Premetastatic shifts of endogenous and exogenous mutational processes support consolidative therapy in EGFR-driven lung adenocarcinoma.

The progression of cancer is an evolutionary process that is challenging to assess between sampling timepoints. However, investigation of cancer evolution over specific time periods is crucial to the elucidation of key events such as the acquisition of therapeutic resistance and subsequent fatal metastatic spread of therapy-resistant cell populations. Here we apply mutational signature analyses within clinically annotated cancer chronograms to detect and describe the shifting mutational processes caused by both endogenous (e.g. mutator gene mutation) and exogenous (e.g. mutagenic therapeutics) factors between tumor sampling timepoints. In one patient, we find that cisplatin therapy can introduce mutations that confer genetic resistance to subsequent targeted therapy with Erlotinib. In another patient, we trace detection of defective mismatch-repair associated mutational signature SBS3 to the emergence of known driver mutation CTNNB1 S37C. In both of these patients, metastatic lineages emerged from a single ancestral lineage that arose during therapy-a finding that argues for the consideration of local consolidative therapy over other therapeutic approaches in EGFR-positive non-small cell lung cancer. Broadly, these results demonstrate the utility of phylogenetic analysis that incorporates clinical time course and mutational signature deconvolution to inform therapeutic decision making and retrospective assessment of disease etiology.

Incidence and temporal trends of co-occurring personality disorder diagnoses in immune-mediated inflammatory diseases.

AIMS: Although immune-mediated inflammatory diseases (IMID) are associated with multiple mental health conditions, there is a paucity of literature assessing personality disorders (PDs) in these populations. We aimed to estimate and compare the incidence of any PD in IMID and matched cohorts over time, and identify sociodemographic characteristics associated with the incidence of PD. METHODS: We used population-based administrative data from Manitoba, Canada to identify persons with incident inflammatory bowel disease (IBD), multiple sclerosis (MS) and rheumatoid arthritis (RA) using validated case definitions. Unaffected controls were matched 5:1 on sex, age and region of residence. PDs were identified using hospitalisation or physician claims. We used unadjusted and covariate-adjusted negative binomial regression to compare the incidence of PDs between the IMID and matched cohorts. RESULTS: We identified 19 572 incident cases of IMID (IBD n = 6,119, MS n = 3,514, RA n = 10 206) and 97 727 matches overall. After covariate adjustment, the IMID cohort had an increased incidence of PDs (incidence rate ratio [IRR] 1.72; 95%CI: 1.47-2.01) as compared to the matched cohort, which remained consistent over time. The incidence of PDs was similarly elevated in IBD (IRR 2.19; 95%CI: 1.69-2.84), MS (IRR 1.79; 95%CI: 1.29-2.50) and RA (IRR 1.61; 95%CI: 1.29-1.99). Lower socioeconomic status and urban residence were associated with an increased incidence of PDs, whereas mid to older adulthood (age 45-64) was associated with overall decreased incidence. In a restricted sample with 5 years of data before and after IMID diagnosis, the incidence of PDs was also elevated before IMID diagnosis among all IMID groups relative to matched controls. CONCLUSIONS: IMID are associated with an increased incidence of PDs both before and after an IMID diagnosis. These results support the relevance of shared risk factors in the co-occurrence of PDs and IMID conditions.

Overexpression of T-bet in HIV infection is associated with accumulation of B cells outside germinal centers and poor affinity maturation.

Nearly all chronic human infections are associated with alterations in the memory B cell (MBC) compartment, including a large expansion of CD19hiT-bethi MBC in the peripheral blood of HIV-infected individuals with chronic viremia. Despite their prevalence, it is unclear how these B cells arise and whether they contribute to the inefficiency of antibody-mediated immunity in chronic infectious diseases. We addressed these questions by characterizing T-bet-expressing B cells in lymph nodes (LN) and identifying a strong T-bet signature among HIV-specific MBC associated with poor immunologic outcome. Confocal microscopy and quantitative imaging revealed that T-bethi B cells in LN of HIV-infected chronically viremic individuals distinctly accumulated outside germinal centers (GC), which are critical for optimal antibody responses. In single-cell analyses, LN T-bethi B cells of HIV-infected individuals were almost exclusively found among CD19hi MBC and expressed reduced GC-homing receptors. Furthermore, HIV-specific B cells of infected individuals were enriched among LN CD19hiT-bethi MBC and displayed a distinct transcriptome, with features similar to CD19hiT-bethi MBC in blood and LN GC B cells (GCBC). LN CD19hiT-bethi MBC were also related to GCBC by B cell receptor (BCR)-based phylogenetic linkage but had lower BCR mutation frequencies and reduced HIV-neutralizing capacity, consistent with diminished participation in GC-mediated affinity selection. Thus, in the setting of chronic immune activation associated with HIV viremia, failure of HIV-specific B cells to enter or remain in GC may help explain the rarity of high-affinity protective antibodies.

