Robert W. Eppsteiner

Surgeon volume impacts hospital mortality for pancreatic resection.

Objective:Improved outcomes after pancreatic resection (PR) by high volume (HV) surgeons have been reported in single center studies, which may be confounded with potential selection and referral bias. We attempted to determine if improved outcomes by HV surgeons are reproducible when patient demographic factors are controlled at the population level. Methods:Using the Nationwide Inpatient Sample, discharge records with surgeon identifiers for all nontrauma PR (n = 3581) were examined from 1998 to 2005. Surgeons were divided into 2 groups: (HV; ≥5 operations/year) or low volume (LV; <5 operations/year). We created a logistic regression model to examine the relationship between surgeon type and operative mortality while accounting for patient and hospital factors. To further eliminate differences in cohorts and determine the true effect of surgeon volume on mortality, case-control groups based on patient demographics were created using propensity scores. Results:One hundred thirty-four HV and 1450 LV surgeons performed 3581 PR in 742 hospitals across 12 states that reported surgeon identifier information over the 8-year period. Patients who underwent PR by HV surgeons were more likely to be male, white raced, and a resident of a high-income zip code (P < 0.05). Significant independent factors for in-hospital mortality after PR included increasing age, male gender, Medicaid insurance, and surgery by HV surgeon. HV surgeons had a lower adjusted mortality compared with LV surgeons (2.4% vs. 6.4%; P < 0.0001). Conclusions:After controlling for patient demographics and factors, pancreatic resection by a HV surgeon in this case-controlled cohort was independently associated with a 51% reduction in in-hospital mortality.

Advancing genetic testing for deafness with genomic technology

Background Non-syndromic hearing loss (NSHL) is the most common sensory impairment in humans. Until recently its extreme genetic heterogeneity precluded comprehensive genetic testing. Using a platform that couples targeted genomic enrichment (TGE) and massively parallel sequencing (MPS) to sequence all exons of all genes implicated in NSHL, we tested 100 persons with presumed genetic NSHL and in so doing established sequencing requirements for maximum sensitivity and defined MPS quality score metrics that obviate Sanger validation of variants. Methods We examined DNA from 100 sequentially collected probands with presumed genetic NSHL without exclusions due to inheritance, previous genetic testing, or type of hearing loss. We performed TGE using post-capture multiplexing in variable pool sizes followed by Illumina sequencing. We developed a local Galaxy installation on a high performance computing cluster for bioinformatics analysis. Results To obtain maximum variant sensitivity with this platform 3.2–6.3 million total mapped sequencing reads per sample were required. Quality score analysis showed that Sanger validation was not required for 95% of variants. Our overall diagnostic rate was 42%, but this varied by clinical features from 0% for persons with asymmetric hearing loss to 56% for persons with bilateral autosomal recessive NSHL. Conclusions These findings will direct the use of TGE and MPS strategies for genetic diagnosis for NSHL. Our diagnostic rate highlights the need for further research on genetic deafness focused on novel gene identification and an improved understanding of the role of non-exonic mutations. The unsolved families we have identified provide a valuable resource to address these areas.

Utilizing Ethnic-Specific Differences in Minor Allele Frequency to Recategorize Reported Pathogenic Deafness Variants

Ethnic-specific differences in minor allele frequency impact variant categorization for genetic screening of nonsyndromic hearing loss (NSHL) and other genetic disorders. We sought to evaluate all previously reported pathogenic NSHL variants in the context of a large number of controls from ethnically distinct populations sequenced with orthogonal massively parallel sequencing methods. We used HGMD, ClinVar, and dbSNP to generate a comprehensive list of reported pathogenic NSHL variants and re-evaluated these variants in the context of 8,595 individuals from 12 populations and 6 ethnically distinct major human evolutionary phylogenetic groups from three sources (Exome Variant Server, 1000 Genomes project, and a control set of individuals created for this study, the OtoDB). Of the 2,197 reported pathogenic deafness variants, 325 (14.8%) were present in at least one of the 8,595 controls, indicating a minor allele frequency (MAF) > 0.00006. MAFs ranged as high as 0.72, a level incompatible with pathogenicity for a fully penetrant disease like NSHL. Based on these data, we established MAF thresholds of 0.005 for autosomal-recessive variants (excluding specific variants in GJB2) and 0.0005 for autosomal-dominant variants. Using these thresholds, we recategorized 93 (4.2%) of reported pathogenic variants as benign. Our data show that evaluation of reported pathogenic deafness variants using variant MAFs from multiple distinct ethnicities and sequenced by orthogonal methods provides a powerful filter for determining pathogenicity. The proposed MAF thresholds will facilitate clinical interpretation of variants identified in genetic testing for NSHL. All data are publicly available to facilitate interpretation of genetic variants causing deafness.

