Positive thinking about negative studies.

The non-reporting of negative studies results in a scientific record that is incomplete, one-sided and misleading. The consequences of this range from inappropriate initiation of further studies that might put participants at unnecessary risk to treatment guidelines that may be in error, thus compromising day-to-day clinical practice.

Deep Learning and Geriatric Mental Health.

The goal of this overview is to help clinicians develop basic proficiency with the terminology of deep learning and understand its fundamentals and early applications. We describe what machine learning and deep learning represent and explain the underlying data science principles. We also review current promising applications and identify ethical issues that bear consideration. Deep Learning is a new type of machine learning that is remarkably good at finding patterns in data, and in some cases generating realistic new data. We provide insights into how deep learning works and discuss its relevance to geriatric psychiatry.

Intravenous Ketamine for Late-Life Treatment-Resistant Depression: A Pilot Study of Tolerability, Safety, Clinical Benefits, and Effect on Cognition.

OBJECTIVE: Evidence-based treatment options for late-life treatment-resistant depression (TRD) are limited. Ketamine is a promising treatment for TRD; however, there is a paucity of data on its safety and efficacy in older adults. METHODS: In this pilot clinical trial, 25 adults aged ≥60 years with TRD received IV ketamine openly twice a week for 4 weeks; partial responders at the end of this acute phase were eligible to receive weekly infusions for 4 more weeks in a continuation phase. Acceptability, tolerability, and safety, including adverse and serious adverse events (AEs and SAEs), blood pressure changes, dissociation, craving, in addition to rates of depression response and remission were evaluated. The NIH Toolbox Cognitive Battery was used to assess specific measures of executive function (EF) and overall fluid cognition. RESULTS: Completion rates were 88% for the acute phase and 100% for the continuation phase. No AEs resulted in participant discontinuation, and there were no SAEs. Treatment-emergent elevation of blood pressure, dissociation, and craving were transient and did not result in any participant discontinuation. Depressive symptoms improved significantly and 48% of participants responded. During the acute phase, the EF measures and the fluid cognition composite score improved (Cohen's d = 0.61), and these improvements were sustained in the continuation phase. CONCLUSION: This pilot study suggests that repeated IV ketamine infusions are well-tolerated and are associated with improvement in depression and EF in older adults with TRD. These promising findings need to be confirmed and extended in a larger randomized controlled trial.

Post-stroke cognitive impairment and the risk of stroke recurrence and death in patients with insulin resistance.

OBJECTIVE: Post-stroke cognitive impairment (PSCI) is associated with etiology, severity, and functional outcome of stroke. The risks of recurrent stroke and death in patients with PSCI and insulin resistance (IR) is unknown. The goal of this study was to determine whether global and domain-specific cognitive impairment after stroke in patients with IR was associated with recurrent stroke and death. MATERIALS AND METHODS: We studied patients with recent stroke or transient ischemic attack (TIA) and IR with a baseline Modified Mini-Mental State Examination (3MS) cognitive exam at median of 79 days after stroke. We considered a baseline score of ≤ 88 on the 3MS to indicate global cognitive impairment, and domain-specific summary scores in the lowest quartile to indicate language, attention, orientation, memory and visuospatial impairments. The primary endpoint was fatal or non-fatal recurrent stroke, and the secondary endpoints were all-cause mortality, and fatal or non-fatal myocardial infarction (MI). RESULTS: Among studied n = 3,338 patients 13.6% had global cognitive impairment. During the median 4.96 years of follow-up, 7.4% patients experienced recurrent stroke, 3.5% MI, and 7.3% died. In the fully adjusted model, impairment in language (HR 1.35; 95% CI 1.01-1.81) and orientation (HR 1.41; 95% CI: 1.06-1.87) were associated with a higher risk of recurrent stroke, while attention impairment was associated with all-cause mortality (HR 1.34; 95% CI: 1.01-1.78). DISCUSSION/CONCLUSION: In patients with recent stroke/TIA and IR, post-stroke language and orientation impairments independently predicted recurrent stroke, while attention deficit was associated with increased risk of all-cause mortality.

Frailty Worsens Antidepressant Treatment Outcomes in Late Life Depression.

