Add-On Cannabidiol Treatment for Drug-Resistant Seizures in Tuberous Sclerosis Complex A Placebo-Controlled Randomized Clinical Trial

IMPORTANCE Efficacy of cannabidiol has been demonstrated in seizures associated with Lennox-Gastaut and Dravet syndromes but appears not yet to have been established in conditions with primarily focal seizures, such as tuberous sclerosis complex (TSC). OBJECTIVE To evaluate efficacy and safety of 25-mg/kg/day and 50-mg/kg/day cannabidiol dosages vs placebo against seizures associated with TSC. DESIGN, SETTING, AND PARTICIPANTS This double-blind, placebo-controlled randomized clinical trial (GWPCARE6) enrolled patients between April 6, 2016, and October 4, 2018; follow-up was completed on February 15, 2019. The trial was conducted at 46 sites in Australia, Poland, Spain, the Netherlands, United Kingdom, and United States. Eligible patients (aged 1-65 years) were those with a clinical diagnosis of TSC and medicationresistant epilepsy who had had at least 8 TSC-associated seizures during the 4-week baseline period, with at least 1 seizure occurring in at least 3 of the 4 weeks, and were currently taking at least 1 antiepileptic medication. INTERVENTIONS Patients received oral cannabidiol at 25mg/kg/day (CBD25) or 50 mg/kg/day (CBD50) or a matched placebo for 16 weeks. MAIN OUTCOMES AND MEASURES The prespecified primary outcomewas the change from baseline in number of TSC-associated seizures for cannabidiol vs placebo during the treatment period. RESULTS Of 255 patients screened for eligibility, 31 were excluded and 224 were randomized. Of the 224 included patients (median [range] age, 11.4 [1.1-56.8] years; 93 female patients [41.5%]), 75 were randomized to CBD25, 73 to CBD50, and 76 to placebo, with 201 completing treatment. The percentage reduction from baseline in the type of seizures considered the primary end point was 48.6%(95%CI, 40.4%-55.8%) for the CBD25 group, 47.5%(95%CI, 39.0%-54.8%) for the CBD50 group, and 26.5%(95%CI, 14.9%-36.5%) for the placebo group; the percentage reduction from placebo was 30.1% (95%CI, 13.9%-43.3%; P < .001) for the CBD25 group and 28.5%(95%CI, 11.9%-42.0%; nominal P = .002) for the CBD50 group. The most common adverse events were diarrhea (placebo group, 19 [25%]; CBD25 group, 23 [31%]; CBD50 group, 41 [56%]) and somnolence (placebo group, 7 [9%]; CBD25 group, 10 [13%]; CBD50 group, 19 [26%]), which occurred more frequently with cannabidiol than placebo. Eight patients in CBD25 group, 10 in CBD50 group, and 2 in the placebo group discontinued treatment because of adverse events. Twenty-eight patients taking cannabidiol (18.9%) had elevated liver transaminase levels vs none taking placebo. CONCLUSIONS AND RELEVANCE Cannabidiol significantly reduced TSC-associated seizures compared with placebo. The 25-mg/kg/day dosage had a better safety profile than the 50-mg/kg/day dosage. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT0254476

Differential inflammasome activation predisposes to acute-on-chronic liver failure in human and experimental cirrhosis with and without previous decompensation

OBJECTIVE Systemic inflammation predisposes acutely decompensated (AD) cirrhosis to the development of acute-on-chronic liver failure (ACLF). Supportive treatment can improve AD patients, becoming recompensated. Little is known about the outcome of patients recompensated after AD. We hypothesise that different inflammasome activation is involved in ACL F development in compensated and recompensated patients. DESIGN 249 patients with cirrhosis, divided into compensated and recompensated (previous AD), were followed prospectively for fatal ACL F development. Two external cohorts (n=327) (recompensation, AD and ACL F) were included. Inflammasome-driving interleukins (ILs), IL-1α (caspase-4/11-dependent) and IL-1β (caspase-1- dependent), were measured. In rats, bile duct ligationinduced cirrhosis and lipopolysaccharide exposition were used to induce AD and subsequent recompensation. IL-1α and IL-1β levels and upstream/downstream gene expression were measured. RESULTS Patients developing ACL F showed higher baseline levels of ILs. Recompensated patients and patients with detectable ILs had higher rates of ACL F development than compensated patients. Baseline CLIF-­C (European Foundation for the study of chronic liver failure consortium) AD, albumin and IL-1α were independent predictors of ACL F development in compensated and CLIF-­C AD and IL-1β in recompensated patients. Compensated rats showed higher IL-1α gene expression and recompensated rats higher IL-1β levels with higher hepatic gene expression. Higher IL-1β detection rates in recompensated patients developing ACL F and higher IL-1α and IL-1β detection rates in patients with ACL F were confirmed in the two external cohorts. CONCLUSION Previous AD is an important risk factor for fatal ACL F development and possibly linked with inflammasome activation. Animal models confirmed the results showing a link between ACL F development and IL-1α in compensated cirrhosis and IL-1β in recompensated cirrhosi

