Antiinflammatory Therapy with Canakinumab for Atherosclerotic Disease

Background: Experimental and clinical data suggest that reducing inflammation without affecting lipid levels may reduce the risk of cardiovascular disease. Yet, the inflammatory hypothesis of atherothrombosis has remained unproved. Methods: We conducted a randomized, double-blind trial of canakinumab, a therapeutic monoclonal antibody targeting interleukin-1β, involving 10,061 patients with previous myocardial infarction and a high-sensitivity C-reactive protein level of 2 mg or more per liter. The trial compared three doses of canakinumab (50 mg, 150 mg, and 300 mg, administered subcutaneously every 3 months) with placebo. The primary efficacy end point was nonfatal myocardial infarction, nonfatal stroke, or cardiovascular death. RESULTS: At 48 months, the median reduction from baseline in the high-sensitivity C-reactive protein level was 26 percentage points greater in the group that received the 50-mg dose of canakinumab, 37 percentage points greater in the 150-mg group, and 41 percentage points greater in the 300-mg group than in the placebo group. Canakinumab did not reduce lipid levels from baseline. At a median follow-up of 3.7 years, the incidence rate for the primary end point was 4.50 events per 100 person-years in the placebo group, 4.11 events per 100 person-years in the 50-mg group, 3.86 events per 100 person-years in the 150-mg group, and 3.90 events per 100 person-years in the 300-mg group. The hazard ratios as compared with placebo were as follows: in the 50-mg group, 0.93 (95% confidence interval [CI], 0.80 to 1.07; P = 0.30); in the 150-mg group, 0.85 (95% CI, 0.74 to 0.98; P = 0.021); and in the 300-mg group, 0.86 (95% CI, 0.75 to 0.99; P = 0.031). The 150-mg dose, but not the other doses, met the prespecified multiplicity-adjusted threshold for statistical significance for the primary end point and the secondary end point that additionally included hospitalization for unstable angina that led to urgent revascularization (hazard ratio vs. placebo, 0.83; 95% CI, 0.73 to 0.95; P = 0.005). Canakinumab was associated with a higher incidence of fatal infection than was placebo. There was no significant difference in all-cause mortality (hazard ratio for all canakinumab doses vs. placebo, 0.94; 95% CI, 0.83 to 1.06; P = 0.31). Conclusions: Antiinflammatory therapy targeting the interleukin-1β innate immunity pathway with canakinumab at a dose of 150 mg every 3 months led to a significantly lower rate of recurrent cardiovascular events than placebo, independent of lipid-level lowering. (Funded by Novartis; CANTOS ClinicalTrials.gov number, NCT01327846.

Pan-cancer analysis of whole genomes

Cancer is driven by genetic change, and the advent of massively parallel sequencing has enabled systematic documentation of this variation at the whole-genome scale(1-3). Here we report the integrative analysis of 2,658 whole-cancer genomes and their matching normal tissues across 38 tumour types from the Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium of the International Cancer Genome Consortium (ICGC) and The Cancer Genome Atlas (TCGA). We describe the generation of the PCAWG resource, facilitated by international data sharing using compute clouds. On average, cancer genomes contained 4-5 driver mutations when combining coding and non-coding genomic elements; however, in around 5% of cases no drivers were identified, suggesting that cancer driver discovery is not yet complete. Chromothripsis, in which many clustered structural variants arise in a single catastrophic event, is frequently an early event in tumour evolution; in acral melanoma, for example, these events precede most somatic point mutations and affect several cancer-associated genes simultaneously. Cancers with abnormal telomere maintenance often originate from tissues with low replicative activity and show several mechanisms of preventing telomere attrition to critical levels. Common and rare germline variants affect patterns of somatic mutation, including point mutations, structural variants and somatic retrotransposition. A collection of papers from the PCAWG Consortium describes non-coding mutations that drive cancer beyond those in the TERT promoter(4); identifies new signatures of mutational processes that cause base substitutions, small insertions and deletions and structural variation(5,6); analyses timings and patterns of tumour evolution(7); describes the diverse transcriptional consequences of somatic mutation on splicing, expression levels, fusion genes and promoter activity(8,9); and evaluates a range of more-specialized features of cancer genomes(8,10-18).Peer reviewe

Frequency of anxiety after stroke: a systematic review and meta-analysis of observational studies.

