Faculty Bibliography

Background: Optical coherence tomography (OCT) studies have shown that retinal nerve fiber layer (RNFL) and ganglion cell + inner plexiform layer (GCIP) thinning are accelerated in multiple sclerosis (MS). Increased inner nuclear layer (INL) thickness has been associated with inflammatory disease activity, but decreased thicknesses of the INL and outer nuclear layer (ONL) have also been identified in a subset of patients with more severe disability. INL atrophy has also been found post-mortem in MS eyes, more frequently in progressive MS (PMS). These data suggest that there exist differences in retinal pathology at various stages of the disease, however these have been incompletely characterized, as the vast majority of OCT studies comparing retinal measures between MS subtypes have been cross-sectional, with small numbers of PMS eyes.
Objective(s): To assess the effects of age and MS subtype on longitudinal changes in retinal layer thicknesses.
Method(s): A cohort of MS patients and healthy controls (HC), followed with serial spectral-domain OCT, was evaluated. Retinal layer thicknesses were derived utilizing a validated, automated segmentation algorithm. Statistical analyses were performed with mixed-effects linear regression models.
Result(s): Data from 364 MS (178 relapsing-remitting MS [RRMS], 186 PMS) and 66 HC participants were analyzed. Median follow-up duration was 3.6 years. Higher age was associated with slower rates of RNFL atrophy in MS (p<0.001), but not in HC. Rates of GCIP atrophy did not differ across age in MS, but in HC higher age was associated with accelerated rates of GCIP atrophy (p=0.006). The proportion of RNFL and GCIP atrophy in MS attributable to normal aging increased from 42.7% and 16.7% respectively at age 25 years, to 83.7% and 81.1% at age 65 years. PMS was independently associated with accelerated RNFL and GCIP atrophy compared to RRMS (RNFL: p=0.002; GCIP: p=0.001). Higher age was associated with accelerated INL and ONL atrophy and this relationship was similar in MS and HC. INL and ONL atrophy rates were faster in PMS compared to HC (INL: p=0.03; ONL: p=0.04) and RRMS (INL: p=0.008; ONL: p=0.01), but did not differ between RRMS and HC.
Conclusion(s): PMS is independently associated with accelerated retinal layer atrophy, and INL and ONL atrophy may be novel biomarkers of neurodegeneration in PMS. The effects of normal aging on retinal layer thicknesses should be considered when designing clinical trials incorporating OCT measures as outcomes

Background: Myopia's axial elongation of the eye causes an irregularly shaped retina. Cross-sectional studies show that increasing diopters and axial lengths in myopia correlate negatively with Optical Coherence Tomography (OCT) derived measures of Retinal Nerve Fiber Layer (RNFL) thickness. This has largely precluded including OCT data from high myopia individuals in Multiple Sclerosis (MS) and other studies. OCT is a promising marker of neurodegeneration in MS. However, the impact of high myopia in longitudinal studies remains to be investigated.
Objective(s): To assess the impact of high myopia on rates of change in OCT retinal layer thicknesses in MS patients and healthy controls (HC).
Method(s): A 1:2 age and sex matching scheme was used in the MS [13 high myopia (MSHM): 26 non myopia (MSNM)] and HC [7 high myopia (HCHM): 14 non myopia (HCNM)] cohorts. OCT thickness measures of the peripapillary RNFL (pRNFL), ganglion cell+inner plexiform layer (GCIP), and other retinal layers were determined using a validated segmentation algorithm. Mixed effects linear regression was used in statistical analyses.
Result(s): Baseline MSHM eyes had lower GCIP (-4.01 mum, p = 0.06) and pRNFL thicknesses (-8.15 mum, p = 0.04), as compared to MSNM eyes. HC GCIP and pRNFL thicknesses were lower in HCHM than HCNM eyes (-4.15 mum, p = 0.01 and -0.84 mum, p = 0.83 respectively). Despite cross-sectional differences in retinal layer thicknesses in eyes stratified by myopia, longitudinal (median duration of follow-up= 4.6, 6.9, 4.0, 5.1 years in MSHM, MSNM, HCHM, and HCNM respectively) rates of retinal layer change did not differ between participants with and without high myopia. In the MS cohort, rates of thinning were significant in both groups but there was no difference between rates of GCIP and pRNFL thinning among MSHM and MSNM (DELTA0.07 mum/y, p = 0.71 and DELTA0.12 mum/y, p = 0.52 respectively) eyes. Similarly, no difference in rates of GCIP and pRNFL change was found between HCHM and HCNM (DELTA0.06 mum/y, p = 0.49 and DELTA0.21 mum/y, p = 0.22 respectively) eyes. Similar results were observed for the inner and outer nuclear layers in MS and HCs.
Conclusion(s): Although cross-sectional retinal thickness measures may vary due to myopia, longitudinal rates of retinal change appear unaffected. Therefore, despite longstanding opinion, our findings suggest high myopia may not confound longitudinal OCT analyses. Future research is needed to verify and validate our preliminary findings in larger, longitudinal studies

