in vitro equivalent of PDX, overcoming certain PDX limitations for dealing with large libraries of organoids or compounds. This study describes a method to create PDX-derived organoids (PDXO), thus resulting in paired models for in vitro and in vivo pharmacology research. Subcutaneously-transplanted PDX-CR2110 tumors were collected from tumor-bearing mice when the tumors reached 200-800 mm3, per an approved autopsy procedure, followed by removal of the adjacent non-tumor tissues and dissociation into small tumor fragments. The small tumor fragments were washed and passed through a 100 µm cell strainer to remove the debris. Cell clusters were collected and suspended in basement membrane extract (BME) solution and plated in a 6-well plate as a solid droplet with surrounding liquid media for growth in a CO2 incubator. Organoid growth was monitored twice weekly under light microscopy and recorded by photography, followed by liquid medium change 2 or 3 times a week. The grown organoids were further passaged (7 days later) at a 1:2 ratio by disrupting the BME embedded organoids using mechanical shearing, aided by addition of trypsin and the addition of 10 µM Y-27632. Organoids were cryopreserved in cryo-tubes for long-term storage, after release from BME by centrifugation, and also sampled (e.g., DNA, RNA and FFPE block) for further characterization.

Promoting Population Behavioral Health in a Safety-Net Health System During the COVID-19 Pandemic.

The COVID-19 pandemic has been expected to lead to substantial increases in need for behavioral health care. A population health framework can facilitate the development of interventions and policies to promote the equitable distribution of care across the population. This column describes the application of population behavioral health principles in a safety-net health system during the pandemic. The approach includes stepped models of care, interventions to target individuals at high behavioral health risk, and measurement-based care. Early data suggest that these strategies have resulted in expanded behavioral health care capacity.

Shear response of granular packings compressed above jamming onset.

We investigate the mechanical response of jammed packings of repulsive, frictionless spherical particles undergoing isotropic compression. Prior simulations of the soft-particle model, where the repulsive interactions scale as a power law in the interparticle overlap with exponent α, have found that the ensemble-averaged shear modulus 〈G(P)〉 increases with pressure P as ∼P^{(α-3/2)/(α-1)} at large pressures. 〈G〉 has two key contributions: (1) continuous variations as a function of pressure along geometrical families, for which the interparticle contact network does not change, and (2) discontinuous jumps during compression that arise from changes in the contact network. Using numerical simulations, we show that the form of the shear modulus G^{f} for jammed packings within near-isostatic geometrical families is largely determined by the affine response G^{f}∼G_{a}^{f}, where G_{a}^{f}/G_{a0}=(P/P_{0})^{(α-2)/(α-1)}-P/P_{0}, P_{0}∼N^{-2(α-1)} is the characteristic pressure at which G_{a}^{f}=0, G_{a0} is a constant that sets the scale of the shear modulus, and N is the number of particles. For near-isostatic geometrical families that persist to large pressures, deviations from this form are caused by significant nonaffine particle motion. We further show that the ensemble-averaged shear modulus 〈G(P)〉 is not simply a sum of two power laws, but 〈G(P)〉∼(P/P_{c})^{a}, where a≈(α-2)/(α-1) in the P→0 limit and 〈G(P)〉∼(P/P_{c})^{b}, where b≳(α-3/2)/(α-1), above a characteristic pressure that scales as P_{c}∼N^{-2(α-1)}.

Management of migraine in the emergency department: Findings from the 2010-2017 National Hospital Ambulatory Medical Care Surveys.

OBJECTIVE: The study objective was to describe trends in the medical management of migraine in the emergency department (ED) using the 2010-2017 National Hospital Ambulatory Medical Care Survey (NHAMCS) datasets. METHODS: Using the 2010-2017 NHAMCS datasets, we analyzed visits with a discharge diagnosis of migraine. Drug prescription frequencies between years were compared with the Rao-Scott chi-squared test. Adjusted odds ratios of opioid administration from 2010 to 2017 were calculated using weighted multivariable logistic regression with sex, age, race/ethnicity, pain-score, primary expected source of payment, and year as predictor variables. RESULTS: Our analysis captured 1846 ED visits with a diagnosis of migraine from 2010 to 2017, representing a weighted average of 1.2 million US ED visits per year. Parenteral opioids were prescribed in 49% (95% CI: 40, 58) of visits in 2010 and 28% (95% CI: 15, 45) of visits in 2017 (p = 0.03). From 2010 to 2017, there was a 10% yearly decrease in opioid prescriptions. Metoclopramide and ketorolac were prescribed more frequently in years 2015 through 2017 than in 2010. Increased opioid administration was associated with female sex, older age, white race, higher pain score, and having Medicare or private insurance as the primary expected source of payment for all years. CONCLUSION: Opioid administration for migraine in EDs across the US declined 10% annually between 2010 and 2017, demonstrating improved adherence to migraine guidelines recommending against opioids. We identified several factors associated with opioid administration for migraine, identifying groups at higher risk for unnecessary opioids in the ED setting.