OBJECTIVE: To investigate the relationship between frailty and treatment response to antidepressant medications in adults with late life depression (LLD). METHODS: Data were evaluated from 100 individuals over age 60 years (34 men, 66 women) with a depressive diagnosis, who were assessed for frailty at baseline (characteristics include gait speed, grip strength, activity levels, fatigue, and weight loss) and enrolled in an 8-week trial of antidepressant medication followed by 10 months of open-treatment. RESULTS: Frail individuals (n = 49 with ≥3 deficits in frailty characteristics) did not differ at baseline from the non/intermediate frail (n = 51 with 0-2 deficits) on demographic, medical comorbidity, cognitive, or depression variables. On average, frail individuals experienced 2.82 fewer Hamilton Rating Scale for Depression (HRSD) points of improvement (t = 2.12, df 89, p = 0.037) than the non/intermediate frail over acute treatment, with this difference persisting over 10 months of open-treatment. Weak grip strength and low physical activity levels were each associated with decreased HRSD improvement, and lower response and remission rates over the course of the study. Despite their poorer outcomes, frail individuals received more antidepressant medication trials than the non/intermediate frail. CONCLUSION: Adults with LLD and frailty have an attenuated response to antidepressant medication and a greater degree of disability compared to non/intermediate frail individuals. This disability and attenuated response remain even after receiving a greater number of antidepressant medication trials. Future research must focus on understanding the specific pathophysiology associated with the frail-depressed phenotype to permit the design and implementation of precision medicine interventions for this high-risk population.

Development of Algorithmic Dementia Ascertainment for Racial/Ethnic Disparities Research in the US Health and Retirement Study.

BACKGROUND: Disparities research in dementia is limited by lack of large, diverse, and representative samples with systematic dementia ascertainment. Algorithmic diagnosis of dementia offers a cost-effective alternate approach. Prior work in the nationally representative Health and Retirement Study has demonstrated that existing algorithms are ill-suited for racial/ethnic disparities work given differences in sensitivity and specificity by race/ethnicity. METHODS: We implemented traditional and machine learning methods to identify an improved algorithm that: (1) had ≤5 percentage point difference in sensitivity and specificity across racial/ethnic groups; (2) achieved ≥80% overall accuracy across racial/ethnic groups; and (3) achieved ≥75% sensitivity and ≥90% specificity overall. Final recommendations were based on robustness, accuracy of estimated race/ethnicity-specific prevalence and prevalence ratios compared to those using in-person diagnoses, and ease of use. RESULTS: We identified six algorithms that met our prespecified criteria. Our three recommended algorithms achieved ≤3 percentage point difference in sensitivity and ≤5 percentage point difference in specificity across racial/ethnic groups, as well as 77%-83% sensitivity, 92%-94% specificity, and 90%-92% accuracy overall in analyses designed to emulate out-of-sample performance. Pairwise prevalence ratios between non-Hispanic whites, non-Hispanic blacks, and Hispanics estimated by application of these algorithms are within 1%-10% of prevalence ratios estimated based on in-person diagnoses. CONCLUSIONS: We believe these algorithms will be of immense value to dementia researchers interested in racial/ethnic disparities. Our process can be replicated to allow minimally biasing algorithmic classification of dementia for other purposes.

Implications of the Use of Algorithmic Diagnoses or Medicare Claims to Ascertain Dementia.

INTRODUCTION: Formal dementia ascertainment with research criteria is resource-intensive, prompting the growing use of alternative approaches. Our objective was to illustrate the potential bias and implications for study conclusions introduced through the use of alternate dementia ascertainment approaches. METHODS: We compared dementia prevalence and risk factor associations obtained using criterion-standard dementia diagnoses to those obtained using algorithmic or Medicare-based dementia ascertainment in participants of the baseline visit of the Aging, Demographics, and Memory Study (ADAMS), a Health and Retirement Study (HRS) sub-study. RESULTS: Estimates of dementia prevalence derived using algorithmic or Medicare-based ascertainment differ substantially from those obtained using criterion-standard ascertainment. Use of algorithmic or Medicare-based dementia ascertainment can, but does not always, lead to risk factor associations that substantially differ from those obtained using criterion-standard ascertainment. DISCUSSION/CONCLUSIONS: Absolute estimates of dementia prevalence should rely on samples with formal dementia ascertainment. The use of multiple algorithms is recommended for risk factor studies when formal dementia ascertainment is not available.