BACKGROUND:STRIVE is a multicenter, observational, open-label, single-arm study of natalizumab in anti-JC virus (JCV) seronegative patients with early relapsing-remitting multiple sclerosis (RRMS). The objective of this prespecified 2-year interim analysis was to determine the effectiveness of natalizumab in establishing and maintaining no evidence of disease activity (NEDA) in early RRMS. METHODS:Patients aged 18-65 years had an RRMS diagnosis < 3 years prior to screening, an Expanded Disability Status Scale (EDSS) score ≤ 4.0, and anti-JCV antibody negative status. Magnetic resonance imaging was performed at baseline and yearly thereafter. Cumulative probabilities of 24-week-confirmed EDSS worsening and improvement were evaluated at 2 years. NEDA (no 24-week-confirmed EDSS worsening, no relapses, no gadolinium-enhancing lesions, and no new/newly enlarging T2-hyperintense lesions) was evaluated over 2 years. The Symbol Digit Modalities Test (SDMT) and Multiple Sclerosis Impact Score (MSIS-29) were assessed at baseline and 1 and 2 years. Statistical analysis used summary statistics and frequency distributions. RESULTS:The study population (N = 222) had early RRMS, with mean (standard deviation [SD]) time since diagnosis of 1.6 (0.77) years and mean (SD) baseline EDSS score of 2.0 (1.13). NEDA was achieved in 105 of 187 patients (56.1%) during year 1 and 120 of 163 (73.6%) during year 2. Over 2 years, 76 of 171 patients (44.4%) attained overall NEDA. Probabilities of 24-week-confirmed EDSS worsening and improvement were 14.1% and 28.4%, respectively. After 2 years, patients exhibited significant improvements from baseline in SDMT (n = 158; mean [SD]: 4.3 [11.8]; p < 0.001) and MSIS-29 physical (n = 153; mean [SD]: - 3.9 [14.7]; p = 0.001), psychological (n = 152; mean [SD]: - 2.0 [7.9]; p < 0.001), and quality-of-life (n = 153; mean [SD]: - 6.0 [21.3]; p < 0.001) scores. CONCLUSIONS:These results support natalizumab's effectiveness over 2 years, during which nearly half of early RRMS patients achieved NEDA. During year 2, nearly 75% of patients exhibited NEDA. Over 2 years, patients continued to experience significant cognitive and quality-of-life benefits. These results are limited by the lack of a comparator group to determine the extent of a placebo effect. TRIAL REGISTRATION/BACKGROUND:clinicaltrials.gov, NCT01485003 , registered 5 December 2011.

