Faculty Bibliography

BACKGROUND: The human monoclonal antibody opicinumab (BIIB033, anti-LINGO-1) has shown remyelinating activity in preclinical studies. We therefore assessed the safety and tolerability, and efficacy of opicinumab given soon after a first acute optic neuritis episode. METHODS: This randomised, double-blind, placebo-controlled, phase 2 study (RENEW) was done at 33 sites in Australia, Canada, and Europe in participants (aged 18-55 years) with a first unilateral acute optic neuritis episode within 28 days from study baseline. After treatment with high-dose methylprednisolone (1 g/day, intravenously, for 3-5 days), participants were assigned with a computer-generated sequence with permuted block randomisation (1:1) using a centralised interactive voice and web response system to receive 100 mg/kg opicinumab intravenously or placebo once every 4 weeks (six doses) and followed up to week 32. All study participants and all study staff, including the central readers, were masked to treatment assignment apart from the pharmacist responsible for preparing the study treatments and the pharmacy monitor at each site. The primary endpoint was remyelination at 24 weeks, measured as recovery of affected optic nerve conduction latency using full-field visual evoked potential (FF-VEP) versus the unaffected fellow eye at baseline. Analysis was by intention-to-treat (ITT); prespecified per-protocol (PP) analyses were also done. This study is registered with ClinicalTrials.gov, number NCT01721161. FINDINGS: The study was done between Dec 21, 2012, and Oct 21, 2014. 82 participants were enrolled, and 41 in each group comprised the ITT population; 33 participants received opicinumab and 36 received placebo in the PP population. Adjusted mean treatment difference of opicinumab versus placebo was -3.5 ms (17.3 vs 20.8 [95% CI -10.6 to 3.7]; 17%; p=0.33) in the ITT population, and -7.6 ms in the PP population (14.7 vs 22.2 [-15.1 to 0.0]; 34%; p=0.050) at week 24 and -6.1 ms (15.1 vs 21.2 [-12.7 to 0.5]; 29%; p=0.071) in the ITT population and -9.1 ms (13.2 vs 22.4 [-16.1 to -2.1]; 41%; p=0.011) in the PP population at week 32. The overall incidence (34 [83%] of 41 in each group) and severity of adverse events (two [5%] of 41 severe adverse events with placebo vs three [7%] of 41 with opicinumab) were similar between groups and no significant effects on brain MRI measures were noted in either group (mean T2 lesion volume change, 0.05 mL [SD 0.21] for placebo vs 0.20 mL [0.52] with opicinumab; 27 [77%] of 35 participants with no change in gadolinium-enhancing [Gd+] lesion number with opicinumab vs 27 [79%] of 34 with placebo; mean 0.4 [SD 0.79 for the placebo group and 0.85 for the opicinumab group] new Gd+ lesions per participant in both groups). Treatment-related serious adverse events were reported in three (7%) of 41 participants in the opicinumab group (hypersensitivity [n=2], asymptomatic increase in transaminase concentrations [n=1]) and none of the participants in the placebo group. INTERPRETATION: Remyelination did not differ significantly between the opicinumab and placebo groups in the ITT population at week 24. However, results from the prespecified PP population suggest that enhancing remyelination in the human CNS with opicinumab might be possible and warrant further clinical investigation. FUNDING: Biogen.

Purpose . Interest and funding continue to grow for bringing supermarkets to underserved areas, yet little is known about their impact. Design . A quasi-experimental study was used to determine the impact of a new supermarket opening as a result of tax and zoning incentives. Setting . The study took place in the South Bronx, New York City, New York. SUBJECTS: Studied were residents of two South Bronx neighborhoods deemed high need. Measures . Food purchasing and consumption were examined via surveys and 24-hour dietary recalls before and at two points after the supermarket opened (1-5, 13-17 months). Analysis . Data were analyzed using difference-in-difference models controlling for gender, race and ethnicity, age, education, marital status, and self-reported income. Ordinary least squares and logistic regression models were estimated for continuous and binary outcomes, respectively. Results . At baseline, 94% to 97% of consumers shopped at a supermarket. There was a 2% increase in this behavior in the intervention community (p < .05) not seen in the comparison community. One year later there was a 7% net increase in eating at home (p < .1) and a 20% decrease in drinking sugary beverages (p < .05), but no appreciable change in fruit/vegetable consumption or overall dietary quality. Conclusion . The new supermarket did not result in substantial or broad changes in purchasing patterns or nutritional quality of food consumed, though smaller, positive changes were observed over a 1-year period. Future work should examine different contexts and a broader set of outcomes, including economic development.

Low-contrast letter acuity (LCLA) has emerged as the leading outcome measure to assess visual disability in multiple sclerosis (MS) research. As visual dysfunction is one of the most common manifestations of MS, sensitive visual outcome measures are important in examining the effect of treatment. Low-contrast acuity captures visual loss not seen in high-contrast visual acuity (HCVA) measurements. These issues are addressed by the MS Outcome Assessments Consortium (MSOAC), including representatives from advocacy organizations, Food and Drug Administration (FDA), European Medicines Agency (EMA), National Institute of Neurological Disorders and Stroke (NINDS), academic institutions, and industry partners along with persons living with MS. MSOAC goals are acceptance and qualification by regulators of performance outcomes that are highly reliable and valid, practical, cost-effective, and meaningful to persons with MS. A critical step is elucidation of clinically relevant benchmarks, well-defined degrees of disability, and gradients of change that are clinically meaningful. This review shows that MS and disease-free controls have similar median HCVA, while MS patients have significantly lower LCLA. Deficits in LCLA and vision-specific quality of life are found many years after an episode of acute optic neuritis, even when HCVA has recovered. Studies reveal correlations between LCLA and the Expanded Disability Status Score (EDSS), Multiple Sclerosis Functional Composite (MSFC), retinal nerve fiber layer (RNFL) and ganglion cell layer plus inner plexiform layer (GCL + IPL) thickness on optical coherence tomography (OCT), brain magnetic resonance imaging (MRI), visual evoked potential (VEP), electroretinogram (ERG), pupillary function, and King-Devick testing. This review also concludes that a 7-point change in LCLA is clinically meaningful. The overall goal of this review is to describe and characterize the LCLA metric for research and clinical use among persons with MS.

