Spatial and temporal clustering of patients hospitalized with laboratory-confirmed influenza in the United States.

BACKGROUND: Timing of influenza spread across the United States is dependent on factors including local and national travel patterns and climate. Local epidemic intensity may be influenced by social, economic and demographic patterns. Data are needed to better explain how local socioeconomic factors influence both the timing and intensity of influenza seasons to result in national patterns. METHODS: To determine the spatial and temporal impacts of socioeconomics on influenza hospitalization burden and timing, we used population-based laboratory-confirmed influenza hospitalization surveillance data from the CDC-sponsored Influenza Hospitalization Surveillance Network (FluSurv-NET) at up to 14 sites from the 2009/2010 through 2013/2014 seasons (n = 35,493 hospitalizations). We used a spatial scan statistic and spatiotemporal wavelet analysis, to compare temporal patterns of influenza spread between counties and across the country. RESULTS: There were 56 spatial clusters identified in the unadjusted scan statistic analysis using data from the 2010/2011 through the 2013/2014 seasons, with relative risks (RRs) ranging from 0.09 to 4.20. After adjustment for socioeconomic factors, there were five clusters identified with RRs ranging from 0.21 to 1.20. In the wavelet analysis, most sites were in phase synchrony with one another for most years, except for the H1N1 pandemic year (2009-2010), wherein most sites had differential epidemic timing from the referent site in Georgia. CONCLUSIONS: Socioeconomic factors strongly impact local influenza hospitalization burden. Influenza phase synchrony varies by year and by socioeconomics, but is less influenced by socioeconomics than is disease burden.

Association of Hypoactive and Hyperactive Delirium With Cognitive Function After Critical Illness.

OBJECTIVES: Delirium, a heterogenous syndrome, is associated with worse long-term cognition after critical illness. We sought to determine if duration of motoric subtypes of delirium are associated with worse cognition. DESIGN: Secondary analysis of prospective multicenter cohort study. SETTING: Academic, community, and Veteran Affairs hospitals. PATIENTS: Five-hundred eighty-two survivors of respiratory failure or shock. INTERVENTIONS: We assessed delirium and level of consciousness using the Confusion Assessment Method-ICU and Richmond Agitation Sedation Scale daily during hospitalization. We defined a day with hypoactive delirium as a day with positive Confusion Assessment Method-ICU and corresponding Richmond Agitation Sedation Scale score less than or equal to 0 and a day with hyperactive delirium as a day with positive Confusion Assessment Method-ICU and corresponding Richmond Agitation Sedation Scale score greater than 0. At 3 and 12 months, we assessed global cognition with the Repeatable Battery for the Assessment of Neurologic Status and executive function with the Trail Making Test Part B. We used multivariable regression to examine the associations between days of hypoactive and hyperactive delirium with cognition outcomes. We allowed for interaction between days of hypoactive and hyperactive delirium and adjusted for baseline and in-hospital covariates. MEASUREMENTS AND RESULTS: Hypoactive delirium was more common and persistent than hyperactive delirium (71% vs 17%; median 3 vs 1 d). Longer duration of hypoactive delirium was associated with worse global cognition at 3 (-5.13 [-8.75 to -1.51]; p = 0.03) but not 12 (-5.76 [-9.99 to -1.53]; p = 0.08) months and with worse executive functioning at 3 (-3.61 [-7.48 to 0.26]; p = 0.03) and 12 (-6.22 [-10.12 to -2.33]; p = 0.004) months; these associations were not modified by hyperactive delirium. Hyperactive delirium was not associated with global cognition or executive function in this cohort. CONCLUSIONS: Longer duration of hypoactive delirium was independently associated with worse long-term cognition. Assessing motoric subtypes of delirium in the ICU might aid in prognosis and intervention allocation. Future studies should consider delineating motoric subtypes of delirium.

Statistical analysis plan for the Maximizing the Efficacy of Sedation and Reducing Neurological Dysfunction and Mortality in Septic Patients with Acute Respiratory Failure trial.