The relation between cortisol and functional connectivity in people with and without stress-sensitive epilepsy

OBJECTIVE: The most common reported seizure-precipitant is stress. We recently showed a biologic basis for stress sensitivity of seizures: cortisol levels in people with stress-sensitive epilepsy correlated with focal interictal epileptiform discharges (IEDs) on electroencephalography (EEG). Here we aimed to determine whether the effect of cortisol on the epileptic brain is global or focal, and whether cortisol affects all brains or just those of stress-sensitive people. Because epilepsy is associated with changes in functional brain connectivity, we studied the relationship between cortisol and changes in global and focal (node-centered) functional connectivity measures for individuals with stress-sensitive and non-stress-sensitive epilepsy. METHODS: Seventeen people with epilepsy underwent long-term (>24 h) EEG recording. During the first 5 h after waking, saliva was collected every 15 min for cortisol measurements. Theta-band functional connectivity was assessed for every 15 min of the recording. We calculated the average phase-lag index (PLI) between all channels as a measure of global functional connectivity. We used network Strength, the averaged PLI per channel, as focal functional connectivity measure. We correlated cortisol, global, and focal functional connectivity (Strength) with IED frequency using linear mixed models. Analyses were split for people with and without stress-sensitivity of seizures. RESULTS: Cortisol was negatively correlated with global functional connectivity in people with stress-sensitive seizures (estimate -0.0020; P < .01), whereas not in those without stress-sensitivity (estimate -0.0003; P = .46). This relationship occurred irrespective of the presence of IEDs on a channel (channels without IEDs and stress-sensitivity: estimate -0.0019; P < .01, non-stress-sensitive -0.0003; P = .41). Global and focal functional connectivity were negatively correlated with IED frequency, irrespective of stress sensitivity of seizures or channel type. SIGNIFICANCE: People with stress-sensitive epilepsy have a whole-brain neuronal response to cortisol that is different from that of people with non-stress-sensitive epilepsy. This offers a basis for understanding seizure genesis in stress-sensitive epilepsy, which might require a different treatment approach

Towards the glueball spectrum from unquenched lattice QCD

We use a variational technique to study heavy glueballs on gauge configurations generated with 2+1 flavours of ASQTAD improved staggered fermions. The variational technique includes glueball scattering states. The measurements were made using 2150 configurations at 0.092 fm with a pion mass of 360 MeV. We report masses for 10 glueball states. We discuss the prospects for unquenched lattice QCD calculations of the oddballs.Comment: 19 pages, 4 tables and 8 figures. One figure added. Now matches the published versio

Gait disorders are associated with non-cardiovascular falls in elderly people: a preliminary study

BACKGROUND: The association between unexplained falls and cardiovascular causes is increasingly recognized. Neurally mediated cardiovascular disorders and hypotensive syndromes are found in almost 20 percent of the patients with unexplained falls. However, the approach to these patients remains unclear. Gait assessment might be an interesting approach to these patients as clinical observations suggests that those with cardiovascular or hypotensive causes may not manifest obvious gait alterations. Our primary objective is to analyze the association between gait disorders and a non-cardiovascular cause of falls in patients with unexplained falls. A second objective is to test the sensitivity and specificity of a gait assessment approach for detecting non-cardiovascular causes when compared with intrinsic-extrinsic classification. METHODS: Cross-sectional study performed in a falls clinic at a university hospital in 41 ambulatory elderly participants with unexplained falls. Neurally mediated cardiovascular conditions, neurological diseases, gait and balance problems were assessed. Gait disorder was defined as a gait velocity < 0.8 m/s or Tinetti Gait Score <9. An attributable etiology of the fall was determined in each participant. Comparisons between the gait assessment approach and the attributable etiology regarding a neurally mediated cardiovascular cause were performed. Fisher exact test was used to test the association hypothesis. Sensitivity and specificity of gait assessment approach and intrinsic-extrinsic classification to detect a non-cardiovascular mediated fall was calculated with 95% confidence intervals (CI95%). RESULTS: A cardiovascular etiology (orthostatic and postprandial hypotension, vasovagal syndrome and carotid sinus hypersensitivity) was identified in 14% of participants (6/41). Of 35 patients with a gait disorder, 34 had a non-cardiovascular etiology of fall; whereas in 5 out of 6 patients without a gait disorder, a cardiovascular diagnosis was identified (p < 0.001). Sensitivity and specificity of the presence of gait disorder for identifying a non-cardiovascular mediated cause was 97.1% (CI95% = 85–99) and 83% (CI95% = 36–99), respectively. CONCLUSION: In community dwelling older persons with unexplained falls, gait disorders were associated with non-cardiovascular diagnosis of falls. Gait assessment was a useful approach for the detection of a non-cardiovascular mediated cause of falls, providing additional value to this assessment