We describe a selection process for a multivariable risk prediction model of death within 30 days of hospital discharge in the SILVER-AMI study. This large, multi-site observational study included observational data from 2000 persons 75 years and older hospitalized for acute myocardial infarction (AMI) from 94 community and academic hospitals across the United States and featured a large number of candidate variables from demographic, cardiac, and geriatric domains, whose missing values were multiply imputed prior to model selection. Our objective was to demonstrate that Bayesian Model Averaging (BMA) represents a viable model selection approach in this context. BMA was compared to three other backward-selection approaches: Akaike information criterion, Bayesian information criterion, and traditional p-value. Traditional backward-selection was used to choose 20 candidate variables from the initial, larger pool of five imputations. Models were subsequently chosen from those candidates using the four approaches on each of 10 imputations. With average posterior effect probability ≥ 50% as the selection criterion, BMA chose the most parsimonious model with four variables, with average C statistic of 78%, good calibration, optimism of 1.3%, and heuristic shrinkage of 0.93. These findings illustrate the utility and flexibility of using BMA for selecting a multivariable risk prediction model from many candidates over multiply imputed datasets.

BACKGROUND:Migraine and epilepsy are comorbid conditions. While it is well known that epilepsy can have an impact on cognitive abilities, there is conflicting evidence in the literature on the relationship between migraine and cognitive function. The aim of this study was to assess whether migraine comorbidity in patients with newly diagnosed focal epilepsy is associated with cognitive dysfunction. METHODS:This is a post hoc analysis of data prospectively collected for the Human Epilepsy Project (HEP). There were 349 participants screened for migraine with the 13 questions used in the American Migraine Prevalence and Prevention (AMPP) study. Participants were also screened for depression using the Neurological Disorder Depression Inventory for Epilepsy (NDDI-E) and the Center for Epidemiologic Studies Depression Scale (CES-D) and for anxiety using the Generalized Anxiety Disorder-7 (GAD-7) scale. Cognitive performance was assessed with the Cogstate Brief Battery and Aldenkamp-Baker Neuropsychological Assessment Schedule (ABNAS). RESULTS:About a fifth (21.2%) of patients with a new diagnosis of focal epilepsy screened positive for migraine. There were more women and less participants employed full time among the participants with comorbid migraine. They reported slightly more depressive and anxious symptoms than the participants without migraine. Migraine comorbidity was associated with ABNAS memory score (median: 2, range: 0-12, Mann Whitney U p-value: 0.015). However, migraine comorbidity was not associated with Cogstate scores nor ABNAS total scores or other ABNAS domain scores. In linear regressions, depression and anxiety scores were associated with the ABNAS memory score. CONCLUSION/CONCLUSIONS:In this study, there was no association between migraine comorbidity and objective cognitive scores in patients with newly diagnosed focal epilepsy. The relationship between migraine comorbidity and subjective memory deficits seemed to be mediated by the higher prevalence of depression and anxiety symptoms in patients with epilepsy with comorbid migraine.

OBJECTIVES/OBJECTIVE:While patients' health priorities should inform healthcare, strategies for doing so are lacking for patients with multiple conditions. We describe challenges to, and strategies that support, patients' priorities-aligned decision-making. DESIGN/METHODS:Participant observation qualitative study. SETTING/METHODS:Primary care and cardiology practices in Connecticut. PARTICIPANTS/METHODS:Ten primary care clinicians, five cardiologists, and the Patient Priorities implementation team (four geriatricians, physician expert in clinician training, behavioral medicine expert). The patients discussed were ≥ 66 years with >3 chronic conditions and ≥10 medications or saw ≥ two specialists. EXPOSURE/METHODS:Following initial training and experience in providing Patient Priorities Care, the clinicians and Patient Priorities implementation team participated in 21 case-based, group discussions (10 face-to-face;11 telephonic). Using emergent learning (i.e. learning which arises from interactions among the participants), participants discussed challenges, posed solutions, and worked together to determine how to align care options with the health priorities of 35 patients participating in the Patient Priorities Care pilot. MAIN OUTCOMES/RESULTS:Challenges to, and strategies for, aligning decision-making with patient's health priorities. RESULTS:Categories of challenges discussed among participants included uncertainty, complexity, and multiplicity of problems and treatments; difficulty switching to patients' priorities as the focus of decision-making; and differing perspectives between patients and clinicians, and among clinicians. Strategies identified to support patient priorities-aligned decision-making included starting with one thing that matters most to each patient; conducting serial trials of starting, stopping, or continuing interventions; focusing on function (i.e. achieving patient's desired activities) rather than eliminating symptoms; basing communications, decision-making, and effectiveness on patients' priorities not solely on diseases; and negotiating shared decisions when there are differences in perspectives. CONCLUSIONS:The discrete set of challenges encountered and the implementable strategies identified suggest that patient priorities-aligned decision-making in the care of patients with multiple chronic conditions is feasible, albeit complicated. Findings require replication in additional settings and determination of their effect on patient outcomes.