BACKGROUND: The best sedative medication to reduce delirium, mortality and long term brain dysfunction in mechanically ventilated septic patients is unclear. This multicentre, double-blind, randomised trial investigates the short term and long term effects of dexmedetomidine versus propofol for sedation in mechanically ventilated severely septic patients. OBJECTIVES: To describe the statistical analysis plan for this randomised clinical trial comprehensively and place it in the public domain before unblinding. METHODS: To ensure that analyses are not selectively reported, we developed a comprehensive statistical analysis plan before unblinding. This trial has an enrolment target of 420 severely septic and mechanically ventilated adult patients, randomly assigned to dexmedetomidine or propofol in a 1:1 ratio. Enrolment was completed in January 2019, and the study was estimated to be completed in September 2019. The primary endpoint is days alive without delirium or coma during first 14 study days. Secondary outcomes include 28-day ventilator-free days, 90-day all-cause mortality and cognitive function at 180 days. Time frames all begin on the day of randomisation. All analyses will be conducted on an intention-to-treat basis. CONCLUSION: This study will compare the effects of two sedatives in mechanically ventilated severely septic patients. In keeping with the guidance on statistical principles for clinical trials, we have developed a comprehensive statistical analysis plan by which we will adhere, as this will avoid bias and support transparency and reproducibility. TRIAL REGISTRATION: ClinicalTrials.gov (NCT01739933).

Association of neuronal repair biomarkers with delirium among survivors of critical illness.

PURPOSE: Delirium is prevalent but with unclear pathogenesis. Neuronal injury repair pathways may be protective. We hypothesized that higher concentrations of neuronal repair biomarkers would be associated with decreased delirium in critically ill patients. MATERIALS AND METHODS: We performed a nested study of hospital survivors within a prospective cohort that enrolled patients within 72 h of respiratory failure or shock. We measured plasma concentrations of ubiquitin carboxyl-terminal-esterase-L1 (UCHL1) and brain-derived neurotrophic factor (BDNF) from blood collected at enrollment. Delirium was assessed twice daily using the CAM-ICU. Multivariable regression was used to examine the associations between biomarkers and delirium prevalence/duration, adjusting for covariates and interactions with age and IL-6 plasma concentration. RESULTS: We included 427 patients with a median age of 59 years (IQR 48-69) and APACHE II score of 25 (IQR 19-30). Higher plasma concentration of UCHL1 on admission was independently associated with lower prevalence of delirium (p = .04) but not associated with duration of delirium (p = .06). BDNF plasma concentration was not associated with prevalence (p = .26) or duration of delirium (p = .36). CONCLUSIONS: During critical illness, higher UCHL1 plasma concentration is associated with lower prevalence of delirium; BDNF plasma concentration is not associated with delirium. Clinical trial number: NCT00392795; https://clinicaltrials.gov/ct2/show/NCT00392795.

Plasma biomarkers of inflammation, coagulation, and brain injury as predictors of delirium duration in older hospitalized patients.

BACKGROUND: Delirium's pathophysiology is poorly understood. We sought to determine if plasma biomarkers of inflammation, coagulation, endothelial activation, and blood brain barrier (BBB) injury were associated with emergency department (ED) delirium duration. METHODS: We enrolled hospitalized patients who were 65 years or older from the ED. Plasma biomarkers of inflammation (interleukin-6 [IL-6], IL-8, soluble tumor necrosis factor receptor I [sTNFRI]), coagulation (Protein C), endothelial activation (plasminogen activating inhibitor-1 [PAI-1]), and BBB injury (S100B) at were measured using blood obtained at enrollment. The dependent variable was ED delirium duration which was determined by the Brief Confusion Assessment Method assessed in the ED and hospitalization. Proportional odds logistic regression analyses were performed adjusted for relevant confounders and allowing for interaction by baseline dementia status. RESULTS: A total of 156 patients were enrolled. IL-6 (POR = 1.59, 95%CI: 1.09-2.32) and PAI-1 (POR = 2.96, 95%CI: 1.48 to 6.85) were independently associated with more prominent ED delirium duration in subjects without dementia only. No significant associations between IL-8, Protein C, sTNRFI, and S100B and ED delirium duration were observed. CONCLUSIONS: Plasma Biomarkers of systemic inflammation and endothelial activation are associated with ED delirium duration in older ED patients without dementia.

A randomized trial of a specialist palliative care intervention for patients undergoing surgery for cancer: rationale and design of the Surgery for Cancer with Option of Palliative Care Expert (SCOPE) Trial.