Prodrome in relapsing-remitting and primary progressive multiple sclerosis.

BACKGROUND AND PURPOSE: The multiple sclerosis prodrome remains poorly understood. We aimed to examine the prodrome in people with relapsing remitting multiple sclerosis at onset (RMS) and primary progressive multiple sclerosis (PPMS). METHODS: We conducted a matched cohort study using clinical and linked health administrative data in two Canadian provinces. We identified people with RMS, PPMS and age- sex- and geographically-matched population controls, and compared the number of physician encounters (total number, per International Classification of Diseases chapter, and per physician speciality) in the five years before symptom onset. Negative binomial regression models were sex, age, socioeconomic status and calendar year adjusted. RESULTS: We identified 1887 RMS, 171 PPMS cases, and 9837 matched population controls. No difference existed in the total number of encounters in the five years before index between RMS and PPMS, or between the phenotypes and their respective controls. Compared to RMS cases, PPMS cases had more nervous system-related encounters (adjusted rate ratio, 3.00; 95% confidence interval, 1.06-8.49) and fewer encounters with dermatologists (adjusted rate ratio 0.53; 95% confidence interval, 0.30-0.96). CONCLUSION: Findings suggest that people with RMS and PPMS may both experience a prodrome, although aspects may differ.

Rising incidence of psychiatric disorders before diagnosis of immune-mediated inflammatory disease.

AIMS: After the diagnosis of immune-mediated inflammatory diseases (IMID) such as inflammatory bowel disease (IBD), multiple sclerosis (MS) and rheumatoid arthritis (RA), the incidence of psychiatric comorbidity is increased relative to the general population. We aimed to determine whether the incidence of psychiatric disorders is increased in the 5 years before the diagnosis of IMID as compared with the general population. METHODS: Using population-based administrative health data from the Canadian province of Manitoba, we identified all persons with incident IBD, MS and RA between 1989 and 2012, and cohorts from the general population matched 5 : 1 on year of birth, sex and region to each disease cohort. We identified members of these groups with at least 5 years of residency before and after the IMID diagnosis date. We applied validated algorithms for depression, anxiety disorders, bipolar disorder, schizophrenia, and any psychiatric disorder to determine the annual incidence of these conditions in the 5-year periods before and after the diagnosis year. RESULTS: We identified 12 141 incident cases of IMID (3766 IBD, 2190 MS, 6350 RA) and 65 424 matched individuals. As early as 5 years before diagnosis, the incidence of depression [incidence rate ratio (IRR) 1.54; 95% CI 1.30-1.84) and anxiety disorders (IRR 1.30; 95% CI 1.12-1.51) were elevated in the IMID cohort as compared with the matched cohort. Similar results were obtained for each of the IBD, MS and RA cohorts. The incidence of bipolar disorder was elevated beginning 3 years before IMID diagnosis (IRR 1.63; 95% CI 1.10-2.40). CONCLUSION: The incidence of psychiatric comorbidity is elevated in the IMID population as compared with a matched population as early as 5 years before diagnosis. Future studies should elucidate whether this reflects shared risk factors for psychiatric disorders and IMID, a shared final common inflammatory pathway or other aetiology.

Lateralized microstructural changes in early-stage Parkinson's disease in anterior olfactory structures, but not in substantia nigra.