Demographic and income disparities may impact food accessibility. Research has not yet well documented the precise location of healthy and unhealthy food resources around children's homes and schools. The objective of this study was to examine the food environment around homes and schools for all public school children, stratified by race/ethnicity and poverty status. This cross-sectional study linked data on the exact home and school addresses of a population-based sample of public school children in New York City from 2013 to all corner stores, supermarkets, fast-food restaurants, and wait-service restaurants. Two measures were created around these addresses for all children: 1) distance to the nearest outlet, and 2) count of outlets within 0.25 miles. The total analytic sample included 789,520 K-12 graders. The average age was 11.78 years (SD ± 4.0 years). Black, Hispanic, and Asian students live and attend schools closer to nearly all food outlet types than White students, regardless of poverty status. Among not low-income students, Black, Hispanic, and Asian students were closer from home and school to corner stores and supermarkets, and had more supermarkets around school than White students. The context in which children live matters, and more nuanced data is important for development of appropriate solutions for childhood obesity. Future research should examine disparities in the food environment in other geographies and by other demographic characteristics, and then link these differences to health outcomes like body mass index. These findings can be used to better understand disparities in food access and to help design policies intended to promote healthy eating among children.

Introduction: We determined whether Obstructive Sleep Apnea (OSA) and beta-Amyloid Burden (Abeta) act additively or synergistically to promote conversion from cognitive normal (CN) to mild cognitive impairment (MCI) and from MCI to AD.
Method(s): In this longitudinal observational study, we examined CN (n=298) and MCI (n=418) older adults from the ADNI database (adni.loni.usc.edu). OSA was self-reported during a clinical interview. Brain Abeta was assessed using Florbetapir-PET imaging. The primary outcome of the analysis was conversion from CN to MCI (CN participants) and from MCI to AD (MCI participants). Participants were required to have a baseline and at least one follow-up clinical visit that identified their cognitive status. Logistic mixed-effects models with random intercept and slope were used to assess associations between OSA, Abeta, and risk of conversion from CN to MCI, and MCI to AD. All models included age at baseline, sex, APOE4 status, years of education, and their interactions with time.
Result(s): Of the 716 participants, 329 (46%) were women. The overall mean (SD) age was 74.7 (5.0) years, and the overall mean (SD) follow-up time was 5.5 (1.7) years (Range: 2.7 - 10.9 years). In CN participants at baseline, conversion to MCI was associated with both OSA (beta = 0.418; 95% CI, 0.133 to 0.703; P < .001) and higher Abeta-burden (beta = 0.554; 95% CI, 0.215 to 0.892; P < .001). The interaction of OSA and Abeta burden with time was significant (beta = 1.169, 95% CI, 0.776 to 1.562; P < .001), suggesting a synergistic effect. In MCI participants at baseline, conversion to AD was associated with both OSA (beta = 0.637; 95% CI, 0.291 to 0.982; P < .001) and higher Abeta-burden (beta = 1.061; 95% CI, 0.625 to 1.497; P < .001). The interaction of OSA and Abeta burden with time was significant (beta = 1.312, 95% CI, 0.952 to 1.671; P < .001), suggesting a synergistic effect.
Conclusion(s): In both CN and MCI elderly, Abeta modified the risk of progression to AD in OSA participants. OSA patients maybe more physiologically susceptible as Abeta load becomes increasingly abnormal

