BackgroundThe lysosphingolipid sphingosine 1-phosphate (S1P) is carried in the blood in association with lipoproteins, predominantly high density lipoproteins (HDL). Emerging evidence suggests that many of the effects of HDL on cardiovascular function may be attributable to its S1P cargo.MethodsHere we have evaluated how levels of S1P and related sphingolipids in an HDL-containing fraction of human serum correlate with occurrence of ischemic heart disease (IHD). To accomplish this we used liquid chromatography-mass spectrometry to measure S1P levels in the HDL-containing fraction of serum (depleted of LDL and VLDL) from 204 subjects in the Copenhagen City Heart Study (CCHS). The study group consisted of individuals having high serum HDL cholesterol (HDL-C) (females:≥73.5 mg/dL; males:≥61.9 mg/dL) and verified IHD; subjects with high HDL-C and no IHD; individuals with low HDL-C (females:≤38.7 mg/dL; males:≤34.1 mg/dL) and IHD, and subjects with low HDL-C and no IHD.ResultsThe results show a highly significant inverse relationship between the level of S1P in the HDL-containing fraction of serum and the occurrence of IHD. Furthermore, an inverse relationship with IHD was also observed for two other sphingolipids, dihydro-S1P and C24:1-ceramide, in the HDL-containing fraction of serum. Additionally, we demonstrated that the amount of S1P on HDL correlates with the magnitude of HDL-induced endothelial cell barrier signaling.ConclusionsThese findings indicate that compositional differences of sphingolipids in the HDL-containing fraction of human serum are related to the occurrence of IHD, and may contribute to the putative protective role of HDL in IHD.

Rationale Cue-elicited craving and stress responses have been identified as predictors of relapse in drug dependence, but little research exists on the contribution of these factors to marijuana use specifically. Objectives The aims of the present study were to evaluate (1) responses to a psychological stressor, (2) responses to marijuana-related cues, and (3) if an exposure to a psychological stressor augmented craving subsequently elicited by marijuana-related cue exposure in marijuana-dependent individuals. Methods Subjective (craving, stress), neuroendocrine (ACTH, cortisol), and physiologic responses to the presentation of neutral and marijuana cues were assessed after randomization to a stress (Trier Social Stress Task; TSST) or no-stress control condition in marijuana-dependent individuals. Outcome measures were assessed at baseline, post-stressor/pre-neutral cue, post-neutral cue, and post marijuana cue. Results 87 participants completed procedures (stress group, n=45; non-stress group, n=42). The stress group had a significant increase over the non-stressed group in stress rating (p<0.001), craving (p=0.028), cortisol (p<0.001), and ACTH (p<0.001) after completion of the TSST. An increased craving response for all participants was seen following presentation of the marijuana cues (p=0.005). Following the TSST or no-stress condition, the non-stressed group had an increase in craving to marijuana cues as compared to neutral cues (p=0.002); an increase in craving was not observed in the stress group (p=0.404). Conclusions Marijuana cue exposure and a social stressor increased craving in marijuana-dependent individuals. Completion of the TSST did not increase craving response to subsequent marijuana-cue exposure.

Summary Objective To examine the effectiveness of intramuscular (IM) midazolam versus intravenous (IV) lorazepam for the treatment of pediatric patients with status epilepticus (SE) in the prehospital care setting. Methods This multicenter clinical trial randomized patients diagnosed with SE to receive either IM midazolam or IV lorazepam administered by paramedics in the prehospital care setting. Included in this secondary analysis were only patients younger than 18 years of age. Evaluated were the associations of the treatment group (IM vs. IV) with the primary outcome, defined as seizure cessation prior to emergency department (ED) arrival, and with patient characteristics, time to important events, and adverse events. Descriptive statistics and 99% confidence intervals (CIs) were used for the analysis. Results Of 893 primary study subjects, 120 met criteria for this study (60 in each treatment group). There were no differences in important baseline characteristics or seizure etiologies between groups. The primary outcome was met in 41 (68.3%) and 43 (71.7%) of subjects in the IM and IV groups, respectively (risk difference [RD] −3.3%, 99% CI −24.9% to 18.2%). Similar results were noted for those younger than 11 years (RD −1.3%, 99% CI −25.7% to 23.1%). Time from initiating the treatment protocol was shorter for children who received IM midazolam, mainly due to the shorter time to administer the active treatment. Safety profiles were similar. Significance IM midazolam can be rapidly administered and appears to be safe and effective for the management of children with SE treated in the prehospital setting. The results must be interpreted in the context of the secondary analysis design and sample size of the study.

Introduction Limited data describe the frequency, timing, or indications for endotracheal intubation (ETI) in patients with status epilepticus. A better understanding of the characteristics of patients with status epilepticus requiring airway interventions could inform clinical care. We sought to characterize ETI use in patients with prehospital status epilepticus. Methods This study was a secondary analysis of the Rapid Anticonvulsant Medication Prior to Arrival Trial, a multi-center, randomized trial comparing intravenous lorazepam to intramuscular midazolam for prehospital status epilepticus treatment. Subjects received ETI in the prehospital, Emergency Department (ED), or inpatient setting at the discretion of caregivers. Results Of 1023 enrollments, 218 (21 %) received ETI. 204 (93.6 %) of the ETIs were performed in the hospital and 14 (6.4 %) in the prehospital setting. Intubated patients were older (52 vs 41 years, p < 0.001), and men underwent ETI more than women (26 vs 21 %, p = 0.047). Patients with ongoing seizures on ED arrival had a higher rate of ETI (32 vs 16 %, p < 0.001), as did those who received rescue anti-seizure medication (29 vs 20 %, p = 0.004). Mortality was higher for intubated patients (7 vs 0.4 %, p < 0.001). Most ETI (n = 133, 62 %) occurred early (prior to or within 30 min after ED arrival), and late ETI was associated with higher mortality (14 vs 3 %, p = 0.002) than early ETI. Conclusions ETI is common in patients with status epilepticus, particularly among the elderly or those with refractory seizures. Any ETI and late ETI are both associated with higher mortality.

SUMMARY The question of when to adjust for important prognostic covariates often arises in the design of clinical trials, and there remain various opinions on whether to adjust during both randomization and analysis, at randomization alone, or at analysis alone. Furthermore, little is known about the impact of covariate adjustment in the context of non-inferiority (NI) designs. The current simulation-based research explores this issue in the NI setting, as compared to the typical superiority setting, by assessing the differential impact on power, type I error, and bias in the treatment estimate as well as its standard error, in the context of logistic regression under both simple and covariate adjusted permuted block randomization algorithms. In both the superiority and NI settings, failure to adjust for covariates that influence outcome in the analysis phase, regardless of prior adjustment at randomization, results in treatment estimates that are biased toward zero, with standard errors that are deflated. However, as no treatment difference is approached under the null hypothesis in superiority and under the alternative in NI, this results in decreased power and nominal or conservative (deflated) type I error in the context of superiority, but inflated power and type I error under NI. Results from the simulation study suggest that, regardless of the use of the covariate in randomization, it is appropriate to adjust for important prognostic covariates in analysis, as this yields nearly unbiased estimates of treatment as well as nominal type I error.