BACKGROUND: In medical oncology settings, early specialist palliative care interventions have demonstrated improvements in patient quality of life and survival compared with usual oncologic care. However, the effect of early specialist palliative care interventions in surgical oncology settings is not well studied. METHODS: The Surgery for Cancer with Option for Palliative Care Expert (SCOPE) Trial is a single-center, prospective, single-blind, randomized controlled trial of a specialist palliative care intervention for cancer patients undergoing non-palliative surgery. It will enroll 236 patients scheduled for major abdominal operations for malignancy, who will be randomized 1:1 at enrollment to receive usual care (control arm) or specialist palliative care consultation (intervention arm). Intervention arm patients will receive consultations from a palliative care specialist (physician or nurse practitioner) preoperatively and postoperatively. The primary outcome is physical and functional wellbeing at 90 days postoperatively. Secondary outcomes are quality of life at 90 days postoperatively, posttraumatic stress disorder symptoms at 180 days postoperatively, days alive at home without an emergency room visit in the first 90 postoperative days, and overall survival at 1 year postoperatively. Participants will be followed for 3 years after surgery for exploratory analyses of their ongoing quality of life, healthcare utilization, and mortality. DISCUSSION: SCOPE is an ongoing randomized controlled trial evaluating specialist palliative care interventions for cancer patients undergoing non-palliative oncologic surgery. Findings from the study will inform ways to identify and improve care of surgical patients who will likely benefit from specialist palliative care services. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT03436290 First Registered: 16 February 2018 Enrollment Began: 1 March 2018 Last Update: 20 December 2018.

Vitamin D Deficiency and Long-Term Cognitive Impairment Among Older Adult Emergency Department Patients.

INTRODUCTION: Approximately 16% of acutely ill older adults develop new, long-term cognitive impairment (LTCI), many of whom initially seek care in the emergency department (ED). Currently, no effective interventions exist to prevent LTCI after an acute illness. Identifying early and modifiable risk factors for LTCI is the first step toward effective therapy. We hypothesized that Vitamin D deficiency at ED presentation was associated with LTCI in older adults. METHODS: This was an observational analysis of a prospective cohort study that enrolled ED patients ≥ 65 years old who were admitted to the hospital for an acute illness. All patients were enrolled within four hours of ED presentation. Serum Vitamin D was measured at enrollment and Vitamin D deficiency was defined as serum concentrations <20 mg/dL. We measured pre-illness and six-month cognition using the short form Informant Questionnaire on Cognitive Decline in the Elderly (IQCODE), which ranges from 1 to 5 (severe cognitive impairment). Multiple linear regression was performed to determine whether Vitamin D deficiency was associated with poorer six-month cognition adjusted for pre-illness IQCODE and other confounders. We incorporated a two-factor interaction into the regression model to determine whether the relationship between Vitamin D deficiency and six-month cognition was modified by pre-illness cognition. RESULTS: We included a total of 134 older ED patients; the median (interquartile range [IQR]) age was 74 (69, 81) years old, 61 (46%) were female, and 14 (10%) were nonwhite race. The median (IQR) vitamin D level at enrollment was 25 (18, 33) milligrams per deciliter and 41 (31%) of enrolled patients met criteria for vitamin D deficiency. Seventy-seven patients survived and had a six-month IQCODE. In patients with intact pre-illness cognition (IQCODE of 3.13), Vitamin D deficiency was significantly associated with worsening six-month cognition (ß-coefficient: 0.43, 95% CI, 0.07 to 0.78, p = 0.02) after adjusting for pre-illness IQCODE and other confounders. Among patients with pre-illness dementia (IQCODE of 4.31), no association with Vitamin D deficiency was observed (ß-coefficient: -0.1;, 95% CI, [-0.50-0.27], p = 0.56). CONCLUSION: Vitamin D deficiency was associated with poorer six-month cognition in acutely ill older adult ED patients who were cognitively intact at baseline. Future studies should determine whether early Vitamin D repletion in the ED improves cognitive outcomes in acutely ill older patients.

Supratherapeutic Psychotropic Drug Levels in the Emergency Department and Their Association with Delirium Duration: A Preliminary Study.

