Structural imaging biomarkers of sudden unexpected death in epilepsy.

Sudden unexpected death in epilepsy is a major cause of premature death in people with epilepsy. We aimed to assess whether structural changes potentially attributable to sudden death pathogenesis were present on magnetic resonance imaging in people who subsequently died of sudden unexpected death in epilepsy. In a retrospective, voxel-based analysis of T1 volume scans, we compared grey matter volumes in 12 cases of sudden unexpected death in epilepsy (two definite, 10 probable; eight males), acquired 2 years [median, interquartile range (IQR) 2.8] before death [median (IQR) age at scanning 33.5 (22) years], with 34 people at high risk [age 30.5 (12); 19 males], 19 at low risk [age 30 (7.5); 12 males] of sudden death, and 15 healthy controls [age 37 (16); seven males]. At-risk subjects were defined based on risk factors of sudden unexpected death in epilepsy identified in a recent combined risk factor analysis. We identified increased grey matter volume in the right anterior hippocampus/amygdala and parahippocampus in sudden death cases and people at high risk, when compared to those at low risk and controls. Compared to controls, posterior thalamic grey matter volume, an area mediating oxygen regulation, was reduced in cases of sudden unexpected death in epilepsy and subjects at high risk. The extent of reduction correlated with disease duration in all subjects with epilepsy. Increased amygdalo-hippocampal grey matter volume with right-sided changes is consistent with histo-pathological findings reported in sudden infant death syndrome. We speculate that the right-sided predominance reflects asymmetric central influences on autonomic outflow, contributing to cardiac arrhythmia. Pulvinar damage may impair hypoxia regulation. The imaging findings in sudden unexpected death in epilepsy and people at high risk may be useful as a biomarker for risk-stratification in future studies

Novel polymorphisms influencing transcription of the human CHRM2 gene in airway smooth muscle

Muscarinic receptors are a functionally important family of G-protein-coupled receptors. Using a combination of rapid amplification of 5′ cDNA ends and reporter gene assays, we characterized the 5′ untranslated region of the CHRM2 gene as expressed in human airway smooth muscle (HASM) cells. A splice site is present 46 bp upstream from the ATG start codon. Five exons with alternative splicing patterns are present upstream of this splice site, separated by introns ranging from 87 bp to > 145 kb. There is evidence for the gene being under the control of a TATA-less promoter with Sp1, GATA, and activator protein-2 binding sites. Multiple transcription start sites (TSSs) were identified. We identified a novel 0.5-kb hypervariable region located 648 bp upstream of the most 5′ TSS, a multiallelic (CA) tandem repeat 96 bp downstream of the most 5′ TSS, and a common C→A SNP located 136 bp upstream of the most 5′ TSS. Functional studies in primary HASM cells and the BEAS-2B cell line demonstrated highest promoter activity to be upstream of the most 3′ TSS, with potential repressor elements operating in a cell type-dependent manner, located upstream of the most 5′ TSS. We present functional data to show that the CA repeat may influence the transcription of the gene in HASM and BEAS-2B cells.peer-reviewe

Mapping preictal and ictal haemodynamic networks using video-electroencephalography and functional imaging

Ictal patterns on scalp-electroencephalography are often visible only after propagation, therefore rendering localization of the seizure onset zone challenging. We hypothesized that mapping haemodynamic changes before and during seizures using simultaneous video-electroencephalography and functional imaging will improve the localization of the seizure onset zone. Fifty-five patients with ≥2 refractory focal seizures/day, and who had undergone long-term video-electroencephalography monitoring were included in the study. ‘Preictal' (30 s immediately preceding the electrographic seizure onset) and ictal phases, ‘ictal-onset'; ‘ictalestablished' and ‘late ictal', were defined based on the evolution of the electrographic pattern and clinical semiology. The functional imaging data were analysed using statistical parametric mapping to map ictal phase-related haemodynamic changes consistent across seizures. The resulting haemodynamic maps were overlaid on co-registered anatomical scans, and the spatial concordance with the presumed and invasively defined seizure onset zone was determined. Twenty patients had typical seizures during functional imaging. Seizures were identified on video-electroencephalography in 15 of 20, on electroencephalography alone in two and on video alone in three patients. All patients showed significant ictal-related haemodynamic changes. In the six cases that underwent invasive evaluation, the ictal-onset phase-related maps had a degree of concordance with the presumed seizure onset zone for all patients. The most statistically significant haemodynamic cluster within the presumed seizure onset zone was between 1.1 and 3.5 cm from the invasively defined seizure onset zone, which was resected in two of three patients undergoing surgery (Class I post-surgical outcome) and was not resected in one patient (Class III post-surgical outcome). In the remaining 14 cases, the ictal-onset phase-related maps had a degree of concordance with the presumed seizure onset zone in six of eight patients with structural-lesions and five of six non-lesional patients. The most statistically significant haemodynamic cluster was localizable at sub-lobar level within the presumed seizure onset zone in six patients. The degree of concordance of haemodynamic maps was significantly better (P < 0.05) for the ictal-onset phase [entirely concordant/concordant plus (13/20; 65%) + some concordance (4/20; 20%) = 17/20; 85%] than ictal-established [entirely concordant/concordant plus (5/13; 38%) + some concordance (4/13; 31%) = 9/13; 69%] and late ictal [concordant plus (1/9; 11%) + some concordance (4/9; 44%) = 5/9; 55%] phases. Ictal propagation-related haemodynamic changes were also seen in symptomatogenic areas (9/20; 45%) and the default mode network (13/20; 65%). A common pattern of preictal changes was seen in 15 patients, starting between 98 and 14 s before electrographic seizure onset, and the maps had a degree of concordance with the presumed seizure onset zone in 10 patients. In conclusion, preictal and ictal haemodynamic changes in refractory focal seizures can non-invasively localize seizure onset at sub-lobar/gyral level when ictal scalp-electroencephalography is not helpfu