Aortic root thrombus is an uncommon complication of continuous-flow left ventricular assist devices (LVAD). We present the case of a 71-year-old man with ischemic cardiomyopathy who underwent destination therapy HeartMate II LVAD placement. Eighteen months later, he presented with a cerebrovascular accident followed by myocardial infarction. Transesophageal echocardiography revealed an aortic root thrombus spanning the left and noncoronary cusps and obliterating the left main coronary artery. We discuss the incidence, risk factors, and management of aortic root thrombus in LVAD patients. To our knowledge, this is the first report of three-dimensional echocardiography used to characterize an LVAD-associated aortic root thrombus.

INTRODUCTION: Electronic medical records represent a new source of longitudinal data on tobacco use. METHODS: Electronic medical records of the U.S. Department of Veterans Affairs were extracted to find patients' tobacco use status in 2009 and at another assessment 12-24 months later. Records from the year prior to the first assessment were used to determine patient demographics and comorbidities. These data were analyzed in 2015. RESULTS: An annual quit rate of 12.0% was observed in 754,504 current tobacco users. Adjusted tobacco use prevalence at follow-up was 3.2% greater with alcohol use disorders at baseline, 1.9% greater with drug use disorders, 3.3% greater with schizophrenia, and lower in patients with cancer, heart disease, and other medical conditions (all differences statistically significant with p<0.05). Annual relapse rates in 412,979 former tobacco users were 29.6% in those who had quit for <1 year, 9.7% in those who had quit for 1-7 years, and 1.9% of those who had quit for >7 years. Among those who had quit for <1 year, adjusted relapse rates were 4.3% greater with alcohol use disorders and 7.2% greater with drug use disorders (statistically significant with p<0.05). CONCLUSIONS: High annual cessation rates may reflect the older age and greater comorbidities of the cohort or the intensive cessation efforts of the U.S. Department of Veterans Affairs. The lower cessation and higher relapse rates in psychiatric and substance use disorders suggest that these groups will need intensive and sustained cessation efforts.

This study attempted to better understand factors associated with relationship conflict between daughters and their parents with dementia. We examined data from 77 daughters self-identified as primary caregivers of a parent with dementia to test the hypothesis that daughters' belief that a parent with dementia can control their symptoms is associated with more conflict, defined as high expressed emotion (EE). Participants completed self-report questionnaires assessing beliefs about parents' ability to control symptoms, stress, relationship conflict, parent agitation, and cognitive status. Results indicated that greater intensity of daughters' belief that their parent can control dementia-related symptoms was associated with more relationship conflict or "high EE" (beta = 0.57, P < .001). Daughters' beliefs about parental behavior may contribute to caregiver stress and exacerbate negative behaviors exhibited by individuals with dementia. Educating caregivers about parental behaviors and examining factors underlying caregiver interpretations of these behaviors hold promise for reducing caregiver stress.

While cerebral amyloid angiopathy is a common cause of lobar hemorrhage, rarely it may be associated with an inflammatory response, thought to be incited by amyloid deposits. We report a 73-year-old woman with an extensive cancer history who presented with tumor-like lesions and symptoms of homonymous hemianopia and prosopagnosia. Found to have cerebral amyloid angiopathy-related inflammation proven by brain biopsy, she was treated successfully with immunosuppression.

BACKGROUND: There is a need for screening and brief assessment instruments to identify primary care patients with substance use problems. This study's aim was to examine the performance of a two-step screening and brief assessment instrument, the TAPS Tool, compared to the WHO ASSIST. METHODS: Two thousand adult primary care patients recruited from five primary care clinics in four Eastern US states completed the TAPS Tool followed by the ASSIST. The ability of the TAPS Tool to identify moderate- and high-risk use scores on the ASSIST was examined using sensitivity and specificity analyses. RESULTS: The interviewer and self-administered computer tablet versions of the TAPS Tool generated similar results. The interviewer-administered version (at cut-off of 2), had acceptable sensitivity and specificity for high-risk tobacco (0.90 and 0.77) and alcohol (0.87 and 0.80) use. For illicit drugs, sensitivities were >0.82 and specificities >0.92. The TAPS (at a cut-off of 1) had good sensitivity and specificity for moderate-risk tobacco use (0.83 and 0.97) and alcohol (0.83 and 0.74). Among illicit drugs, sensitivity was acceptable for moderate-risk of marijuana (0.71), while it was low for all other illicit drugs and non-medical use of prescription medications. Specificities were 0.97 or higher for all illicit drugs and prescription medications. CONCLUSIONS: The TAPS Tool identified adult primary care patients with high-risk ASSIST scores for all substances as well moderate-risk users of tobacco, alcohol, and marijuana, although it did not perform well in identifying patients with moderate-risk use of other drugs or non-medical use of prescription medications. The advantages of the TAPS Tool over the ASSIST are its more limited number of items and focus solely on substance use in the past 3months.