Subclinical Hearing Loss is Associated With Depressive Symptoms.

OBJECTIVE: To assess whether the relationship between hearing and depressive symptoms is present among older adults classified as normal hearing (≤25 dB). DESIGN: Cross-sectional epidemiologic study (Hispanic Community Health Study). SETTING: US multicentered. PARTICIPANTS: Adults ≥50 years old (n = 5,499) with normal hearing or hearing loss (HL). MEASUREMENTS: The primary exposure was hearing, defined continuously by the 4-frequency pure-tone average threshold (dB) on audiometry. Hearing was additionally categorized into normal hearing (≤25 dB) and HL (>25 dB). The main outcome was depressive symptoms, measured with the Center for Epidemiologic Studies Depression Scale-10 (CESD-10). Depressive symptoms were defined both continuously and binarily (where CESD-10 ≥10 was categorized as clinically significant depressive symptoms). Multivariable linear, logistic, and generalized additive modeling (GAM) regressions were performed. RESULTS: Among those with normal hearing, the CESD-10 score increased by 1.04 points (95% confidence interval [CI]: 0.70, 1.37) for every 10 dB decrease in hearing, adjusting for age, gender, education, cardiovascular disease, and hearing aid use. Among those with HL, the CESD-10 score increased by 0.62 points (95% CI: 0.23, 1.01) for every 10 dB decrease in hearing, adjusting for the same confounders. Similar findings were noted when the outcome was clinically significant depressive symptoms (adjusted odds ratio: 1.28 [1.14, 1.44] in normal hearing versus 1.26 [1.11, 1.44] in HL). In certain sensitivity analyses, the relationship between hearing and depressive symptoms was significantly stronger among those with normal hearing than in those with HL. CONCLUSION: The relationship between hearing and clinically significant depressive symptoms is present among older adults with normal hearing (<25 dB). We introduce the term subclinical HL as imperfect hearing that is classically defined as normal (1-25 dB). The relationship between hearing and late life depressive symptoms may be more sensitive than previously recognized.

Frailty and Its Correlates in Adults With Late Life Depression.

OBJECTIVE: To investigate the rates of frailty and frailty characteristics and examine the clinical and neuropsychological correlates of frailty in adults with late life depression (LLD). METHODS: Data were used from the evaluation of 134 individuals over the age of 60 years (45 men, 89 women) with a depressive diagnosis who enrolled in studies for the treatment of their depression. Depression, neuropsychological functioning, white matter hyperintensity (WMH) burden via magnetic resonance imaging, and characteristics of frailty were assessed. RESULTS: Fried frailty burden (≥3 characteristics) was present in 25% of the sample, with this rate increasing to 45.5% when using clinically meaningful cut-scores for gait speed (<1 m/s) and physical activity levels (<1000 kcal/week). Moreover, 62% of the sample exhibited gait slowing (<1 m/s) or weakness (grip strength), with 29% demonstrating both. Greater frailty burden was associated with greater Hamilton Depression Rating Scale severity in covariate adjusted linear regression models (t127 = 2.41, p = 0.02). Greater frailty burden was not associated with neuropsychological dysfunction, nor was it associated with greater WMH burden. CONCLUSION: Findings from this study show that frailty, specifically physical frailty deficits in mobility and strength, is highly comorbid in adults with LLD, associated with greater depressive symptom severity, and does not appear to be associated with the vascular depression subtype of LLD. Future research should investigate the relationship between frailty and antidepressant treatment response as well as test whether there are age-related biological processes that result in the manifestation of the frail-depressed subtype of LLD.

A predictive model for conversion to psychosis in clinical high-risk patients.