Improving genomics-based predictions for precision medicine through active elicitation of expert knowledge

Motivation: Precision medicine requires the ability to predict the efficacies of different treatments for a given individual using high-dimensional genomic measurements. However, identifying predictive features remains a challenge when the sample size is small. Incorporating expert knowledge offers a promising approach to improve predictions, but collecting such knowledge is laborious if the number of candidate features is very large. Results: We introduce a probabilistic framework to incorporate expert feedback about the impact of genomic measurements on the outcome of interest and present a novel approach to collect the feedback efficiently, based on Bayesian experimental design. The new approach outperformed other recent alternatives in two medical applications: prediction of metabolic traits and prediction of sensitivity of cancer cells to different drugs, both using genomic features as predictors. Furthermore, the intelligent approach to collect feedback reduced the workload of the expert to approximately 11%, compared to a baseline approach.Peer reviewe

Earthquakes drive large-scale submarine canyondevelopment and sediment supply to deep-ocean basins

Although the global flux of sediment and carbon from land to the coastal ocean is well known, the volume of material that reaches the deep ocean—the ultimate sink—and the mechanisms by which it is transferred are poorly documented. Using a globally unique data set of repeat seafloor measurements and samples, we show that the moment magnitude (Mw) 7.8 November 2016 Kaikōura earthquake (New Zealand) triggered widespread landslides in a submarine canyon, causing a powerful “canyon flushing” event and turbidity current that traveled >680 km along one of the world’s longest deep-sea channels. These observations provide the first quantification of seafloor landscape change and large-scale sediment transport associated with an earthquake-triggered full canyon flushing event. The calculated interevent time of ~140 years indicates a canyon incision rate of 40 mm year−1, substantially higher than that of most terrestrial rivers, while synchronously transferring large volumes of sediment [850 metric megatons (Mt)] and organic carbon (7 Mt) to the deep ocean. These observations demonstrate that earthquake-triggered canyon flushing is a primary driver of submarine canyon development and material transfer from active continental margins to the deep ocean.peer-reviewe

Neurologic phenotypes associated with COL4A1/2 mutations

Objective: To characterize the neurologic phenotypes associated with COL4A1/2 mutations and to seek genotype–phenotype correlation. Methods: We analyzed clinical, EEG, and neuroimaging data of 44 new and 55 previously reported patients with COL4A1/COL4A2 mutations. Results: Childhood-onset focal seizures, frequently complicated by status epilepticus and resistance to antiepileptic drugs, was the most common phenotype. EEG typically showed focal epileptiform discharges in the context of other abnormalities, including generalized sharp waves or slowing. In 46.4% of new patients with focal seizures, porencephalic cysts on brain MRI colocalized with the area of the focal epileptiform discharges. In patients with porencephalic cysts, brain MRI frequently also showed extensive white matter abnormalities, consistent with the finding of diffuse cerebral disturbance on EEG. Notably, we also identified a subgroup of patients with epilepsy as their main clinical feature, in which brain MRI showed nonspecific findings, in particular periventricular leukoencephalopathy and ventricular asymmetry. Analysis of 15 pedigrees suggested a worsening of the severity of clinical phenotype in succeeding generations, particularly when maternally inherited. Mutations associated with epilepsy were spread across COL4A1 and a clear genotype–phenotype correlation did not emerge. Conclusion: COL4A1/COL4A2 mutations typically cause a severe neurologic condition and a broader spectrum of milder phenotypes, in which epilepsy is the predominant feature. Early identification of patients carrying COL4A1/COL4A2 mutations may have important clinical consequences, while for research efforts, omission from large-scale epilepsy sequencing studies of individuals with abnormalities on brain MRI may generate misleading estimates of the genetic contribution to the epilepsies overall

Fludarabine, cytarabine, granulocyte colony-stimulating factor, and idarubicin with gemtuzumab ozogamicin improves event-free survival in younger patients with newly diagnosed aml and overall survival in patients with npm1 and flt3 mutations