Parkinson's disease (PD) is a progressive neurological disorder characterized by motor symptoms as well as severe deficits in olfactory function and microstructural changes in olfactory brain regions. Because of the evidence of asymmetric neuropathological features in early-stage PD, we examined whether lateralized microstructural changes occur in olfactory brain regions and the substantia nigra in a group of early-stage PD patients. Using diffusion tensor imaging (DTI) and the University of Pennsylvania Smell Identification Test (UPSIT), we assessed 24 early-stage PD patients (Hoehn and Yahr stage 1 or 2) and 26 healthy controls (HC). We used DTI and a region of interest (ROI) approach to study the microstructure of the left and right anterior olfactory structures (AOS; comprising the olfactory bulbs and anterior end of the olfactory tracts) and the substantia nigra (SN). PD patients had reduced UPSIT scores relative to HC and showed increased mean diffusivity (MD) in the SN, with no lateralized differences. Significant group differences in fractional anisotropy (FA) and MD were seen in the AOS, but these differences were restricted to the right side and were not associated with the primary side of motor symptoms amongst PD patients. No associations were observed between lateralized motor impairment and lateralized microstructural changes in AOS. Impaired olfaction and microstructural changes in AOS are useful for early identification of PD but asymmetries in AOS microstructure seem unrelated to the laterality of PD motor symptoms.

Cholinesterases in normal and Alzheimer's disease primary olfactory gyrus.

AIMS: Alzheimer's disease (AD) is characterized by cholinergic dysfunction and deposition of ß-amyloid (Aß) plaques and tau neurofibrillary tangles (NFTs) in the brain. Olfactory abnormalities often precede cognitive symptoms in AD, indicating early involvement of pathology in olfactory structures. The cholinergic system is important not only in cognition but also in modulation of the olfactory system. The primary olfactory gyrus (POG) is comprised of the olfactory tract, anterior olfactory nucleus (AON) and olfactory area (OA). Because of the importance of the olfactory and cholinergic systems, we examined the anatomical and cholinergic organization of the POG in normal human brain and neuropathology in AD. METHODS: Cytoarchitecture of the POG was studied using Nissl staining in normal (n = 8) and AD (n = 6) brains. Distributions of acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) were determined using histochemical methods. Aß plaques and tau NFTs were detected using immunohistochemistry. Abundance of AD pathology was assessed using a semi-quantitative approach. RESULT: Nissl staining showed pyramidal cells in the AON and paleocortical organization of the OA. AChE stained neurons and neuropil in the AON and OA, while BChE activity was noted in the olfactory tract and in AON and OA neurons. Pathology was frequent in the AD POG and the abundance of BChE-associated AD pathology was greater than that associated with AChE. CONCLUSIONS: AChE and BChE activities in normal POG recapitulated their distributions in other cortical regions. Greater abundance of BChE-associated, in comparison to AChE-associated, AD pathology in the POG suggests preferential involvement of BChE in olfactory dysfunction in AD.

PhyInformR: phylogenetic experimental design and phylogenomic data exploration in R.

BACKGROUND: Analyses of phylogenetic informativeness represent an important step in screening potential or existing datasets for their proclivity toward convergent or parallel evolution of molecular sites. However, while new theory has been developed from which to predict the utility of sequence data, adoption of these advances have been stymied by a lack of software enabling application of advances in theory, especially for large next-generation sequence data sets. Moreover, there are no theoretical barriers to application of the phylogenetic informativeness or the calculation of quartet internode resolution probabilities in a Bayesian setting that more robustly accounts for uncertainty, yet there is no software with which a computationally intensive Bayesian approach to experimental design could be implemented. RESULTS: We introduce PhyInformR, an open source software package that performs rapid calculation of phylogenetic information content using the latest advances in phylogenetic informativeness based theory. These advances include modifications that incorporate uneven branch lengths and any model of nucleotide substitution to provide assessments of the phylogenetic utility of any given dataset or dataset partition. PhyInformR provides new tools for data visualization and routines optimized for rapid statistical calculations, including approaches making use of Bayesian posterior distributions and parallel processing. By implementing the computation on user hardware, PhyInformR increases the potential power users can apply toward screening datasets for phylogenetic/genomic information content by orders of magnitude. CONCLUSIONS: PhyInformR provides a means to implement diverse substitution models and specify uneven branch lengths for phylogenetic informativeness or calculations providing quartet based probabilities of resolution, produce novel visualizations, and facilitate analyses of next-generation sequence datasets while incorporating phylogenetic uncertainty through the use parallel processing. As an open source program, PhyInformR is fully customizable and expandable, thereby allowing for advanced methodologies to be readily integrated into local bioinformatics pipelines. Software is available through CRAN and a package containing the software, a detailed manual, and additional sample data is also provided freely through github: https://github.com/carolinafishes/PhyInformR .