Mechanical Compression Versus Subcutaneous Heparin Therapy in Postoperative and Posttrauma Patients: A Systematic Review and Meta-Analysis

BackgroundThe risk of postoperative venous thromboembolic disease is as high as 30%, with an associated fatality risk of 1%. Therefore, prophylaxis is essential, but the optimal regimen remains controversial. This study was designed to systematically review and quantitatively summarize the impact of mechanical compression versus subcutaneous heparin on venous thromboembolic disease and posttreatment bleeding in postsurgical and posttrauma patients.MethodsComputerized searches of the MEDLINE and EMBASE databases through November 2008 were performed and supplemented with manual searches. We included studies that had: (1) a patient population undergoing surgery or admitted immediately posttrauma, (2) a randomized comparison of prophylaxis with mechanical compression versus subcutaneous heparin, (3) outcome measured in terms of deep vein thrombosis (DVT), pulmonary embolism (PE), or bleeding.ResultsTwo reviewers independently extracted data from the original articles, which represented 16 studies, including a total of 3,887 subjects. Meta-analysis was performed using a random effects model. The pooled relative risk for mechanical compression compared with subcutaneous heparin was 1.07 (95% confidence interval [CI] 0.72, 1.61) for DVT and 1.03 (95% CI 0.48, 2.22) for PE. Mechanical compression was associated with a significantly reduced risk of postoperative bleeding compared with subcutaneous heparin (risk ratio 0.47; 95% CI 0.31, 0.70). Subgroup analyses by heparin type suggested that low molecular weight heparin may reduce risk of DVT compared with compression (relative risk 1.80; 95% CI 1.16, 2.79) but remains similarly associated with an increased risk of bleeding.ConclusionsThese results suggest that the overall bleeding risk profile favors the use of compression over heparin, with the benefits in term of venous thromboembolic disease prophylaxis being similar between groups. Subgroup analyses suggest that low molecular weight heparin may have a differential effect; this observation should be further evaluated in future studies.

High volume and outcome after liver resection: surgeon or center

IntroductionIn a case controlled analysis, we attempted to determine if the volume–survival benefit persists in liver resection (LR) after eliminating differences in background characteristics.MethodsUsing the Nationwide Inpatient Sample (NIS), we identified all LR (n = 2,949) with available surgeon/hospital identifiers performed from 1998–2005. Propensity scoring adjusted for background characteristics. Volume cut-points were selected to create equal groups. A logistic regression for mortality was then performed with these matched groups.ResultsAt high volume (HV) hospitals, patients (n = 1423) were more often older, white, private insurance holders, elective admissions, carriers of a malignant diagnosis, and high income residents (p < 0.05). Propensity matching eliminated differences in background characteristics. Adjusted in-hospital mortality was significantly lower in the HV group (2.6% vs. 4.8%, p = 0.02). Logistic regression found that private insurance and elective admission type decreased mortality; preoperative comorbidity increased mortality. Only LR performed by HV surgeons at HV centers was independently associated with improved in-hospital mortality (HR, 0.43; 95% CI, 0.22–0.83).ConclusionsA socioeconomic bias may exist at HV centers. When these factors are accounted for and adjusted, center volume does not appear to influence in-hospital mortality unless LR is performed by HV surgeons at HV centers.

Prediction of cochlear implant performance by genetic mutation: The spiral ganglion hypothesis

BACKGROUND Up to 7% of patients with severe-to-profound deafness do not benefit from cochlear implantation. Given the high surgical implantation and clinical management cost of cochlear implantation (>

Cervical vestibular evoked myogenic potentials (cVEMPs) in patients with superior canal dehiscence syndrome (SCDS)

1 million lifetime cost), prospective identification of the worst performers would reduce unnecessary procedures and healthcare costs. Because cochlear implants bypass the membranous labyrinth but rely on the spiral ganglion for functionality, we hypothesize that cochlear implant (CI) performance is dictated in part by the anatomic location of the cochlear pathology that underlies the hearing loss. As a corollary, we hypothesize that because genetic testing can identify sites of cochlear pathology, it may be useful in predicting CI performance. METHODS 29 adult CI recipients with idiopathic adult-onset severe-to-profound hearing loss were studied. DNA samples were subjected to solution-based sequence capture and massively parallel sequencing using the OtoSCOPE(®) platform. The cohort was divided into three CI performance groups (good, intermediate, poor) and genetic causes of deafness were correlated with audiometric data to determine whether there was a gene-specific impact on CI performance. RESULTS The genetic cause of deafness was determined in 3/29 (10%) individuals. The two poor performers segregated mutations in TMPRSS3, a gene expressed in the spiral ganglion, while the good performer segregated mutations in LOXHD1, a gene expressed in the membranous labyrinth. Comprehensive literature review identified other good performers with mutations in membranous labyrinth-expressed genes; poor performance was associated with spiral ganglion-expressed genes. CONCLUSIONS Our data support the underlying hypothesis that mutations in genes preferentially expressed in the spiral ganglion portend poor CI performance while mutations in genes expressed in the membranous labyrinth portend good CI performance. Although the low mutation rate in known deafness genes in this cohort likely relates to the ascertainment characteristics (postlingual hearing loss in adult CI recipients), these data suggest that genetic testing should be implemented as part of the CI evaluation to test this association prospectively.

