Attention-deficit/hyperactivity disorder medication and seizures

OBJECTIVE: Individuals with attention-deficit/hyperactivity disorder (ADHD) are at increased risk of seizures, but there is uncertainty about whether ADHD medication treatment increases risk among patients with and without preexisting seizures. METHODS: We followed a sample of 801,838 patients with ADHD who had prescribed drug claims from the Truven Health MarketScan Commercial Claims and Encounters databases to examine whether ADHD medication increases the likelihood of seizures among ADHD patients with and without a history of seizures. First, we assessed overall risk of seizures among patients with ADHD. Second, within-individual concurrent analyses assessed odds of seizure events during months when a patient with ADHD received ADHD medication compared with when the same individual did not, while adjusting for antiepileptic medications. Third, within-individual long-term analyses examined odds of seizure events in relation to the duration of months over the previous 2 years patients received medication. RESULTS: Patients with ADHD were at higher odds for any seizure compared with non-ADHD controls (odds ratio [OR] = 2.33, 95% confidence interval [CI] = 2.24-2.42 males; OR = 2.31, 95% CI = 2.22-2.42 females). In adjusted within-individual comparisons, ADHD medication was associated with lower odds of seizures among patients with (OR = 0.71, 95% CI = 0.60-0.85) and without (OR = 0.71, 95% CI = 0.62-0.82) prior seizures. Long-term within-individual comparisons suggested no evidence of an association between medication use and seizures among individuals with (OR = 0.87, 95% CI = 0.59-1.30) and without (OR = 1.01, 95% CI = 0.80-1.28) a seizure history. CONCLUSIONS: Results reaffirm that patients with ADHD are at higher risk of seizures. However, ADHD medication was associated with lower risk of seizures within individuals while they were dispensed medication, which is not consistent with the hypothesis that ADHD medication increases risk of seizures

Search for Eccentric Black Hole Coalescences during the Third Observing Run of LIGO and Virgo

Despite the growing number of confident binary black hole coalescences observed through gravitational waves so far, the astrophysical origin of these binaries remains uncertain. Orbital eccentricity is one of the clearest tracers of binary formation channels. Identifying binary eccentricity, however, remains challenging due to the limited availability of gravitational waveforms that include effects of eccentricity. Here, we present observational results for a waveform-independent search sensitive to eccentric black hole coalescences, covering the third observing run (O3) of the LIGO and Virgo detectors. We identified no new high-significance candidates beyond those that were already identified with searches focusing on quasi-circular binaries. We determine the sensitivity of our search to high-mass (total mass $M>70$ $M_\odot$) binaries covering eccentricities up to 0.3 at 15 Hz orbital frequency, and use this to compare model predictions to search results. Assuming all detections are indeed quasi-circular, for our fiducial population model, we place an upper limit for the merger rate density of high-mass binaries with eccentricities $0 < e \leq 0.3$ at $0.33$ Gpc$^{-3}$ yr$^{-1}$ at 90\% confidence level.Comment: 24 pages, 5 figure

Guidelines for the use and interpretation of assays for monitoring autophagy (3rd edition)

In 2008 we published the first set of guidelines for standardizing research in autophagy. Since then, research on this topic has continued to accelerate, and many new scientists have entered the field. Our knowledge base and relevant new technologies have also been expanding. Accordingly, it is important to update these guidelines for monitoring autophagy in different organisms. Various reviews have described the range of assays that have been used for this purpose. Nevertheless, there continues to be confusion regarding acceptable methods to measure autophagy, especially in multicellular eukaryotes. For example, a key point that needs to be emphasized is that there is a difference between measurements that monitor the numbers or volume of autophagic elements (e.g., autophagosomes or autolysosomes) at any stage of the autophagic process versus those that measure fl ux through the autophagy pathway (i.e., the complete process including the amount and rate of cargo sequestered and degraded). In particular, a block in macroautophagy that results in autophagosome accumulation must be differentiated from stimuli that increase autophagic activity, defi ned as increased autophagy induction coupled with increased delivery to, and degradation within, lysosomes (inmost higher eukaryotes and some protists such as Dictyostelium ) or the vacuole (in plants and fungi). In other words, it is especially important that investigators new to the fi eld understand that the appearance of more autophagosomes does not necessarily equate with more autophagy. In fact, in many cases, autophagosomes accumulate because of a block in trafficking to lysosomes without a concomitant change in autophagosome biogenesis, whereas an increase in autolysosomes may reflect a reduction in degradative activity. It is worth emphasizing here that lysosomal digestion is a stage of autophagy and evaluating its competence is a crucial part of the evaluation of autophagic flux, or complete autophagy. Here, we present a set of guidelines for the selection and interpretation of methods for use by investigators who aim to examine macroautophagy and related processes, as well as for reviewers who need to provide realistic and reasonable critiques of papers that are focused on these processes. These guidelines are not meant to be a formulaic set of rules, because the appropriate assays depend in part on the question being asked and the system being used. In addition, we emphasize that no individual assay is guaranteed to be the most appropriate one in every situation, and we strongly recommend the use of multiple assays to monitor autophagy. Along these lines, because of the potential for pleiotropic effects due to blocking autophagy through genetic manipulation it is imperative to delete or knock down more than one autophagy-related gene. In addition, some individual Atg proteins, or groups of proteins, are involved in other cellular pathways so not all Atg proteins can be used as a specific marker for an autophagic process. In these guidelines, we consider these various methods of assessing autophagy and what information can, or cannot, be obtained from them. Finally, by discussing the merits and limits of particular autophagy assays, we hope to encourage technical innovation in the field

Adolescent substance use in the multimodal treatment study of attention-deficit/hyperactivity disorder (ADHD) (MTA) as a function of childhood ADHD, random assignment to childhood treatments, and subsequent medication

Objective: To determine long-term effects on substance use and substance use disorder (SUD), up to 8 years after childhood enrollment, of the randomly assigned 14-month treatments in the multisite Multimodal Treatment Study of Children with Attention-Deficit/Hyperactivity Disorder (MTA; n = 436); to test whether medication at follow-up, cumulative psychostimulant treatment over time, or both relate to substance use/SUD; and to compare substance use/SUD in the ADHD sample to the non-ADHD childhood classmate comparison group (n = 261). Method: Mixed-effects regression models with planned contrasts were used for all tests except the important cumulative stimulant treatment question, for which propensity score matching analysis was used. Results: The originally randomized treatment groups did not differ significantly on substance use/SUD by the 8-year follow-up or earlier (mean age = 17 years). Neither medication at follow-up (mostly stimulants) nor cumulative stimulant treatment was associated with adolescent substance use/SUD. Substance use at all time points, including use of two or more substances and SUD, were each greater in the ADHD than in the non-ADHD samples, regardless of sex. Conclusions: Medication for ADHD did not protect from, or contribute to, visible risk of substance use or SUD by adolescence, whether analyzed as randomized treatment assignment in childhood, as medication at follow-up, or as cumulative stimulant treatment over an 8-year follow-up from childhood. These results suggest the need to identify alternative or adjunctive adolescent-focused approaches to substance abuse prevention and treatment for boys an