Development of the Central Dogma Concept Inventory (CDCI) Assessment Tool.

Scientific teaching requires scientifically constructed, field-tested instruments to accurately evaluate student thinking and gauge teacher effectiveness. We have developed a 23-question, multiple select-format assessment of student understanding of the essential concepts of the central dogma of molecular biology that is appropriate for all levels of undergraduate biology. Questions for the Central Dogma Concept Inventory (CDCI) tool were developed and iteratively revised based on student language and review by experts. The ability of the CDCI to discriminate between levels of understanding of the central dogma is supported by field testing (N= 54), and large-scale beta testing (N= 1733). Performance on the assessment increased with experience in biology; scores covered a broad range and showed no ceiling effect, even with senior biology majors, and pre/posttesting of a single class focused on the central dogma showed significant improvement. The multiple-select format reduces the chances of correct answers by random guessing, allows students at different levels to exhibit the extent of their knowledge, and provides deeper insight into the complexity of student thinking on each theme. To date, the CDCI is the first tool dedicated to measuring student thinking about the central dogma of molecular biology, and version 5 is ready to use.

The Impact of Fine-Scale Disturbances on the Predictability of Vegetation Dynamics and Carbon Flux.

Predictions from forest ecosystem models are limited in part by large uncertainties in the current state of the land surface, as previous disturbances have important and lasting influences on ecosystem structure and fluxes that can be difficult to detect. Likewise, future disturbances also present a challenge to prediction as their dynamics are episodic and complex and occur across a range of spatial and temporal scales. While large extreme events such as tropical cyclones, fires, or pest outbreaks can produce dramatic consequences, small fine-scale disturbance events are typically much more common and may be as or even more important. This study focuses on the impacts of these smaller disturbance events on the predictability of vegetation dynamics and carbon flux. Using data on vegetation structure collected for the same domain at two different times, i.e. "repeat lidar data", we test high-resolution model predictions of vegetation dynamics and carbon flux across a range of spatial scales at an important tropical forest site at La Selva Biological Station, Costa Rica. We found that predicted height change from a height-structured ecosystem model compared well to lidar measured height change at the domain scale (~150 ha), but that the model-data mismatch increased exponentially as the spatial scale of evaluation decreased below 20 ha. We demonstrate that such scale-dependent errors can be attributed to errors predicting the pattern of fine-scale forest disturbances. The results of this study illustrate the strong impact fine-scale forest disturbances have on forest dynamics, ultimately limiting the spatial resolution of accurate model predictions.

Systematic review and meta-analysis of interventions for depression and anxiety in persons with multiple sclerosis.

BACKGROUND: Depression and anxiety are common in persons with multiple sclerosis (MS), and adversely affect fatigue, medication adherence, and quality of life. Though effective treatments for depression and anxiety exist in the general population, their applicability in the MS population has not been definitively established. OBJECTIVE: To determine the overall effect of psychological and pharmacological treatments for depression or anxiety in persons with MS. METHODS: We searched the Medline, EMBASE, PsycINFO, PsycARTICLES Full Text, Cochrane Central Register of Controlled Trials, CINAHL, Web of Science, and Scopus databases using systematic review methodology from database inception until March 25, 2015. Two independent reviewers screened abstracts, extracted data, and assessed risk of bias and strength of evidence. We included controlled clinical trials reporting on the effect of pharmacological or psychological interventions for depression or anxiety in a sample of persons with MS. We calculated standardized mean differences (SMD) and pooled using random effects meta-analysis. RESULTS: Of 1753 abstracts screened, 21 articles reporting on 13 unique clinical trials met the inclusion criteria. Depression severity improved in nine psychological trials of depression treatment (N=307; SMD: -0.45 (95%CI: -0.74, -0.16)). The severity of depression also improved in three pharmacological trials of depression treatment (SMD: -0.63 (N=165; 95%CI: -1.07, -0.20)). For anxiety, only a single trial examined psychological therapy for injection phobia and reported no statistically significant improvement. CONCLUSION: Pharmacological and psychological treatments for depression were effective in reducing depressive symptoms in MS. The data are insufficient to determine the effectiveness of treatments for anxiety.