Method for evaluating prediction models that apply the results of randomized trials to individual patients

<p>Abstract</p> <p>Introduction</p> <p>The clinical significance of a treatment effect demonstrated in a randomized trial is typically assessed by reference to differences in event rates at the group level. An alternative is to make individualized predictions for each patient based on a prediction model. This approach is growing in popularity, particularly for cancer. Despite its intuitive advantages, it remains plausible that some prediction models may do more harm than good. Here we present a novel method for determining whether predictions from a model should be used to apply the results of a randomized trial to individual patients, as opposed to using group level results.</p> <p>Methods</p> <p>We propose applying the prediction model to a data set from a randomized trial and examining the results of patients for whom the treatment arm recommended by a prediction model is congruent with allocation. These results are compared with the strategy of treating all patients through use of a net benefit function that incorporates both the number of patients treated and the outcome. We examined models developed using data sets regarding adjuvant chemotherapy for colorectal cancer and Dutasteride for benign prostatic hypertrophy.</p> <p>Results</p> <p>For adjuvant chemotherapy, we found that patients who would opt for chemotherapy even for small risk reductions, and, conversely, those who would require a very large risk reduction, would on average be harmed by using a prediction model; those with intermediate preferences would on average benefit by allowing such information to help their decision making. Use of prediction could, at worst, lead to the equivalent of an additional death or recurrence per 143 patients; at best it could lead to the equivalent of a reduction in the number of treatments of 25% without an increase in event rates. In the Dutasteride case, where the average benefit of treatment is more modest, there is a small benefit of prediction modelling, equivalent to a reduction of one event for every 100 patients given an individualized prediction.</p> <p>Conclusion</p> <p>The size of the benefit associated with appropriate clinical implementation of a good prediction model is sufficient to warrant development of further models. However, care is advised in the implementation of prediction modelling, especially for patients who would opt for treatment even if it was of relatively little benefit.</p

The value of episodic, intensive blood glucose monitoring in non-insulin treated persons with type 2 diabetes: Design of the Structured Testing Program (STeP) Study, a cluster-randomised, clinical trial [NCT00674986]

<p>Abstract</p> <p>Background</p> <p>The value and utility of self-monitoring of blood glucose (SMBG) in non-insulin treated T2DM has yet to be clearly determined. Findings from studies in this population have been inconsistent, due mainly to design differences and limitations, including the prescribed frequency and timing of SMBG, role of the patient and physician in responding to SMBG results, inclusion criteria that may contribute to untoward floor effects, subject compliance, and cross-arm contamination. We have designed an SMBG intervention study that attempts to address these issues.</p> <p>Methods/design</p> <p>The Structured Testing Program (STeP) study is a 12-month, cluster-randomised, multi-centre clinical trial to evaluate whether poorly controlled (HbA1c ≥ 7.5%), non-insulin treated T2DM patients will benefit from a comprehensive, integrated physician/patient intervention using structured SMBG in US primary care practices. Thirty-four practices will be recruited and randomly assigned to an active control group (ACG) that receives enhanced usual care or to an enhanced usual care group plus structured SMBG (STG). A total of 504 patients will be enrolled; eligible patients at each site will be randomly selected using a defined protocol. Anticipated attrition of 20% will yield a sample size of at least 204 per arm, which will provide a 90% power to detect a difference of at least 0.5% in change from baseline in HbA1c values, assuming a common standard deviation of 1.5%. Differences in timing and degree of treatment intensification, cost effectiveness, and changes in patient self-management behaviours, mood, and quality of life (QOL) over time will also be assessed. Analysis of change in HbA1c and other dependent variables over time will be performed using both intent-to-treat and per protocol analyses. Trial results will be available in 2010.</p> <p>Discussion</p> <p>The intervention and trial design builds upon previous research by emphasizing appropriate and collaborative use of SMBG by both patients and physicians. Utilization of per protocol and intent-to-treat analyses facilitates a comprehensive assessment of the intervention. Use of practice site cluster-randomisation reduces the potential for intervention contamination, and inclusion criteria (HbA1c ≥ 7.5%) reduces the possibility of floor effects. Inclusion of multiple dependent variables allows us to assess the broader impact of the intervention, including changes in patient and physician attitudes and behaviours.</p> <p>Trial Registration</p> <p>Current Controlled Trials NCT00674986.</p