OBJECTIVES: Polypharmacy is associated with delirium, but the mechanisms for this connection are unclear. Our goal was to determine the frequency of supratherapeutic psychotropic drug levels (SPDLs) in older hospitalized patients and if it is associated with the duration of emergency department (ED) delirium. DESIGN: Secondary analysis of a prospective cohort study. SETTING: Tertiary care academic medical center. PARTICIPANTS: ED patients 65 years or older who were admitted to the hospital. MEASUREMENTS: Delirium was assessed in the ED and during the first 7 days of hospitalization using the modified Brief Confusion Assessment Method. Drug concentrations were determined in serum samples collected at enrollment via a novel platform based on liquid chromatography-tandem mass spectrometry capable of identifying and quantitating 78 clinically approved medications including opioids, benzodiazepines, antidepressants, antipsychotics, and amphetamines. Patients with serum psychotropic drug concentrations above established reference ranges were considered supratherapeutic and have a SPDL. We performed proportional odds logistic regression to determine if SPDLs were associated with ED delirium duration adjusted for confounders. Medical record review was performed to determine if the doses of medications associated with SPDLs were adjusted at hospital discharge. RESULTS: A total of 158 patients were enrolled; of these, 66 were delirious in the ED. SPDLs were present in 11 (17%) of the delirious and 4 (4%) of the non-delirious ED patients. SPDLs were significantly associated with longer ED delirium duration (adjusted proportional odds ratio = 6.0; 95% confidence interval = 2.1-17.3) after adjusting for confounders. Of the 15 medications associated with SPDLs, 9 (60%) were prescribed at the same or higher doses at the time of hospital discharge. CONCLUSION: SPDLs significantly increased the odds of prolonged ED delirium episodes. Approximately half of the medications associated with SPDLs were continued after hospital discharge at the same or higher doses. J Am Geriatr Soc 67:2387-2392, 2019.

Mitochondrial DNA Haplogroups and Delirium During Sepsis.

OBJECTIVES: Studies suggest that mitochondrial dysfunction underlies some forms of sepsis-induced organ failure. We sought to test the hypothesis that variations in mitochondrial DNA haplogroup affect susceptibility to sepsis-associated delirium, a common manifestation of acute brain dysfunction during sepsis. DESIGN: Retrospective cohort study. SETTING: Medical and surgical ICUs at a large tertiary care center. PATIENTS: Caucasian and African American adults with sepsis. MEASUREMENTS AND MAIN RESULTS: We determined each patient's mitochondrial DNA haplogroup using single-nucleotide polymorphisms genotyping data in a DNA databank and extracted outcomes from linked electronic medical records. We then used zero-inflated negative binomial regression to analyze age-adjusted associations between mitochondrial DNA haplogroups and duration of delirium, identified using the Confusion Assessment Method for the ICU. Eight-hundred ten patients accounted for 958 sepsis admissions, with 802 (84%) by Caucasians and 156 (16%) by African Americans. In total, 795 patient admissions (83%) involved one or more days of delirium. The 7% of Caucasians belonging to mitochondrial DNA haplogroup clade IWX experienced more delirium than the 49% in haplogroup H, the most common Caucasian haplogroup (age-adjusted rate ratio for delirium 1.36; 95% CI, 1.13-1.64; p = 0.001). Alternatively, among African Americans the 24% in haplogroup L2 experienced less delirium than those in haplogroup L3, the most common African haplogroup (adjusted rate ratio for delirium 0.60; 95% CI, 0.38-0.94; p = 0.03). CONCLUSIONS: Variations in mitochondrial DNA are associated with development of and protection from delirium in Caucasians and African Americans during sepsis. Future studies are now required to determine whether mitochondrial DNA and mitochondrial dysfunction contribute to the pathogenesis of delirium during sepsis so that targeted treatments can be developed.

Delirium's Arousal Subtypes and Their Relationship with 6-Month Functional Status and Cognition.

