Spatial variation in automated burst suppression detection in pharmacologically induced coma

Burst suppression is actively studied as a control signal to guide anesthetic dosing in patients undergoing medically induced coma. The ability to automatically identify periods of EEG suppression and compactly summarize the depth of coma using the burst suppression probability (BSP) is crucial to effective and safe monitoring and control of medical coma. Current literature however does not explicitly account for the potential variation in burst suppression parameters across different scalp locations. In this study we analyzed standard 19-channel EEG recordings from 8 patients with refractory status epilepticus who underwent pharmacologically induced burst suppression as medical treatment for refractory seizures. We found that although burst suppression is generally considered a global phenomenon, BSP obtained using a previously validated algorithm varies systematically across different channels. A global representation of information from individual channels is proposed that takes into account the burst suppression characteristics recorded at multiple electrodes. BSP computed from this representative burst suppression pattern may be more resilient to noise and a better representation of the brain state of patients. Multichannel data integration may enhance the reliability of estimates of the depth of medical coma.National Institutes of Health (U.S.) (Grant K23 NS090900)National Institute of Neurological Diseases and Stroke (U.S.) (Grant K23 NS090900)National Institutes of Health (U.S.) (Grant DP2-OD006454)National Institutes of Health (U.S.) (Grant TROI-GMI04948

Variability in pharmacologically-induced coma for treatment of refractory status epilepticus

Objective To characterize the amount of EEG suppression achieved in refractory status epilepticus (RSE) patients treated with pharmacologically-induced coma (PIC). Methods We analyzed EEG recordings from 35 RSE patients between 21–84 years-old who received PIC that target burst suppression and quantified the amount of EEG suppression using the burst suppression probability (BSP). Then we measured the variability of BSPs with respect to a reference level of BSP 0.8 ± 0.15. Finally, we also measured the variability of BSPs with respect to the amount of intravenous anesthetic drugs (IVADs) received by the patients. Results Patients remained in the reference BSP range for only 8% (median, interquartile range IQR [0, 29] %) of the total time under treatment. The median time with BSP below the reference range was 84% (IQR [37, 100] %). BSPs in some patients drifted significantly over time despite constant infusion rates of IVADs. Similar weight-normalized infusion rates of IVADs in different patients nearly always resulted in distinct BSPs (probability 0.93 (IQR [0.82, 1.0]). Conclusion This study quantitatively identified high variability in the amount of EEG suppression achieved in clinical practice when treating RSE patients. While some of this variability may arise from clinicians purposefully deviating from clinical practice guidelines, our results show that the high variability also arises in part from significant inter- and intra- individual pharmacokinetic/pharmacodynamic variation. Our results indicate that the delicate balance between maintaining sufficient EEG suppression in RSE patients and minimizing IVAD exposure in clinical practice is challenging to achieve. This may affect patient outcomes and confound studies seeking to determine an optimal amount of EEG suppression for treatment of RSE. Therefore, our analysis points to the need for developing an alternative paradigm, such as vigilant anesthetic management as happens in operating rooms, or closed-loop anesthesia delivery, for investigating and providing induced-coma therapy to RSE patients

A systematic review of the safety of lisdexamfetamine dimesylate

BACKGROUND: Here we review the safety and tolerability profile of lisdexamfetamine dimesylate (LDX), the first long-acting prodrug stimulant for the treatment of attention-deficit/hyperactivity disorder (ADHD). METHODS: A PubMed search was conducted for English-language articles published up to 16 September 2013 using the following search terms: (lisdexamfetamine OR lisdexamphetamine OR SPD489 OR Vyvanse OR Venvanse OR NRP104 NOT review [publication type]). RESULTS: In short-term, parallel-group, placebo-controlled, phase III trials, treatment-emergent adverse events (TEAEs) in children, adolescents, and adults receiving LDX were typical for those reported for stimulants in general. Decreased appetite was reported by 25-39 % of patients and insomnia by 11-19 %. The most frequently reported TEAEs in long-term studies were similar to those reported in the short-term trials. Most TEAEs were mild or moderate in severity. Literature relating to four specific safety concerns associated with stimulant medications was evaluated in detail in patients receiving LDX. Gains in weight, height, and body mass index were smaller in children and adolescents receiving LDX than in placebo controls or untreated norms. Insomnia was a frequently reported TEAE in patients with ADHD of all ages receiving LDX, although the available data indicated no overall worsening of sleep quality in adults. Post-marketing survey data suggest that the rate of non-medical use of LDX was lower than that for short-acting stimulants and lower than or equivalent to long-acting stimulant formulations. Small mean increases were seen in blood pressure and pulse rate in patients receiving LDX. CONCLUSIONS: The safety and tolerability profile of LDX in individuals with ADHD is similar to that of other stimulants

Plasma Proteomic Profiling in HIV-1 Infected Methamphetamine Abusers

We wanted to determine whether methamphetamine use affects a subset of plasma proteins in HIV-infected persons. Plasma samples from two visits were identified for subjects from four groups: HIV+, ongoing, persistent METH use; HIV+, short-term METH abstinent; HIV+, long term METH abstinence; HIV negative, no history of METH use. Among 390 proteins identified, 28 showed significant changes in expression in the HIV+/persistent METH+ group over the two visits, which were not attributable to HIV itself. These proteins were involved in complement, coagulation pathways and oxidative stress. Continuous METH use is an unstable condition, altering levels of a number of plasma proteins

The positions of TFIIF and TFIIE in the RNA polymerase II transcription preinitiation complex.

