Faculty Bibliography

BACKGROUND: Structural retinal imaging biomarkers are important for early recognition and monitoring of inflammation and neurodegeneration in multiple sclerosis. With the introduction of spectral domain optical coherence tomography (SD-OCT), supervised automated segmentation of individual retinal layers is possible. We aimed to investigate which retinal layers show atrophy associated with neurodegeneration in multiple sclerosis when measured with SD-OCT. METHODS: In this systematic review and meta-analysis, we searched for studies in which SD-OCT was used to look at the retina in people with multiple sclerosis with or without optic neuritis in PubMed, Web of Science, and Google Scholar between Nov 22, 1991, and April 19, 2016. Data were taken from cross-sectional cohorts and from one timepoint from longitudinal studies (at least 3 months after onset in studies of optic neuritis). We classified data on eyes into healthy controls, multiple-sclerosis-associated optic neuritis (MSON), and multiple sclerosis without optic neuritis (MSNON). We assessed thickness of the retinal layers and we rated individual layer segmentation performance by random effects meta-analysis for MSON eyes versus control eyes, MSNON eyes versus control eyes, and MSNON eyes versus MSON eyes. We excluded relevant sources of bias by funnel plots. FINDINGS: Of 25 497 records identified, 110 articles were eligible and 40 reported data (in total 5776 eyes from patients with multiple sclerosis [1667 MSON eyes and 4109 MSNON eyes] and 1697 eyes from healthy controls) that met published OCT quality control criteria and were suitable for meta-analysis. Compared with control eyes, the peripapillary retinal nerve fibre layer (RNFL) showed thinning in MSON eyes (mean difference -20.10 mum, 95% CI -22.76 to -17.44; p<0.0001) and in MSNON eyes (-7.41 mum, -8.98 to -5.83; p<0.0001). The macula showed RNFL thinning of -6.18 mum (-8.07 to -4.28; p<0.0001) in MSON eyes and -2.15 mum (-3.15 to -1.15; p<0.0001) in MSNON eyes compared with control eyes. Atrophy of the macular ganglion cell layer and inner plexiform layer (GCIPL) was -16.42 mum (-19.23 to -13.60; p<0.0001) for MSON eyes and -6.31 mum (-7.75 to -4.87; p<0.0001) for MSNON eyes compared with control eyes. A small degree of inner nuclear layer (INL) thickening occurred in MSON eyes compared with control eyes (0.77 mum, 0.25 to 1.28; p=0.003). We found no statistical difference in the thickness of the combined outer nuclear layer and outer plexiform layer when we compared MSNON or MSON eyes with control eyes, but we found a small degree of thickening of the combined layer when we compared MSON eyes with MSNON eyes (1.21 mum, 0.24 to 2.19; p=0.01). INTERPRETATION: The largest and most robust differences between the eyes of people with multiple sclerosis and control eyes were found in the peripapillary RNFL and macular GCIPL. Inflammatory disease activity might be captured by the INL. Because of the consistency, robustness, and large effect size, we recommend inclusion of the peripapillary RNFL and macular GCIPL for diagnosis, monitoring, and research. FUNDING: None.

BACKGROUND: Data on both known and unknown drug use in the electronic dance music (EDM) scene is important to inform prevention and harm reduction. While surveys are the most common method of querying drug use, additional biological data can help validate use and detect unknown/unintentional use of drugs such as new psychoactive substances (NPS). We sought to determine the extent of both known and unknown use of various substances in this high-risk scene. METHODS: We hair-tested 90 self-reported past-year ecstasy/MDMA/Molly users attending EDM parties in New York City during the summer of 2016 using UHPLC-MS/MS. Results were compared to self-reported past-year use. RESULTS: Three quarters (74.4%) tested positive for MDMA, a third (33.3%) tested positive for an NPS, and 27.8% tested positive specifically for one or more synthetic cathinones (e.g., butylone, ethylone, pentylone, methylone, alpha-PVP). Half (51.1%) of participants tested positive for a drug not self-reported, with most testing positive for synthetic cathinones (72.0%), methamphetamine (69.0%), other NPS stimulants (e.g., 4-FA, 5/6-APB; 66.7%), or new dissociatives (e.g., methoxetamine, diphenidine; 60.0%). Attending parties every other week or more often, reporting higher-frequency ecstasy pill use, having tested one's ecstasy, and having found out one's ecstasy was adulterated, were risk factors for testing positive for synthetic cathinones and NPS in general. CONCLUSION: Hair testing appears to be a valuable addition to drug epidemiology studies. Many EDM party attendees-even those who test their ecstasy-are unknowingly using NPS and/or other drugs. Prevention information and harm reduction may help reduce unknown/unintentional use.