BACKGROUND AND PURPOSE: Negative psychological outcomes occur frequently after stroke; however, there is uncertainty regarding the occurrence of anxiety disorders and anxiety symptoms after stroke. A systematic review of observational studies was conducted that assessed the frequency of anxiety in stroke patients using a diagnostic or screening tool. SUMMARY OF REVIEW: Databases were searched up to March 2011. A random effects model was used to summarize the pooled estimate. Statistical heterogeneity was assessed using the I(2) statistic. Forty-four published studies comprising 5760 stroke patients were included. The overall pooled estimate of anxiety disorders assessed by clinical interview was 18% (95%confidence interval 8-29%, I(2)  = 97%) and was 25% (95% confidence interval 21-28%, I(2)  = 90%) for anxiety assessed by rating scale. The Hospital Anxiety and Depression Scale-Anxiety subscale 'probable' and 'possible' cutoff scores were the most widely used assessment criteria. The combined rate of anxiety by time after stroke was: 20% (95% confidence interval 13-27%, I(2)  = 96%) within one-month of stroke; 23% (95% confidence interval 19-27%, I(2)  = 84%) one to five-months after stroke; and 24% (95% confidence interval 19-29%, I(2)  = 89%) six-months or more after stroke. CONCLUSION: Anxiety after stroke occurs frequently although methodological limitations in the primary studies may limit generalizability. Given the association between prevalence rates and the Hospital Anxiety and Depression Scale-Anxiety cutoff used in studies, reported rates could in fact underrepresent the extent of the problem. Additionally, risk factors for anxiety, its impact on patient outcomes, and effects in tangent with depression remain unclear

Part II: predictors of depression after stroke and impact of depression on stroke outcome: an updated systematic review of observational studies

BACKGROUND: We previously published a systematic review in 2005 on factors associated with the development of depression in people with stroke. AIM: To update and expand that review to include published data on the impact of depression on stroke outcome. METHODS: We included all published observational studies (to May 31, 2013) with prospective consecutive recruitment of people with a clinical diagnosis of stroke where an attempt was made to assess the variables associated with, or predictive of, the development of depression. RESULTS: We included data from 23 studies including 18,374 people. Depression after stroke was associated with prestroke depression, more severe neurological deficit and physical disability in the acute phase, and later after stroke. No consistent relationship between depression and demographic parameters or stroke features was identified. The review of the impact of depression on stroke outcome included data from 14 cohorts, including 4498 people, and found that depression was negatively associated with functional outcome in stroke survivors. CONCLUSIONS: Early identification of patients at high risk of depression after stroke, those with a history of depression and physical disability after stroke, would enable the early implementation of effective management and prevention strategies for depression. The reciprocal relationship between depression and physical disability highlights the need for interventions that reduce disability after stroke, which may in turn improve mood and overall recovery for an increasingly large number of stroke survivors

Aseptic meningoencephalitis mimicking transient ischaemic attacks.

PURPOSE: To highlight meningoencephalitis as a transient ischaemic attack (TIA) mimic and suggest clinical clues for differential diagnosis. METHODS: This was an observational study of consecutively admitted patients over a 9.75-year period presenting as TIAs at a stroke unit. RESULTS: A total of 790 patients with TIAs and seven with TIA-like symptoms but a final diagnosis of viral meningoencephalitis were recognised. The most frequent presentations of meningoencephalitis patients were acute sensory hemisyndrome (6) and cognitive deficits (5). Signs of meningeal irritation were minor or absent on presentation. Predominantly lymphocytic pleocytosis, hyperproteinorachia and a normal cerebrospinal fluid (CSF)/serum glucose index (in 5 out of 6 documented patients) were present. Meningeal thickening on a brain magnetic resonance imaging (MRI) scan was the only abnormal imaging finding. Six patients received initial vascular treatment; one thrombolysed. Finally, six patients were treated with antivirals and/or antibiotics. Although neither bacterial nor viral agents were identified on extensive testing, viral meningoencephalitis was the best explanation for all clinical and laboratory findings. CONCLUSIONS: Aseptic meningoencephalitis should be part of the differential diagnosis in patients presenting as TIA. The threshold for a lumbar puncture in such patients should be set individually and take into account the presence of mild meningeal symptoms, age and other risk factors for vascular disease, the results of brain imaging and the basic diagnostic work-up for a stroke source