We incorporated the non-natural photoreactive amino acid p-benzoyl-L-phenylalanine (Bpa) into the RNA polymerase II (Pol II) surface surrounding the central cleft formed by the Rpb1 and Rpb2 subunits. Photo-cross-linking of preinitiation complexes (PICs) with these Pol II derivatives and hydroxyl-radical cleavage assays revealed that the TFIIF dimerization domain interacts with the Rpb2 lobe and protrusion domains adjacent to Rpb9, while TFIIE cross-links to the Rpb1 clamp domain on the opposite side of the Pol II central cleft. Mutations in the Rpb2 lobe and protrusion domains alter both Pol II-TFIIF binding and the transcription start site, a phenotype associated with mutations in TFIIF, Rpb9 and TFIIB. Together with previous biochemical and structural studies, these findings illuminate the structural organization of the PIC and the network of protein-protein interactions involved in transcription start site selection

Enantioselective Protein-Sterol Interactions Mediate Regulation of Both Prokaryotic and Eukaryotic Inward Rectifier K+ Channels by Cholesterol

Cholesterol is the major sterol component of all mammalian cell plasma membranes and plays a critical role in cell function and growth. Previous studies have shown that cholesterol inhibits inward rectifier K+ (Kir) channels, but have not distinguished whether this is due directly to protein-sterol interactions or indirectly to changes in the physical properties of the lipid bilayer. Using purified bacterial and eukaryotic Kir channels reconstituted into liposomes of controlled lipid composition, we demonstrate by 86Rb+ influx assays that bacterial Kir channels (KirBac1.1 and KirBac3.1) and human Kir2.1 are all inhibited by cholesterol, most likely by locking the channels into prolonged closed states, whereas the enantiomer, ent-cholesterol, does not inhibit these channels. These data indicate that cholesterol regulates Kir channels through direct protein-sterol interactions likely taking advantage of an evolutionarily conserved binding pocket

Significance testing as perverse probabilistic reasoning

Truth claims in the medical literature rely heavily on statistical significance testing. Unfortunately, most physicians misunderstand the underlying probabilistic logic of significance tests and consequently often misinterpret their results. This near-universal misunderstanding is highlighted by means of a simple quiz which we administered to 246 physicians at two major academic hospitals, on which the proportion of incorrect responses exceeded 90%. A solid understanding of the fundamental concepts of probability theory is becoming essential to the rational interpretation of medical information. This essay provides a technically sound review of these concepts that is accessible to a medical audience. We also briefly review the debate in the cognitive sciences regarding physicians' aptitude for probabilistic inference

The predictive validity of a Brain Care Score for dementia and stroke: data from the UK Biobank cohort

IntroductionThe 21-point Brain Care Score (BCS) was developed through a modified Delphi process in partnership with practitioners and patients to promote behavior changes and lifestyle choices in order to sustainably reduce the risk of dementia and stroke. We aimed to assess the associations of the BCS with risk of incident dementia and stroke.MethodsThe BCS was derived from the United Kingdom Biobank (UKB) baseline evaluation for participants aged 40–69 years, recruited between 2006–2010. Associations of BCS and risk of subsequent incident dementia and stroke were estimated using Cox proportional hazard regressions, adjusted for sex assigned at birth and stratified by age groups at baseline.ResultsThe BCS (median: 12; IQR:11–14) was derived for 398,990 UKB participants (mean age: 57; females: 54%). There were 5,354 incident cases of dementia and 7,259 incident cases of stroke recorded during a median follow-up of 12.5 years. A five-point higher BCS at baseline was associated with a 59% (95%CI: 40-72%) lower risk of dementia among participants aged <50. Among those aged 50–59, the figure was 32% (95%CI: 20-42%) and 8% (95%CI: 2-14%) for those aged >59 years. A five-point higher BCS was associated with a 48% (95%CI: 39-56%) lower risk of stroke among participants aged <50, 52% (95%CI, 47-56%) among those aged 50–59, and 33% (95%CI, 29-37%) among those aged >59.DiscussionThe BCS has clinically relevant and statistically significant associations with risk of dementia and stroke in approximately 0.4 million UK people. Future research includes investigating the feasibility, adaptability and implementation of the BCS for patients and providers worldwide

Ultraviolet photoconductive devices with an n-GaN nanorodgraphene hybrid structure synthesized by metal-organic chemical vapor deposition

The superior photoconductive behavior of a simple, cost-effective n-GaN nanorod (NR)-graphene hybrid device structure is demonstrated for the first time. The proposed hybrid structure was synthesized on a Si (111) substrate using the high-quality graphene transfer method and the relatively low-temperature metal-organic chemical vapor deposition (MOCVD) process with a high V/III ratio to protect the graphene layer from thermal damage during the growth of n-GaN nanorods. Defect-free n-GaN NRs were grown on a highly ordered graphene monolayer on Si without forming any metal-catalyst or droplet seeds. The prominent existence of the undamaged monolayer graphene even after the growth of highly dense n-GaN NRs, as determined using Raman spectroscopy and high-resolution transmission electron microscopy (HR-TEM), facilitated the excellent transport of the generated charge carriers through the photoconductive channel. The highly matched n-GaN NR-graphene hybrid structure exhibited enhancement in the photocurrent along with increased sensitivity and photoresponsivity, which were attributed to the extremely low carrier trap density in the photoconductive channelclose00