BACKGROUND: The authors developed a practical and clinically useful model to predict the risk of psychosis that utilizes clinical characteristics empirically demonstrated to be strong predictors of conversion to psychosis in clinical high-risk (CHR) individuals. The model is based upon the Structured Interview for Psychosis Risk Syndromes (SIPS) and accompanying clinical interview, and yields scores indicating one's risk of conversion. METHODS: Baseline data, including demographic and clinical characteristics measured by the SIPS, were obtained on 199 CHR individuals seeking evaluation in the early detection and intervention for mental disorders program at the New York State Psychiatric Institute at Columbia University Medical Center. Each patient was followed for up to 2 years or until they developed a syndromal DSM-4 disorder. A LASSO logistic fitting procedure was used to construct a model for conversion specifically to a psychotic disorder. RESULTS: At 2 years, 64 patients (32.2%) converted to a psychotic disorder. The top five variables with relatively large standardized effect sizes included SIPS subscales of visual perceptual abnormalities, dysphoric mood, unusual thought content, disorganized communication, and violent ideation. The concordance index (c-index) was 0.73, indicating a moderately strong ability to discriminate between converters and non-converters. CONCLUSIONS: The prediction model performed well in classifying converters and non-converters and revealed SIPS measures that are relatively strong predictors of conversion, comparable with the risk calculator published by NAPLS (c-index = 0.71), but requiring only a structured clinical interview. Future work will seek to externally validate the model and enhance its performance with the incorporation of relevant biomarkers.

Declining Skeletal Muscle Mitochondrial Function Associated With Increased Risk of Depression in Later Life.

OBJECTIVE: Late-life depression (LLD) is a chronic and heterogeneous disorder. Recent studies have implicated non-normative age-related processes in its pathogenesis. This investigation examined both cross-sectional and longitudinal associations between skeletal muscle mitochondrial function and LLD. METHODS: Data from 603 men and women from the Baltimore Longitudinal Study on Aging were analyzed, of whom 167 provided data from a follow-up visit. Muscle bioenergetics was measured by postexercise recovery rate of phosphocreatine (PCr) using phosphorus magnetic resonance spectroscopy. Depressive symptoms were assessed using the Center for Epidemiologic Studies Depression (CES-D) Scale. RESULTS: There was no cross-sectional association between baseline depression status and either the PCr recovery rate constant (kPCr; t = -0.553, df = 542; p = 0.580) or mitochondrial capacity largely independent of exercise intensity (adenosine triphosphate maximum [ATPmax]; t = 0.804, df = 553; p = 0.422). Covariate-adjusted Firth logistic regression models however showed that greater decreases in skeletal muscle mitochondrial function from baseline to follow-up were associated with higher odds of clinically significant depressive symptoms (CES-D ≥16) at follow-up (ΔATPmax: odds ratio = 2.63, χ2 = 5.62, df =1; p = 0.018; ΔkPCr: odds ratio = 2.32, χ2 = 5.79, df =1; p = 0.016). CONCLUSION: Findings suggest that declining skeletal muscle mitochondrial function in older adults is associated with clinically significant depressive symptoms at follow-up, thereby providing preliminary support for the hypothesis that mitochondrial dysfunction may be a potential key pathophysiological mechanism in adults with LLD.

Age-Related Hearing Loss and Its Association with Depression in Later Life.

OBJECTIVES: To evaluate the association between age-related hearing loss (ARHL) and depressive symptoms in older adults over time. METHODS: Data from the Health Aging and Body Composition study (N = 3075, aged 70-79 at baseline) were used previously to conduct a longitudinal latent class analysis to evaluate depression trajectories (Center for Epidemiologic Studies Depression [CES-D] Scale) over 10 years. Restricting to the subset of subjects who had hearing information available (N = 1204), self-reported hearing categories were evaluated over the same period. Association between depression classes and hearing categories were assessed via multinomial logistic regression analyses. Correlation analyses and two-sample t-tests were used to assess cross-sectional associations between depression status and audiometric hearing measures. RESULTS: Low-probability (N = 644), increasing-probability (N = 385), and high-probability (N = 175) trajectories of depressive symptoms were identified for the 10-year period. Impaired/Worsening (N = 182) and Healthy/Improving (N = 1,022) hearing categories were defined using self-reports. With the low-probability depression trajectory as the reference group, subjects reporting Impaired/Worsening hearing had 1.63 times increased odds of having an increasing- (p = 0.0088, 95% CI [1.13, 2.34]) and 1.85 times increased odds of having a high-probability depression trajectory (p = 0.0102, 95% CI [1.16, 2.96]). At Year 5, individuals with depressive symptoms (10CES-D ≥ 10) had impaired hearing ability measured by audiometric threshold for low-frequency (Adjusted mean difference = 2.29 dBHL, p = 0.0005) and mid-frequency sounds (Adjusted mean difference = 2.28 dBHL,p = 0.0049) compared to those with 10CES-D < 10. CONCLUSIONS: ARHL was associated with increased depressive symptoms in older adults. Future studies should investigate whether treatment of ARHL may be an effective prevention and/or therapeutic strategy for depressive symptoms.