Purpose To determine the optimal induction chemotherapy regimen for younger adults with newly diagnosed AML without known adverse risk cytogenetics. Patients and Methods One thousand thirty-three patients were randomly assigned to intensified (fludarabine, cytarabine, granulocyte colony-stimulating factor, and idarubicin [FLAG-Ida]) or standard (daunorubicin and Ara-C [DA]) induction chemotherapy, with one or two doses of gemtuzumab ozogamicin (GO). The primary end point was overall survival (OS). Results There was no difference in remission rate after two courses between FLAG-Ida + GO and DA + GO (complete remission [CR] + CR with incomplete hematologic recovery 93% v 91%) or in day 60 mortality (4.3% v 4.6%). There was no difference in OS (66% v 63%; P = .41); however, the risk of relapse was lower with FLAG-Ida + GO (24% v 41%; P < .001) and 3-year event-free survival was higher (57% v 45%; P < .001). In patients with an NPM1 mutation (30%), 3-year OS was significantly higher with FLAG-Ida + GO (82% v 64%; P = .005). NPM1 measurable residual disease (MRD) clearance was also greater, with 88% versus 77% becoming MRD-negative in peripheral blood after cycle 2 (P = .02). Three-year OS was also higher in patients with a FLT3 mutation (64% v 54%; P = .047). Fewer transplants were performed in patients receiving FLAG-Ida + GO (238 v 278; P = .02). There was no difference in outcome according to the number of GO doses, although NPM1 MRD clearance was higher with two doses in the DA arm. Patients with core binding factor AML treated with DA and one dose of GO had a 3-year OS of 96% with no survival benefit from FLAG-Ida + GO. Conclusion Overall, FLAG-Ida + GO significantly reduced relapse without improving OS. However, exploratory analyses show that patients with NPM1 and FLT3 mutations had substantial improvements in OS. By contrast, in patients with core binding factor AML, outcomes were excellent with DA + GO with no FLAG-Ida benefit

La consommation de cannabis chez les sujets présentant un abus, une pharmacodépendance ou sous traitement de substitution de la dépendance aux opiacés : données OPPIDUM 2006 et principales tendances depuis 2004 du réseau des Centres d'Évaluation et d'Information sur la Pharmacodépendance (CEIP)

Les données sur la consommation de cannabis chez les jeunes sont bien documentées en revanche elles sont moins décrites chez des sujets pharmacodépendants. Les modalités de consommation de cannabis en 2006 et les principales tendances depuis 2004 ont été étudiées à partir de l'enquête OPPIDUM (Observation des Produits Psychotropes Illicites ou Détournés de leur Usage Médicamenteux). OPPIDUM est une étude pharmaco-épidémiologique nationale transversale annuelle menée chez des patients sous traitement de substitution de la dépendance aux opiacés ou présentant une pharmacodépendance ou un abus. En octobre 2006, 3743 sujets ont été inclus. Trente huit pour cent (n = 1437) d'entre eux sont consommateurs de cannabis, parmi eux 27 % ont signalé consommer uniquement du cannabis et 73 % le consomment avec d'autres substances psychoactives. Les consommateurs de cannabis seul sont plus jeunes, mieux insérés socialement et présentent des modalités de consommation de cannabis en terme d'abus et de dépendance plus importantes. Cette étude souligne la problématique de la polyconsommation. Les caractéristiques ont peu évolué entre 2004 et 2006. Cette étude met en évidence, parmi les consommateurs de cannabis fréquentant une structure sanitaire, la présence de deux sous populations distinctes au niveau des caractéristiques socio-économiques et des modalités de consommation

A local perspective to asthma management in the accident and emergency department in Malta

This study was performed to assess the management of adult patients presenting to the Mater Dei Hospital Accident and Emergency (A&E) department with acute asthma. Subjects and Methods: Asthmatic patients age 14 or older who presented to A&E department between January and October 2010 with asthma exacerbations were included. Data were collected from the clinical notes and analyzed. Results: A total of 244 patients (67.2% females) were included, 126 (51.6%) were admitted, 97 (39.8%) discharged and 21 (8.6%) discharged themselves against medical advice. There was a decline in the presentations between January and July, followed by an upward trend until October (P = 0.42). Pulse oximetry was performed in 207 patients (84.8%), arterial blood gases in 133 (54.5%), peak expiratory flow rate in 106 (43.4%) and chest radiography in 206 (84.4%) patients. The respiratory rate was documented in 151 (61.8%), heart rate in 204 (83.6%) and ability to complete sentences in 123 (50.4%) patients. One hundred and ninety six patients (80.3%) were given nebulized bronchodilators, 103 (42.2%) intravenous corticosteroids, 7 (2.87%) oral corticosteroids, 109 (44.7%) oxygen, 28 (11.5%) antibiotics and 9 (3.69%) magnesium. Systemic corticosteroids and antibiotics were more commonly prescribed to patients admitted (P < 0.001). Conclusion: Management of acute asthma in Malta requires optimization in order to compare with international guidelines.peer-reviewe