Genetic disorders of the vestibular system.

Objective: To determine the usefulness of both amplitude and threshold data from tone-burst cervical vestibular evoked myogenic potential (cVEMP) testing for the evaluation of superior canal dehiscence syndrome (SCDS). Study Design: Case series with chart review. Subjects and Methods: Sixty-seven patients underwent cVEMP testing. We correlated mean tone burst cVEMP amplitude and threshold data with temporal bone CT findings. Patients were excluded for Ménières disease, middle ear disease, or otologic surgery. Results: Superior canal dehiscence patients had higher mean cVEMP amplitudes (SCDS 173.8 μV vs non-SCDS 69.7 μV, P = 0.031) and lower mean thresholds (SCDS 72.8 dB nHL vs non-SCDS 80.9 dB nHL) at 500 Hz. Conclusion: Patients with SCDS have larger amplitudes and lower thresholds on cVEMP testing at 500 Hz. This study supports the utility of tone burst cVEMPs for the evaluation of SCDS and is one of few large single-center studies to establish normative data.

Leiomyosarcoma of the Head and Neck: A Population-Based Analysis

Purpose of reviewThis review highlights the current body of literature related to the genetics of inherited vestibular disorders and provides a framework for the characterization of these disorders. We emphasize peripheral causes of vestibular dysfunction and highlight recent advances in the field, point out gaps in understanding, and focus on key areas for future investigation. Recent findingsThe discovery of a modifier gene that leads to a more severe Usher syndrome phenotype calls into question the assumption that Usher syndrome is universally a monogenic disorder. Despite the use of several investigational approaches, the genetic basis of Menières disease remains poorly understood. Evidence for a vestibular phenotype associated with DFNB1 suggests that mutations in other genes causally related to nonsyndromic hearing loss also may have an unrecognized vestibular phenotype. SummaryOur understanding of the genetic basis for vestibular disorders is superficial. Significant challenges include defining the genetics of inherited isolated vestibular dysfunction and understanding the pathological basis of Menières disease. However, improved characterization of inherited vestibular dysfunction, coupled with advanced genetic techniques such as targeted genome capture and massively parallel sequencing, provides an opportunity to investigate these diseases at the genetic level.

AudioGene: Predicting Hearing Loss Genotypes from Phenotypes to Guide Genetic Screening

OBJECTIVES To describe the characteristics of head and neck leiomyosarcoma and to identify factors associated with survival. DESIGN Retrospective population-based study. PATIENTS The 17-registry Surveillance, Epidemiology, and End Results database was used to identify 578 patients with leiomyosarcoma of the head and neck. INTERVENTIONS Surgery and primary and adjuvant radiotherapy. MAIN OUTCOME MEASURES Patient demographics and tumor characteristics were examined. Treatment modalities were compared, and survival was assessed using the log-rank test. RESULTS The mean age at diagnosis was 64 years. Most tumors were smaller than 5 cm in greatest dimension (87%) and high grade (44% were moderately differentiated and 39% were poorly differentiated). The primary tumor demonstrated deep extension in 39% of cases, and 2% had lymph node metastases. The most common primary site was the skin and soft tissue of the head and neck (83%). Surgical treatment was provided to 89% of patients, 14% received adjuvant radiotherapy, and 4% received radiotherapy alone. The median observed survival was 84.7 months. The 5-year disease-specific survival rate was 87.6% in patients with well-differentiated tumors, 85.7% in patients with moderately differentiated tumors, and 52.7% in patients with poorly differentiated tumors (P < .001). Survival was better for patients who received surgery alone (median survival, 100.1 months [n = 413]) than for those who received radiotherapy alone (median survival, 16 months [n = 16]) or adjuvant radiotherapy (median survival, 64.2 months [n = 80]) (P < .001). The latter group was more likely to have poorly differentiated, large, locally invasive tumors. CONCLUSIONS Leiomyosarcoma typically presents in older patients; it is often poorly differentiated; and improved survival is associated with surgical treatment.