BACKGROUND:Among older adults (age≥75) hospitalized for acute myocardial infarction, acute kidney injury after coronary angiography is common. Aging-related conditions may independently predict acute kidney injury, but have not yet been analyzed in large acute myocardial infarction cohorts. METHODS:We analyzed data from 2212 participants age≥75 in the SILVER-AMI study who underwent coronary angiography. Acute kidney injury was defined using KDIGO criteria (serum Cr increase ≥0.3mg/dL from baseline or≥1.5 times baseline). We analyzed the associations of traditional acute kidney injury risk factors and aging-related conditions (ADL impairment, prior falls, cachexia, low physical activity) with acute kidney injury, and then performed logistic regression to identify independent predictors. RESULTS:Participants' mean age was 81.3years, 45.2% were female, and 9.5% were nonwhite; 421 (19.0%) experienced acute kidney injury. Comorbid diseases and aging-related conditions were both more common among individuals experiencing acute kidney injury. However, after multivariable adjustment, no aging-related conditions were retained. There were 11 risk factors in the final model; the strongest were heart failure on presentation (OR 1.91, 95% CI 1.41-2.59), BMI >30 (vs. BMI 18-25: OR 1.75, 95% CI 1.27-2.42), and nonwhite race (OR 1.65, 95% CI 1.16-2.33). The final model achieved an AUC of 0.72 and was well calibrated (Hosmer-Lemeshow P=0.50). Acute kidney injury was independently associated with 6month mortality (OR 1.98, 95% CI 1.36-2.88) but not readmission (OR 1.26, 95% CI 0.98-1.61). CONCLUSIONS:Acute kidney injury is common among older adults with acute myocardial infarction undergoing coronary angiography. Predictors largely mirrored those in previous studies of younger individuals, which suggests that geriatric conditions mediate their influence through other risk factors.

BACKGROUND:Given the growing burden of cardiovascular diseases in sub-Saharan Africa, global donors and governments are exploring strategies for integrating evidence-based cardiovascular diseases prevention into HIV clinics. We assessed the capabilities, motivations and opportunities that exist for HIV clinics to apply evidence-based strategies for hypertension control among people living with HIV (PLHIV) in Nigeria. METHODS:We used a concurrent Quan-Qual- study approach (a quantitative first step using structured questionnaires followed by a qualitative approach using stakeholder meetings).We invited key stakeholders and representatives of HIV and non-communicable disease organizations in Lagos, Nigeria to 1) assess the capacity of HIV clinics (n = 29) to, and; 2) explore their attitudes and perceptions towards implementing evidence-based strategies for hypertension management in Lagos, Nigeria (n = 19)The quantitative data were analyzed using SPSS whereas responses from the stakeholders meeting were coded and analyzed using thematic approach and an implementation science framework, the COM-B (Capabilities, Opportunities, Motivations and Behavior) model, guided the mapping and interpretation of the data. RESULTS:Out of the 29 HIV clinics that participated in the study, 28 clinics were public, government-owned facilities with 394 HIV patients per month with varying capabilities, opportunities and motivations for integrating evidence-based hypertension interventions within their services for PLHIV. Majority of the clinics (n = 26) rated medium-to-low on the psychological capability domains, while most of the clinics (n = 25) rated low on the physical capabilities of integrating evidence-based hypertension interventions within HIV clinics. There was high variability in the ratings for the opportunity domains, with physical opportunities rated high in only eight HIV clinics, two clinics with a medium rating and nineteen clinics with a low rating. Social opportunity domain tended to be rated low in majority of the HIV clinics (n = 21). Lastly, almost all the HIV clinics (n = 23) rated high on the reflective motivation domain although automatic motivations tended to be rated low across the HIV clinics. CONCLUSION/CONCLUSIONS:In this study, we found that with the exception of motivations, the relative capabilities whether physical or psychological and the relative opportunities for integrating evidence-based hypertension intervention within HIV clinics in Nigeria were minimal. Thus, there is need to strengthen the HIV clinics in Lagos for the implementation of evidence-based hypertension interventions within HIV clinics to improve patient outcomes and service delivery in Southwest Nigeria.