Donepezil Treatment in Patients With Depression and Cognitive Impairment on Stable Antidepressant Treatment: A Randomized Controlled Trial.

OBJECTIVE: Depression and cognitive impairment are often comorbid in older adults, but optimal treatment strategies remain unclear. In a two-site study, the efficacy and safety of add-on donepezil versus placebo were compared in depressed patients with cognitive impairment receiving stable antidepressant treatment. METHODS: A randomized, double-blind, placebo-controlled trial was conducted in older adults with depression and cognitive impairment (https://clinicaltrials.gov/ct2/show/NCT01658228; NCT01658228). Patients received open-label antidepressant treatment for 16 weeks, initially with citalopram and then with venlafaxine, if needed, followed by random assignment to add-on donepezil 5-10 mg daily or placebo for another 62 weeks. Outcome measures were neuropsychological test performance (Alzheimer's Disease Assessment Scale-Cognitive subscale [ADAS-Cog] and Selective Reminding Test [SRT] total immediate recall) and instrumental activities of daily living (Functional Activities Questionnaire). RESULTS: Of 81 patients who signed informed consent, 79 patients completed the baseline evaluation. Open antidepressant treatment was associated with improvement in depression in 63.93% responders by week 16. In the randomized trial, there were no treatment group differences between donepezil and placebo on dementia conversion rates, ADAS-Cog, SRT total immediate recall, or FAQ. Neither baseline cognitive impairment severity nor apolipoprotein E e4 genotype influenced donepezil efficacy. Donepezil was associated with more adverse effects than placebo. CONCLUSION: The results do not support adjunctive off-label cholinesterase inhibitor treatment in patients with depression and cognitive impairment. The findings highlight the need to prioritize discovery of novel treatments for this highly prevalent population with comorbid illnesses.

Association of Obstructive Sleep Apnea with Episodic Memory and Cerebral Microvascular Pathology: A Preliminary Study.

OBJECTIVES: To evaluate the impact of obstructive sleep apnea (OSA) on neurocognitive function and brain morphology in older adults with depression and cognitive impairment. METHODS: We prospectively screened OSA with the STOP-Bang questionnaire in the last 25 patients enrolled into the Donepezil Treatment of Cognitive Impairment and Depression (DOTCODE) trial. High and low probability of OSA were defined as a STOP-Bang score of ≥5 (h-OSA) and of <5 (l-OSA), respectively. Baseline magnetic resonance imaging (MRI) was used to evaluate brain morphology. The initial 16 weeks of antidepressant treatment were part of the DOTCODE trial. RESULTS: After 16 weeks of antidepressant treatment, the h-OSA group performed significantly worse on the Selective Reminding Test delayed recall task than the l-OSA group, controlling for baseline performance (F = 19.1, df = 1,22, p < 0.001). In 19 of 25 participants who underwent brain MRI, the h-OSA group had significantly greater volumes of MRI hyperintensities in deep white matter, periventricular white matter, and subcortical gray matter compared with the l-OSA group. There was no significant association between OSA and hippocampal or entorhinal cortex volumes in our sample, even after controlling for intracranial volume. CONCLUSIONS: OSA is associated with impaired verbal episodic memory and microvascular damage in older adults with depression and cognitive impairment. One possibility is that by contributing to cerebral microvascular damage, OSA may exacerbate progressive memory decline.

Asthma and subjective sleep disordered breathing in a large cohort of urban adolescents.