Comorbidity is associated with pain-related activity limitations in multiple sclerosis.

BACKGROUND: Comorbidities are common in multiple sclerosis (MS). The high prevalence of pain in MS is well-established but the influence of comorbidities on pain, specifically, pain-related interference in activity is not. OBJECTIVE: To examine the relationship between comorbidity and pain in MS. METHODS: We recruited 949 consecutive patients with definite MS from four Canadian centres. Participants completed the Health Utilities Index (HUI-Mark III) and a validated comorbidity questionnaire at 3 visits over 2 years. The HUI's pain scale was dichotomized into two groups: those with/without pain that disrupts normal activities. We used logistic regression to assess the association of pain with each comorbidity individually at baseline and over time. RESULTS: The incidence of disruptive pain over two years was 31.1 per 100 persons. Fibromyalgia, rheumatoid arthritis, irritable bowel syndrome, migraine, chronic lung disease, depression, anxiety, hypertension, and hypercholesterolemia were associated with disruptive pain (p<0.006). Individual-level effects on the presence of worsening pain were seen for chronic obstructive pulmonary disease (odds ratio [OR]: 1.50 95% CI: 1.08-2.09), anxiety (OR: 1.49 95% CI: 1.07-2.08), and autoimmune thyroid disease (OR: 1.40 95% CI: 1.00-1.97). CONCLUSION: Comorbidity is associated with pain in persons with MS. Closer examination of these associations may provide guidance for better management of this disabling symptom in MS.

Differences in prefrontal blood oxygenation during an acute multitasking stressor in ecstasy polydrug users.

BACKGROUND: Cognitive deficits are well documented in ecstasy (3,4-methylenedioxymethamphetamine; MDMA) users, with such deficits being taken as evidence of dysregulation of the serotonin (5-hydroxytryptamine; 5-HT) system. More recently neuroimaging has been used to corroborate these deficits. The present study aimed to assess multitasking performance in ecstasy polydrug users, polydrug users and drug-naive individuals. It was predicted that ecstasy polydrug users would perform worse than non-users on the behavioural measure and this would be supported by differences in cortical blood oxygenation. METHOD: In the study, 20 ecstasy-polydrug users, 17 polydrug users and 19 drug-naive individuals took part. On day 1, drug use history was taken and questionnaire measures were completed. On day 2, participants completed a 20-min multitasking stressor while brain blood oxygenation was measured using functional near infrared spectroscopy (fNIRS). RESULTS: There were no significant differences between the three groups on the subscales of the multitasking stressor. In addition, there were no significant differences on self-report measures of perceived workload (NASA Task Load Index). In terms of mood, ecstasy users were significantly less calm and less relaxed compared with drug-naive controls. There were also significant differences at three voxels on the fNIRS, indicating decreased blood oxygenation in ecstasy users compared with drug-naive controls at voxel 2 (left dorsolateral prefrontal cortex), voxel 14 and voxel 16 (right dorsolateral prefrontal cortex), and compared with polydrug controls at V14. CONCLUSIONS: The results of the present study provide support for changes in brain activation during performance of demanding tasks in ecstasy polydrug users, which could be related to cerebral vasoconstriction.

The effects of CO2 pressure and pH on the Suzuki coupling of basic nitrogen containing substrates.

The Suzuki coupling reaction of basic nitrogen containing substrates (2-bromo- and 2-chloro-4-aminopyridine, and 2-bromo and 2-chloropyridine) with phenylboronic acid using Pd(TPP)2Cl2/K3PO4 in acetonitrile-water biphasic solvent systems under a CO2 or a N2 atmosphere is discussed. It was observed that 2-halo-4-aminopyridine produced quantitative yields of coupled products under a CO2 atmosphere while the yields for the 2-halopyridines were poor. In contrast, the yields of coupled products for the 2-halopyridines substrates were quantitative under a N2 atmosphere while only poor yields were realized for the 2-halo-4-aminopyridines under the same conditions. Evidence is presented which suggests that the presence of CO2 alters the pH of the aqueous phase of the reaction system and the accompanying efficiency of the coupling process. Using a series of buffers to adjust the pH of the aqueous phase, the pH dependence associated with the efficiency of the coupling process is illustrated.

