Background Genome-wide association studies (GWASs) in Parkinson's disease (PD) have increased the scope of biological knowledge about the disease over the past decade. We sought to use the largest aggregate of GWAS data to identify novel risk loci and gain further insight into disease etiology. Methods We performed the largest meta-GWAS of PD to date, involving the analysis of 7.8M SNPs in 37.7K cases, 18.6K UK Biobank proxy-cases (having a first degree relative with PD), and 1.4M controls. We carried out a meta-analysis of this GWAS data to nominate novel loci. We then evaluated heritable risk estimates and predictive models using this data. We also utilized large gene expression and methylation resources to examine possible functional consequences as well as tissue, cell type and biological pathway enrichments for the identified risk factors. Additionally we examined shared genetic risk between PD and other phenotypes of interest via genetic correlations followed by Mendelian randomization. Findings We identified 90 independent genome-wide significant risk signals across 78 genomic regions, including 38 novel independent risk signals in 37 loci. These 90 variants explained 16-36% of the heritable risk of PD depending on prevalence. Integrating methylation and expression data within a Mendelian randomization framework identified putatively associated genes at 70 risk signals underlying GWAS loci for follow-up functional studies. Tissue-specific expression enrichment analyses suggested PD loci were heavily brain-enriched, with specific neuronal cell types being implicated from single cell data. We found significant genetic correlations with brain volumes, smoking status, and educational attainment. Mendelian randomization between cognitive performance and PD risk showed a robust association. Interpretation These data provide the most comprehensive understanding of the genetic architecture of PD to date by revealing many additional PD risk loci, providing a biological context for these risk factors, and demonstrating that a considerable genetic component of this disease remains unidentified. Funding See supplemental materials (Text S2). lead to earlier detection and refined diagnostics, which may help improve clinical trials (4). The generation of copious amounts of public summary statistics created by this effort relating to both the GWAS and subsequent analyses of gene expression and methylation patterns may be of use to investigators planning follow-up functional studies in stem cells or other cellular screens, allowing them to prioritize targets more efficiently using our data as additional evidence. We hope our findings may have some downstream clinical impact in the future such as improved patient stratification for clinical trials and genetically informed drug targets.

We performed the largest genome-wide association study of PD to date, involving the analysis of 7.8M SNPs in 37.7K cases, 18.6K UK Biobank proxy-cases, and 1.4M controls. We identified 90 independent genome-wide significant signals across 78 loci, including 38 independent risk signals in 37 novel loci. These variants explained 26-36% of the heritable risk of PD. Tests of causality within a Mendelian randomization framework identified putatively causal genes for 70 risk signals. Tissue expression enrichment analysis suggested that signatures of PD loci were heavily brain-enriched, consistent with specific neuronal cell types being implicated from single cell expression data. We found significant genetic correlations with brain volumes, smoking status, and educational attainment. In sum, these data provide the most comprehensive understanding of the genetic architecture of PD to date by revealing many additional PD risk loci, providing a biological context for these risk factors, and demonstrating that a considerable genetic component of this disease remains unidentified.

As surgeons performed higher annual volumes of elective open AAA repairs, significantly lower mortality rates were demonstrated. Surgeons wishing to perform elective AAA repairs should achieve a minimum case volume of 13 repairs per annum.

PMT appears feasible and safe, though the level of evidence available is poor. Major RCTs and registry data are required to determine the economic and clinical benefit of various devices used alone or in combination, for differing thrombus characteristics and clinical scenarios. Until these data are available there is little substantial evidence to support the routine use of PMT over CDT alone.

The absence of randomized data is a major hurdle to understanding the effect of anesthetic technique on morbidity after EVAR. The data presented are encouraging in selected patients. The use of locoregional anesthesia for EVAR should be further investigated with better reporting of aneurysm morphology to clarify its potential benefits and identify the subgroups that will derive greatest benefit.