OBJECTIVE: We sought to determine how delirium subtyped by arousal affected 6-month function and cognition in acutely ill older patients. METHODS: This was secondary analysis of a prospective cohort study which enrolled hospitalized patients ≥65 years old. Delirium and arousal were ascertained daily in the emergency department and the first 7 days of hospitalization using the modified Brief Confusion Assessment Method and Richmond Agitation Sedation Scale, respectively. For each day, patients were categorized as having no delirium, delirium with normal arousal, delirium with decreased arousal, or delirium with increased arousal. Preillness and 6-month functional status were determined using the Older American Resources and Services activities of daily living scale which ranges from 0 (completely dependent) to 28 (completely independent). Preillness and 6-month cognition were determined using the Informant Questionnaire on Cognitive Decline in the Elderly which ranges from 1 (markedly improved cognition) to 5 (severe cognitive impairment). Multiple linear regression was performed adjusted for preillness Older American Resources and Services activities of daily living and Informant Questionnaire on Cognitive Decline in the Elderly and other relevant confounders. RESULTS: In 228 older patients, delirium with normal arousal was the only subtype independently associated with poorer 6-month function and cognition. For every day spent in this subtype, the 6-month Older American Resources and Services activities of daily living decreased by 0.84 points (95% confidence interval: -1.59 to -0.09) and the patient's 6-month Informant Questionnaire on Cognitive Decline in the Elderly significantly increased by 0.14 points (95% confidence interval: 0.06-0.23). CONCLUSIONS: Delirium with normal arousal, as opposed to delirium with decreased or increased arousal, was the only arousal subtype significantly associated with worsening 6-month function and cognition. Subtyping delirium by arousal may have important prognostic value.

A Brief Informant Screening Instrument for Dementia in the ICU: The Diagnostic Accuracy of the AD8 in Critically Ill Adults Suspected of Having Pre-Existing Dementia.

BACKGROUND/AIM: The diagnostic accuracy of brief informant screening instruments to detect dementia in critically ill adults is unknown. We sought to determine the diagnostic accuracy of the 2- to 3-min Ascertain Dementia 8 (AD8) completed by surrogates in detecting dementia among critically ill adults suspected of having pre-existing dementia by comparing it to the Clinical Dementia Rating Scale (CDR). METHODS: This substudy of BRAIN-ICU included a subgroup of 75 critically ill medical/surgical patients determined to be at medium risk of having pre-existing dementia (Informant Questionnaire on Cognitive Decline in the Elderly [IQCODE] score ≥3.3). We calculated the sensitivity, specificity, positive and negative predictive values (PPV and NPV), and AUC for the standard AD8 cutoff of ≥2 versus the reference standard CDR score of ≥1 for mild dementia. RESULTS: By the CDR, 38 patients had very mild or no dementia and 37 had mild dementia or greater. For diagnosing mild dementia, the AD8 had a sensitivity of 97% (95% CI 86-100), a specificity of 16% (6-31), a PPV of 53% (40-65), an NPV of 86% (42-100), and an AUC of 0.738 (0.626-0.850). CONCLUSIONS: Among critically ill patients judged at risk for pre-existing dementia, the 2- to 3-min AD8 is highly sensitive and has a high NPV. These data indicate that the brief tool can serve to rule out dementia in a specific patient population.

Deficits in Self-Reported Initiation Are AssociatedWith Subsequent Disability in ICU Survivors.

OBJECTIVE: To determine whether deficits in a key aspect of executive functioning, namely, initiation, were associated with current and future functional disabilities in intensive care unit survivors. METHODS: A nested substudy within a 2-center prospective observational cohort. We used 3 tests of initiation at 3 and 12 months: the Ruff Total Unique Design, Controlled Oral Word Association, and Behavior Rating Inventory of Executive Function initiation. Disability in instrumental activities of daily living (IADL) was measured with the Functional Activities Questionnaire. We used a proportional odds logistic regression model to evaluate the association between initiation and disability. Covariates in the model included age, education, baseline Functional Activities Questionnaire, pre-existing cognitive impairment, comorbidities, admission severity of illness, episodes of hypoxia, and days of severe sepsis. RESULTS: In 195 patients, after adjusting for covariates, only the Behavior Rating Inventory of Executive Function initiation was associated with disability at any time point. Comparing the 25th vs the 75th percentile scores (95% confidence interval) of the Behavior Rating Inventory of Executive Function initiation at 3 months, patients with worse initiation scores had 5.062 times the odds (95% confidence interval: 2.539, 10.092) of disability according to the Functional Activities Questionnaire at 3 months, with similar odds at 12 months (odds ratio: 3.476, 95% confidence interval: 1.943, 6.216). Worse Behavior Rating Inventory of Executive Function initiation scores at 3 months were associated with future disability at 12 months odds ratio (95% confidence interval) 5.079 (2.579, 10.000). CONCLUSIONS: Executive function deficits acquired after a critical illness in the domain of initiation are common in intensive care unit survivors, and when they are identified via self-report tools, they are associated with current and future disability in instrumental activities of daily living.