Performance of administrative case definitions for comorbidity in multiple sclerosis in Manitoba and Nova Scotia.

INTRODUCTION: As the population ages and the prevalence of comorbid conditions increases, the need for feasible, validated methods of comorbidity surveillance in chronic diseases such as multiple sclerosis (MS) increases. METHODS: Using kappa (k) statistics, we evaluated the performance of administrative case definitions for comorbidities commonly observed in MS by comparing agreement between Manitoba (MB) administrative data and self-report (n = 606) and Nova Scotia (NS) administrative data and self-report (n = 1923). RESULTS: Agreement between the administrative definitions and self-report was substantial for hypertension (k = 0.69 [NS], 0.76 [MB]) and diabetes (k = 0.70 [NS], 0.66 [MB]); moderate for hyperlipidemia (k = 0.53 [NS], 0.51 [MB]) and heart disease (k = 0.42 [NS], 0.51 [MB]) and fair for anxiety (k = 0.27 [NS], 0.26 [MB]). In NS, agreement was substantial for inflammatory bowel disease (k = 0.71) and moderate for epilepsy (k = 0.48). CONCLUSION: Administrative definitions for commonly observed comorbidities in MS performed well in 2 distinct jurisdictions. This suggests that they could be used more broadly across Canada and in national studies.

TITRE: Performance des définitions administratives de cas pour les affections concomitantes de la sclérose en plaques au Manitoba et en Nouvelle-Écosse. INTRODUCTION: Au fur et à mesure du vieillissement de la population et de l'augmentation de la prévalence d'affections concomitantes, le recours à des méthodes fiables et efficaces de surveillance des affections concomitantes de maladies chroniques telles que la sclérose en plaques (SP) s'avère de plus en plus nécessaire. MÉTHODOLOGIE: Nous avons évalué, au moyen de la statistique kappa (k), la performance des définitions administratives de cas pour les affections concomitantes fréquemment observées en lien avec la SP en comparant les concordances entre les données administratives et les données provenant d'autodéclarations au Manitoba (MB) (n = 606) et en Nouvelle-Écosse (NS) (n = 1 923). RÉSULTATS: Les concordances entre les définitions administratives et les autodéclarations étaient bonnes pour l'hypertension (k = 0,69 [NS] et 0,76 [MB]) et le diabète (k = 0,70 [NS] et 0,66 [MB]), modérées pour l'hyperlipidémie (k = 0,53 [NS] et 0,51 [MB]) et la cardiopathie (k = 0,42 [NS] et 0,51 [MB]) et médiocres pour l'anxiété (k = 0,27 [NS] et 0,26 [MB]). La concordance était bonne en Nouvelle-Écosse pour la maladie inflammatoire chronique de l'intestin (k = 0,71) et modérée pour l'épilepsie (k = 0,48). CONCLUSION: Les définitions administratives étaient performantes dans les deux provinces pour plusieurs affections concomitantes fréquemment observées en lien avec la SP. À la lumière de ces résultats, il semble que ces définitions puissent être utilisées plus largement au Canada et dans les études nationales.

DNA → RNA: What Do Students Think the Arrow Means?

The central dogma of molecular biology, a model that has remained intact for decades, describes the transfer of genetic information from DNA to protein though an RNA intermediate. While recent work has illustrated many exceptions to the central dogma, it is still a common model used to describe and study the relationship between genes and protein products. We investigated understanding of central dogma concepts and found that students are not primed to think about information when presented with the canonical figure of the central dogma. We also uncovered conceptual errors in student interpretation of the meaning of the transcription arrow in the central dogma representation; 36% of students (n = 128; all undergraduate levels) described transcription as a chemical conversion of DNA into RNA or suggested that RNA existed before the process of transcription began. Interviews confirm that students with weak conceptual understanding of information flow find inappropriate meaning in the canonical representation of central dogma. Therefore, we suggest that use of this representation during instruction can be counterproductive unless educators are explicit about the underlying meaning.