OBJECTIVE: Sleep disordered breathing (SDB) has not been well studied in urban adolescents with asthma in community settings. Nor has the association of SDB symptoms and asthma severity been studied. We characterized self-reported symptoms suggesting SDB and investigated the association of SDB symptoms, probable asthma, and asthma severity. METHODS: 9,565 adolescents from 21 inner-city high schools were screened for an asthma intervention study. Students reported on symptoms suggesting SDB using questions from the 2007 NHANES, if they were ever diagnosed with asthma, and on asthma symptoms. Using generalized linear mixed models with logit link with school as a random intercept and adjusting for age, gender, and race/ethnicity, we examined associations of SDB symptoms, and demographic characteristics, probable asthma, and asthma severity. RESULTS: 12% reported SDB symptoms. Older and bi-racial participants (compared to Caucasian) had higher odds of symptoms suggesting SDB (p <.001). Compared to those without probable asthma, adolescents with probable asthma had 2.63 greater odds of reporting SDB symptoms (p <.001). Among those with probable asthma, the odds of reporting SDB symptoms increased with asthma severity. When exploring daytime severity and severity due to night wakening separately, results were similar. All results remained significant when controlling for age, gender, and ethnicity. CONCLUSIONS: In a large urban community cohort of predominately ethnic minority adolescents, self-reported SDB symptoms were associated with probable asthma and increased asthma severity. This study highlights the importance of SDB as a modifiable co-morbidity of asthma.

The Norwood operation: Relative effects of surgeon and institutional volumes on outcomes and resource utilization.

BACKGROUND: Hypoplastic left heart syndrome is the most expensive birth defect managed in the United States, with a 5-year survival rate below 70%. Increasing evidence suggests that hospital volumes are inversely associated with mortality for infants with single ventricles undergoing stage 1 surgical palliation. Our aim was to examine the relative effects of surgeon and institutional volumes on outcomes and resource utilisation for these children. METHODS: A retrospective study was conducted using the Pediatric Health Information System database to examine the effects of the number of procedures performed per surgeon and per centre on mortality, costs, and post-operative length of stay for infants undergoing Risk Adjustment for Congenital Heart Surgery risk category six operations at tertiary-care paediatric hospitals, from 1 January, 2004 to 31 December, 2013. Multivariable modelling was used, adjusting for patient and institutional characteristics. Gaussian kernel densities were constructed to show the relative distributions of the effects of individual institutions and surgeons, before and after adjusting for the number of cases performed. RESULTS: A total of 2880 infants from 35 institutions met the inclusion criteria. Mortality was 15.0%. Median post-operative length of stay was 24 days (IQR 14-41). Median standardized inpatient hospital costs were $156,000 (IQR $108,000-$248,000) in 2013 dollars. In the multivariable analyses, higher institutional volume was inversely associated with mortality (p=0.001), post-operative length of stay (p=0.004), and costs (p=0.001). Surgeon volume was associated with none of the measured outcomes. Neither institutional nor surgeon volumes explained much of the wide variation in outcomes and resource utilization observed between institutions and between surgeons. CONCLUSIONS: Increased institutional - but not surgeon - volumes are associated with reduced mortality, post-operative length of stay, and costs for infants undergoing stage 1 palliation.

Wavelet-Based Scalar-on-Function Finite Mixture Regression Models.

Classical finite mixture regression is useful for modeling the relationship between scalar predictors and scalar responses arising from subpopulations defined by the di ering associations between those predictors and responses. The classical finite mixture regression model is extended to incorporate functional predictors by taking a wavelet-based approach in which both the functional predictors and the component-specific coefficient functions are represented in terms of an appropriate wavelet basis. By using the wavelet representation of the model, the coefficients corresponding to the functional covariates become the predictors. In this setting, there are typically many more predictors than observations. Hence a lasso-type penalization is employed to simultaneously perform feature selection and estimation. Specification of the model is discussed and a fitting algorithm is provided. The wavelet-based approach is evaluated on synthetic data as well as applied to a real data set from a study of the relationship between cognitive ability and di usion tensor imaging measures in subjects with multiple sclerosis.

Treatment decisions based on scalar and functional baseline covariates.

The amount and complexity of patient-level data being collected in randomized-controlled trials offer both opportunities and challenges for developing personalized rules for assigning treatment for a given disease or ailment. For example, trials examining treatments for major depressive disorder are not only collecting typical baseline data such as age, gender, or scores on various tests, but also data that measure the structure and function of the brain such as images from magnetic resonance imaging (MRI), functional MRI (fMRI), or electroencephalography (EEG). These latter types of data have an inherent structure and may be considered as functional data. We propose an approach that uses baseline covariates, both scalars and functions, to aid in the selection of an optimal treatment. In addition to providing information on which treatment should be selected for a new patient, the estimated regime has the potential to provide insight into the relationship between treatment response and the set of baseline covariates. Our approach can be viewed as an extension of "advantage learning" to include both scalar and functional covariates. We describe our method and how to implement it using existing software. Empirical performance of our method is evaluated with simulated data in a variety of settings and also applied to data arising from a study of patients with major depressive disorder from whom baseline scalar covariates as well as functional data from EEG are available.