BACKGROUND:Using change in estimated glomerular filtration rate (eGFR) based on creatinine concentration as a surrogate outcome in clinical trials of chronic kidney disease has been proposed. Risk for end-stage renal disease (ESRD) and all-cause mortality associated with change in concentrations of other filtration markers has not been studied in chronic kidney disease populations. STUDY DESIGN/METHODS:Observational analysis of 2 clinical trials. SETTING & PARTICIPANTS/METHODS:Participants in the MDRD (Modification of Diet in Renal Disease; n=317) Study and AASK (African American Study of Kidney Disease and Hypertension; n=373). PREDICTORS/METHODS:-microglobulin (B2M) were measured in serum samples collected at the 12- and 24-month follow-up visits, along with measured GFR (mGFR) at these time points. OUTCOMES/RESULTS:ESRD and all-cause mortality. MEASUREMENTS/METHODS:Poisson regression was used to estimate incidence rate ratios and 95% CIs for ESRD and all-cause mortality during long-term follow-up (10-16 years) per 30% decline in mGFR or eGFR for each filtration marker and the average of all 4 markers. RESULTS:, but not mGFR or the other filtration markers, was significantly associated with risk for all-cause mortality in AASK only (incidence rate ratio per 30% decline, 4.17; 95% CI, 1.78-9.74; P<0.001), but this association was not significantly different from decline in mGFR (P=0.2). LIMITATIONS/CONCLUSIONS:Small sample size. CONCLUSIONS:, and the average of 4 filtration markers (creatinine, cystatin C, BTP, and B2M) were consistently associated with progression to ESRD.

Chronic kidney disease (CKD) is a major global public health problem with significant gaps in research, care, and policy. In order to mitigate the risks and adverse effects of CKD, the International Society of Nephrology has created a cohesive set of activities to improve the global outcomes of people living with CKD. Improving monitoring of renal disease progression can be done by screening and monitoring albuminuria and estimated glomerular filtration rate in primary care. Consensus on how many times and how often albuminuria and estimated glomerular filtration rate are measured should be defined. Meaningful changes in both renal biomarkers should be determined in order to ascertain what is clinically relevant. Increasing social awareness of CKD and partnering with the technological community may be ways to engage patients. Furthermore, improving the prediction of cardiovascular events in patients with CKD can be achieved by including the renal risk markers albuminuria and estimated glomerular filtration rate in cardiovascular risk algorithms and by encouraging uptake of assessing cardiovascular risk by general practitioners and nephrologists. Finally, examining ways to further validate and implement novel biomarkers for CKD will help mitigate the global problem of CKD. The more frequent use of renal biopsy will facilitate further knowledge into the underlying etiologies of CKD and help put new biomarkers into biological context. Real-world assessments of these biomarkers in existing cohorts is important, as well as obtaining regulatory approval to use these biomarkers in clinical practice. Collaborations among academia, physician and patient groups, industry, payer organizations, and regulatory authorities will help improve the global outcomes of people living with CKD.