MS incidence and prevalence in Africa, Asia, Australia and New Zealand: A systematic review.

OBJECTIVES: Studies of multiple sclerosis (MS) incidence and prevalence from Africa, Asia, Australia and New Zealand are relatively scarce. We systematically reviewed MS incidence and prevalence in these regions including a standardized evaluation of study quality. METHODS: We searched MEDLINE and EMBASE databases for studies of MS prevalence or incidence in Africa, Asia, Australia and New Zealand published in English or French between January 1, 1985 and January 31, 2011. Study quality was assessed using a standardized tool. All steps of the review were performed in duplicate. RESULTS: Of 3925 citations identified, 28 studies met inclusion criteria and 21 of these were from Asia. Quality scores ranged from 1/8 to 8/8; the lowest scores were observed in studies from Asia (median 4/8, IQR 3,6). Prevalence was lowest in South African Blacks (0.22/100,000) and highest amongst Australian-born individuals in Australia (125/100,000). Prevalence increased over time in many countries. MS prevalence increased with increasing latitude only in some regions, and prevalence varied significantly with ethnicity. Eight studies reported incidence, which ranged from 0.67/100,000/year in Taiwan to 3.67/100,00/year in Australia. CONCLUSIONS: This comprehensive study provides an update of MS epidemiology in Africa, Asia, Australia, and New Zealand. Incidence and prevalence were lowest in Africa and Asia and highest in Australia, but many Asian studies were of poor quality. Use of consistent case ascertainment methods, standardized data collection tools, and similar outcomes would all improve study quality and comparability. The underlying basis of observed ethnic differences is an important area for future study.

Electrophysiological indices of response inhibition in human polydrug users.

Previous research in ecstasy users suggests impairment of various executive functions. In general, the executive function of response inhibition appears unaffected by ecstasy use. Nonetheless, it remains a possibility that cognitive tasks alone are not sensitive enough to pick up subtle changes in function. The current study sought to investigate behavioural measures of response inhibition and their electrophysiological correlates in drug users. Twenty ecstasy polydrug users, 20 non-ecstasy polydrug users and 20 drug naïve controls were recruited. Participants completed questionnaires about their background drug use, sleep quality, fluid intelligence and mood state. Each individual also completed a Go/NoGo response inhibition task whilst electroencephalography (EEG) measures were recorded. Analysis of variance (ANOVA) revealed that there were no between-group differences on the behavioural measure of response inhibition. Multivariate analysis of variance (MANOVA) revealed no main effect of group across midline electrodes for the P3, N2 and P2 components. Univariate ANOVA revealed significant between-group differences in the P2 component with the ecstasy user group having a significantly higher mean amplitude than drug naïve controls at two midline frontal electrodes: at Fz and significantly higher mean amplitude than both control groups at FCz. The present study provides evidence of atypical early processing in ecstasy users that is suggestive of compensatory mechanisms ameliorating any behavioural differences.

ERP evidence suggests executive dysfunction in ecstasy polydrug users.

BACKGROUND: Deficits in executive functions such as access to semantic/long-term memory have been shown in ecstasy users in previous research. Equally, there have been many reports of equivocal findings in this area. The current study sought to further investigate behavioural and electro-physiological measures of this executive function in ecstasy users. METHOD: Twenty ecstasy-polydrug users, 20 non-ecstasy-polydrug users and 20 drug-naïve controls were recruited. Participants completed background questionnaires about their drug use, sleep quality, fluid intelligence and mood state. Each individual also completed a semantic retrieval task whilst 64 channel Electroencephalography (EEG) measures were recorded. RESULTS: Analysis of Variance (ANOVA) revealed no between-group differences in behavioural performance on the task. Mixed ANOVA on event-related potential (ERP) components P2, N2 and P3 revealed significant between-group differences in the N2 component. Subsequent exploratory univariate ANOVAs on the N2 component revealed marginally significant between-group differences, generally showing greater negativity at occipito-parietal electrodes in ecstasy users compared to drug-naïve controls. Despite absence of behavioural differences, differences in N2 magnitude are evidence of abnormal executive functioning in ecstasy-polydrug users.