Background The underlying pathophysiology of idiopathic sudden sensorineural hearing loss (ISSNHL) is still unknown. However, an increasing number of observational studies report intralabyrinthine signal alterations in patients with ISSNHL using three‐dimensional fluid‐attenuated inversion recovery (3D‐FLAIR) magnetic resonance imaging (MRI). These findings warrant a meta‐analysis. Objective of review To conduct a meta‐analysis assessing the value of 3D‐FLAIR MRI in identifying possible underlying labyrinthine pathophysiologic mechanisms and prognostication in patients with ISSNHL. Search strategy Two reviewers independently searched the Pubmed, Embase and Cochrane Library from inception until October 10, 2018 and evaluated eligibility based on titles and abstracts of all retrieved studies. All studies reporting on 3D‐FLAIR imaging in ISSNHL were included. Subsequently, the full text of eligible studies were evaluated. Evaluation method Adhering to the MOOSE guideline, two independent reviewers extracted data, assessed risk of bias and evaluated the relevance and quality of evidence. Data on the number of patients and events were extracted and hearing levels were converted to standardised mean differences (SMD) for conducting meta‐analyses. Random effects models for meta‐analyses were applied. Results Eight observational studies met our inclusion criteria (n = 638 patients). In 29%, high signal intensity was found on 3D‐FLAIR imaging, suggesting labyrinthine pathology (labyrinthitis [79%], intralabyrinthine haemorrhage [21%]). High signal intensity on 3D‐FLAIR was associated with poorer hearing (SMD: 14 dB, 95% CI 5.67‐22.94) and vertigo (RR: 1.92, 95% CI 1.16‐3.17) at baseline. Multivariate analyses demonstrated that patients with high 3D‐FLAIR signal intensity had 21 dB lower final hearing pure‐tone averages (SMD: 21 dB, 95% CI 9.08‐33.24). Conclusions Three‐dimensional fluid‐attenuated inversion recovery MR imaging can identify an underlying labyrinthine condition in up to 29% of patients with sudden hearing loss in whom previously no cause could be identified. Their final pure‐tone averages are more than 20 dB worse than 3D‐FLAIR–negative patients, suggesting more severe labyrinthine damage. Findings such as these may contribute to our understanding of pathophysiologic mechanisms of ISSNHL.

BackgroundCardiopulmonary exercise testing (CPET) has become well established in the preoperative assessment of patients presenting for major surgery in the United Kingdom. There is evidence supporting its use in risk-stratifying patients prior to major high-risk surgical procedures.We set out to establish how CPET services in England have developed since the only survey on this subject was undertaken in 2008 (J Intensive Care Soc 2009, 10:275–278).MethodsAvailability of preoperative CPET and contact details were collected via a telephone survey and email invites to complete the online survey were sent to all contacts. The survey was live during March and April 2011.ResultsWe received 123 (74%) responses from the 166 emails that were sent out. In total, 32% (53/166) of all adult anesthetic departments in England have access to preoperative CPET services and a further 4% (6) were in the process of setting up services. The number of departments offering preoperative CPET, including those in the process of setting up services, has risen from 42 in 2008 to 59 in 2011, a rise of over 40%. Only 61% of the clinics are run by anesthetists and 39% of clinics have trained cardiorespiratory technicians assisting in the performance of the test. Most of the clinics (55%) rely solely on a bicycle ergometer. Vascular surgical patients are the largest group of patients tested, and the majority of tests are run to a symptom-limited maximum. We estimate that 15,000 tests are performed annually for preoperative assessment in England. Only 37% of respondents were confident that the tests performed were being billed for.ConclusionsCPET is increasing in popularity as a preoperative risk assessment tool. There remains a lack of consistency in the way tests are reported and utilized. The results highlight the extent and diversity of the use of preoperative CPET and the potential for further research into its use in unstudied patient groups.

Objective Cochlear implantation can result in post-operative vestibular dysfunction of unknown clinical significance. The objective of this study was to characterize the presence, magnitude, and clinical significance of vestibular dysfunction that occurs after pediatric cochlear implantation. Data sources The databases Embase, Medline (OvidSP), and PubMed were used. Only articles published in English were included. Grey literature and unpublished sources were also reviewed. Study selection Articles published from 1980 until the present which documented pre-operative and post-operative vestibular testing on children under the age of 18 were used. Data extraction Parameters that were assessed included number of patients, pre- and post-operative vestibular-evoked myogenic potentials (VEMPs), head impulse testing (HIT), calorics, and posturography, timing of pre- and post-operative testing, symptomatology, and other demographic data such as etiology of the hearing loss. Data synthesis Ten articles were included. Relative risk values evaluating the effect of cochlear implantation on vestibular function were calculated for VEMPs and caloric testing due to the availability of published data. I 2 values were calculated and 95% confidence intervals were reported. Separate analyses were conducted for each individual study and a pooled analysis was conducted to yield an overall relative risk. Assessment on risk of bias in individual studies and overall was performed. Conclusion Pediatric cochlear implantation is associated with a statistically significant decrease in VEMP responses post-operatively (RR 1.8, p < 0.001, I 2 91.86, 95%CI 1.57–2.02). Similar results are not seen in caloric testing. Insufficient data is available for analysis of HIT and posturography. Further studies are necessary to determine the effect of cochlear implantation on objective vestibular measures post-operatively and whether any changes seen are clinically relevant in this population.