Background: Emerging evidence suggests novel roles for bacterially derived vitamin K forms known as menaquinones in health and disease, which may be attributable in part to anti-inflammatory effects. However, the relevance of menaquinones produced by gut bacteria to vitamin K requirements and inflammation is undetermined.Objective: This study aimed to quantify fecal menaquinone concentrations and identify associations between fecal menaquinone concentrations and serum vitamin K concentrations, gut microbiota composition, and inflammation.Design: Fecal and serum menaquinone concentrations, fecal microbiota composition, and plasma and fecal cytokine concentrations were measured in 80 men and postmenopausal women (48 men, 32 women, age 40-65 y) enrolled in a randomized, parallel-arm, provided-food trial. After consuming a run-in diet for 2 wk, participants were randomly assigned to consume a whole grain-rich (WG) or a refined grain-based (RG) diet for 6 wk. Outcomes were measured at weeks 2 and 8.Results: The median total daily excretion of menaquinones in feces was 850 nmol/d but was highly variable (range: 64-5358 nmol/d). The total median (IQR) fecal concentrations of menaquinones decreased in the WG diet compared with the RG diet [-6.8 nmol/g (13.0 nmol/g) dry weight for WG compared with 1.8 nmol/g (12.3 nmol/g) dry weight for RG; P < 0.01)]. However, interindividual variability in fecal menaquinone concentrations partitioned individuals into 2 distinct groups based on interindividual differences in concentrations of different menaquinone forms rather than the diet group or the time point. The relative abundances of several gut bacteria taxa, Bacteroides and Prevotella in particular, differed between these groups, and 42% of identified genera were associated with ≥1 menaquinone form. Menaquinones were not detected in serum, and neither fecal concentrations of individual menaquinones nor the menaquinone group was associated with any marker of inflammation.Conclusion: Menaquinone concentrations in the human gut appear highly variable and are associated with gut microbiota composition. However, the health implications remain unclear. This trial was registered at clinicaltrials.gov as NCT01902394.

OBJECTIVES: In this study, we examined the prevalence and correlates of current synthetic cannabinoid (SC) use among high school seniors in the United States. METHODS: Monitoring the Future, an annual nationally representative survey of high school seniors, began querying current (30-day) SC use in 2014. Data were examined from the 2 most recent cohorts (2014-2015; N = 7805). Prevalence of self-reported use was examined and differences in demographics and recency and frequency of other drug use was compared between current marijuana-only users and current SC (plus marijuana) users using chi2 and generalized linear model using Poisson. RESULTS: We found that 2.9% of students reported current SC use; 1.4% of students (49.7% of users) reported using SCs on >/=3 days in the past month. SC users were more likely to report more recent (and often more frequent) use of lysergic acid diethylamide, cocaine, heroin, and/or nonmedical use of opioids compared with marijuana-only users. Compared with current marijuana-only users, SC users were more likely to report lower parent education (P < .05) and current use of a higher number of illegal drugs other than marijuana (Ps < .001). Students using SCs >/=10 times in the past month were more likely to be boys, frequent marijuana users (Ps < .01), African American, and users of multiple other illegal drugs (Ps < .001). CONCLUSIONS: SC use is typically part of a repertoire of polydrug use, and polydrug use is less prevalent among marijuana-only users. Current SC users are at risk for poisoning from use of the newest generation of SCs and from concurrent drug use.

Concerns persist that individuals with substance use disorders who are under community criminal justice supervision experience circumstances that might compromise their provision of valid, informed consent for research participation. These concerns include the possibilities that desire to obtain access to treatment might lead individuals to ignore important information about research participation, including information about risks, or that cognitive impairment associated with substance use might interfere with attending to important information. We report results from a consent quiz (CQ) administered in a multisite randomized clinical trial of long-acting naltrexone to prevent relapse to opioid use disorder among adults under community criminal justice supervision-a treatment option difficult to access by this population of individuals. Participants were required to answer all 11 items correctly before randomization. On average, participants answered 9.8 items correctly (89%) at baseline first attempt (n=306). At week 21 (n=212), participants scored 87% (9.5 items correct) without review. Performance was equivalent to, or better than, published results from other populations on a basic consent quiz instrument across multiple content domains. The consent quiz is an efficient method to screen for adequate knowledge of consent information as part of the informed consent process. Clinical researchers who are concerned about these issues should consider using a consent quiz with corrected feedback to enhance the informed consent process. Overall, while primarily useful as an educational tool, employing a CQ as part of the gateway to participation in research may be particularly important as the field continues to advance and tests novel experimental treatments with significant risks and uncertain potential for benefit.

There is now an unprecedented opportunity to improve the care of the over 5 million people who are living with Alzheimer's disease and related dementias and many more with cognitive impairment due to brain injury, systemic diseases, and other causes. The introduction of a new Medicare care planning benefit-long sought openly by advocacy organizations and clinicians and badly needed by patients and families-could greatly improve health care quality, but only if widely and fully implemented. We describe the components of this new benefit and its promise of better clinical care, as well as its potential to create a new platform for clinical and health outcomes research. We highlight external factors-and some that are internal to the benefit structure itself-that challenge the full realization of its value, and we call for broad public and professional engagement to ensure that it will not fail.