Delirium etiology subtypes and their effect on six-month function and cognition in older emergency department patients.

ABSTRACTBackground:Delirium is heterogeneous and can vary by etiology. OBJECTIVES: We sought to determine how delirium subtyped by etiology affected six-month function and cognition. DESIGN: Prospective cohort study. SETTING: Tertiary care, academic medical center. PARTICIPANTS: A total of 228 hospitalized patients > 65 years old were admitted from the emergency department (ED). MEASUREMENTS: The modified Brief Confusion Assessment Method was used to determine delirium in the ED. Delirium etiology was determined by three trained physician reviewers using a Delirium Etiology checklist. Pre-illness and six-month function and cognition were determined using the Older American Resources and Services Activities of Daily Living (OARS ADL) questionnaire and the short-form Informant Questionnaire on Cognitive Decline in the Elderly (IQCODE). Multiple linear regression was performed to determine if delirium etiology subtypes were associated with six-month function and cognition adjusted for baseline OARS ADL and IQCODE. Two-factor interactions were incorporated to determine pre-illness function or cognition-modified relationships between delirium subtypes and six-month function and cognition. RESULTS: In patients with poorer pre-illness function only, delirium secondary to metabolic disturbance (ß coefficient = -2.9 points, 95%CI: -0.3 to -5.6) and organ dysfunction (ß coefficient = -4.3 points, 95%CI: -7.2 to -1.4) was significantly associated with poorer six-month function. In patients with intact cognition only, delirium secondary to central nervous system insults was significantly associated with poorer cognition (ß coefficient = 0.69, 95%CI: 0.19 to 1.20). CONCLUSIONS: Delirium is heterogeneous and different etiologies may have different prognostic implications. Furthermore, the effect of these delirium etiologies on outcome may be dependent on the patient's pre-illness functional status and cognition.

Haloperidol and Ziprasidone for Treatment of Delirium in Critical Illness.

BACKGROUND: There are conflicting data on the effects of antipsychotic medications on delirium in patients in the intensive care unit (ICU). METHODS: In a randomized, double-blind, placebo-controlled trial, we assigned patients with acute respiratory failure or shock and hypoactive or hyperactive delirium to receive intravenous boluses of haloperidol (maximum dose, 20 mg daily), ziprasidone (maximum dose, 40 mg daily), or placebo. The volume and dose of a trial drug or placebo was halved or doubled at 12-hour intervals on the basis of the presence or absence of delirium, as detected with the use of the Confusion Assessment Method for the ICU, and of side effects of the intervention. The primary end point was the number of days alive without delirium or coma during the 14-day intervention period. Secondary end points included 30-day and 90-day survival, time to freedom from mechanical ventilation, and time to ICU and hospital discharge. Safety end points included extrapyramidal symptoms and excessive sedation. RESULTS: Written informed consent was obtained from 1183 patients or their authorized representatives. Delirium developed in 566 patients (48%), of whom 89% had hypoactive delirium and 11% had hyperactive delirium. Of the 566 patients, 184 were randomly assigned to receive placebo, 192 to receive haloperidol, and 190 to receive ziprasidone. The median duration of exposure to a trial drug or placebo was 4 days (interquartile range, 3 to 7). The median number of days alive without delirium or coma was 8.5 (95% confidence interval [CI], 5.6 to 9.9) in the placebo group, 7.9 (95% CI, 4.4 to 9.6) in the haloperidol group, and 8.7 (95% CI, 5.9 to 10.0) in the ziprasidone group (P=0.26 for overall effect across trial groups). The use of haloperidol or ziprasidone, as compared with placebo, had no significant effect on the primary end point (odds ratios, 0.88 [95% CI, 0.64 to 1.21] and 1.04 [95% CI, 0.73 to 1.48], respectively). There were no significant between-group differences with respect to the secondary end points or the frequency of extrapyramidal symptoms. CONCLUSIONS: The use of haloperidol or ziprasidone, as compared with placebo, in patients with acute respiratory failure or shock and hypoactive or hyperactive delirium in the ICU did not significantly alter the duration of delirium. (Funded by the National Institutes of Health and the VA Geriatric Research Education and Clinical Center; MIND-USA ClinicalTrials.gov number, NCT01211522 .).