D-dimer can help differentiate suspected pulmonary embolism patients that require anti-coagulation.

OBJECTIVES: Determine whether D-dimer concentration in the absence of imaging can differentiate patients that require anti-coagulation from patients who do not require anti-coagulation. METHODS: Data was obtained retrospectively from 366 hemodynamically stable adult ED patients with suspected pulmonary embolism (PE). Patients were categorized by largest occluded artery and aggregated into: 'Require anti-coagulation' (main, lobar, and segmental PE), 'Does not require anti-coagulation' (sub-segmental and No PE), 'High risk of deterioration' (main and lobar PE), and 'Not high risk of deterioration' (segmental, sub-segmental, and No PE) groups. Wilcoxon rank-sum test was used for 2 sample comparisons of median D-dimer concentrations. Receiver operating characteristic (ROC) curve analysis was utilized to determine a D-dimer cut-off that could differentiate 'Require anti-coagulation' from 'Does not require anti-coagulation' and 'High risk of deterioration' from 'Low risk of deterioration' groups. RESULTS: The 'Require anti-coagulation' group had a maximum area under the curve (AUC) of 0.92 at an age-adjusted D-dimer cut-off of 1540 with a specificity of 86% (95% CI, 81-91%), and sensitivity of 84% (79-90%). The 'High risk of deterioration' group had a maximum AUC of 0.93 at an age-adjusted D-dimer cut-off of 2500 with a specificity of 90% (85-93%) and sensitivity of 83% (77-90%). CONCLUSIONS: An age-adjusted D-dimer cut-off of 1540 ng/mL differentiates suspected PE patients requiring anti-coagulation from those not requiring anti-coagulation. A cut-off of 2500 differentiates those with high risk of clinical deterioration from those not at high risk of deterioration. When correlated with clinical outcomes, these cut-offs can provide an objective method for clinical decision making when imaging is unavailable.

Harmonized Outcome Measures for Use in Depression Patient Registries and Clinical Practice.

Major depressive disorder is a common mental health condition that affects an estimated 16.2 million adults and 3.1 million adolescents in the United States. Yet, a lack of uniformity remains in measurements and monitoring for depression both in clinical practice and in research settings. This project aimed to develop a minimum set of standardized outcome measures relevant to both patients and clinicians that can be collected in depression registries and clinical practice. Twenty-nine depression registries and related data collection efforts were identified and invited to submit outcome measures. Additional measures were identified through literature searches and reviews of quality measures. A multistakeholder panel representing clinicians; payers; government agencies; industry; and medical specialty, health care quality, and patient advocacy organizations categorized the 27 identified measures using the Agency for Healthcare Research and Quality's supported Outcome Measures Framework. The panel identified 10 broadly relevant measures and harmonized definitions for these measures through in-person and virtual meetings. The harmonized measures represent a minimum set of outcomes that are relevant to clinicians and patients and appropriate for use in depression research and clinical practice. Routine and consistent collection of these measures in registries and other systems would support creation of a national research infrastructure to efficiently address new questions, improve patient management and outcomes, and facilitate care coordination.

An in vivo test of the biologically relevant roles of carotenoids as antioxidants in animals.

Carotenoids are well known for their contribution to the vibrant coloration of many animals and have been hypothesized to be important antioxidants. Surprisingly few examples of carotenoids acting as biologically relevant antioxidants in vivo exist, in part because experimental designs often employ carotenoid doses at levels that are rarely observed in nature. Here, we used an approach that reduces carotenoid content from wild-type levels to test for the effect of carotenoids as protectants against an oxidative challenge. We used the marine copepod Tigriopus californicus reared on a carotenoid-free or a carotenoid-restored diet of nutritional yeast and then exposed them to a pro-oxidant. We found that carotenoid-deficient copepods not only accumulated more damage but also were more likely to die during an oxidative challenge than carotenoid-restored copepods. We suggest that carotenoid reduction, and not supplementation, better tests the proposed roles of carotenoids in other physiological functions in animals.