Effect of pioglitazone on vascular events in post-stroke cognitive impairment: Post hoc analysis of the IRIS trial.

BACKGROUND: In stroke patients with insulin resistance (IR), post-stroke cognitive impairment (PSCI) is associated with higher risk of recurrent stroke, but the effect of pioglitazone on that risk has not been explored. The goal of this study was to compare the secondary stroke prevention effect of pioglitazone against placebo in patients with versus without PSCI. METHODS: We studied patients enrolled in the Insulin Resistance Intervention after Stroke (IRIS) trial with a post-stroke modified Mini-Mental State Examination (3MS) cognitive assessment (mean time of assessment: 79 days post-stroke). We considered a baseline score of ⩽ 88 on the 3MS to indicate global PSCI, and domain-specific summary scores in the lowest quartile to indicate attention, language, memory, orientation, and visuospatial impairments. RESULTS: In n = 3338 patients with IR, the effect of pioglitazone versus placebo on secondary stroke significantly differed by initial post-stroke global (interaction p = 0.0127) and memory impairment status (interaction p = 0.0003). Hazard ratios (HRs) were time-dependent such that, among those with either global or memory impairment, pioglitazone has an increasingly stronger protective effect at later timepoints. There was no statistically significant effect of pioglitazone among those without either global or memory impairment. The effect of pioglitazone versus placebo on myocardial infarction (MI) also significantly differed by global impairment status (interaction p = 0.030). Pioglitazone was protective among those with global impairment (HR = 0.23 [95% CI: 0.08, 0.71]) but not among those without (HR = 0.88 [95% CI: 0.59, 1.31]). CONCLUSION: These data indicate that pioglitazone treatment may be more effective at reducing risk of recurrent stroke and MI in stroke patients with PSCI. Simple cognitive testing 2-3 months post-stroke may identify patients for whom treatment would be most beneficial.

Prevalence of Distal Symmetrical Polyneuropathy by Diabetes Prevention Program Treatment Group, Diabetes Status, Duration of Diabetes, and Cumulative Glycemic Exposure.

OBJECTIVE: To assess associations between distal symmetric polyneuropathy (DSPN) and Diabetes Prevention Program (DPP) treatment groups, diabetes status or duration, and cumulative glycemic exposure approximately 21 years after DPP randomization. RESEARCH DESIGN AND METHODS: In the DPP, 3,234 adults ≥25 years old at high risk for diabetes were randomized to an intensive lifestyle (ILS), metformin, or placebo intervention to prevent diabetes. After the DPP ended, 2,779 joined the Diabetes Prevention Program Outcomes Study (DPPOS). Open-label metformin was continued, placebo was discontinued, ILS was provided in the form of semiannual group-based classes, and all participants were offered quarterly lifestyle classes. Symptoms and signs of DSPN were assessed in 1,792 participants at DPPOS year 17. Multivariable logistic regression models were used to evaluate DSPN associations with treatment group, diabetes status/duration, and cumulative glycemic exposure. RESULTS: At 21 years after DPP randomization, 66% of subjects had diabetes. DSPN prevalence did not differ by initial DPP treatment assignment (ILS 21.5%, metformin 21.5%, and placebo 21.9%). There was a significant interaction between treatment assignment to ILS and age (P < 0.05) on DSPN. At DPPOS year 17, the odds ratio for DSPN in comparison with ILS with placebo was 17.4% (95% CI 3.0, 29.3) lower with increasing 5-year age intervals. DSPN prevalence was slightly lower for those at risk for diabetes (19.6%) versus those with diabetes (22.7%) and was associated with longer diabetes duration and time-weighted HbA1c (P values <0.001). CONCLUSIONS: The likelihood of DSPN was similar across DPP treatment groups but higher for those with diabetes, longer diabetes duration, and higher cumulative glycemic exposure. ILS may have long-term benefits on DSPN for older adults.