Timothy W.I. Clark

The FAIR Guiding Principles for scientific data management and stewardship

There is an urgent need to improve the infrastructure supporting the reuse of scholarly data. A diverse set of stakeholders—representing academia, industry, funding agencies, and scholarly publishers—have come together to design and jointly endorse a concise and measureable set of principles that we refer to as the FAIR Data Principles. The intent is that these may act as a guideline for those wishing to enhance the reusability of their data holdings. Distinct from peer initiatives that focus on the human scholar, the FAIR Principles put specific emphasis on enhancing the ability of machines to automatically find and use the data, in addition to supporting its reuse by individuals. This Comment is the first formal publication of the FAIR Principles, and includes the rationale behind them, and some exemplar implementations in the community.

Renal angiomyolipoma: Long-term results after arterial embolization

PURPOSE Selective arterial embolization of renal angiomyolipomas (AMLs) was performed to prevent hemorrhage in patients with AMLs larger than 4 cm. This study was conducted to evaluate the long-term efficacy of AML embolization. MATERIALS AND METHODS Nineteen patients underwent embolization for 30 renal AMLs between July 1991 and June 2002. Of these, 10 patients had tuberous sclerosis (TS) with multiple AMLs and nine patients had a solitary sporadic AML. Embolization was performed with use of ethanol mixed with iodized oil (Ethiodol) in 29 tumors; coils were used in addition to the ethanol/Ethiodol mixture in one case. All tumors were completely embolized according to angiographic criteria including vascular stasis and absence of arterial feeders. The efficacy of embolization was determined over a mean follow-up period of 51.5 months (range, 6-132 months). Recurrence was defined as an increase in tumor size of greater than 2 cm on follow-up imaging and/or recurrent symptoms that required repeat embolization. An institutional review board exemption was obtained to perform this retrospective study. RESULTS Embolization of the renal AMLs was technically successful in all 19 patients and for all 30 lesions. AML recurrence was noted in 31.6% of patients (n = 19) and for 30% of lesions overall (n = 9). Six of 10 patients in the TS group had AML recurrences. No recurrences occurred in the patients with sporadic AML. In the TS group of 10 patients, there was a total of 21 AMLs and the overall tumor recurrence rate was 42.9% (nine of 21). Six lesions in four patients had to be reembolized because of recurrent symptoms, including one hemorrhage, and three lesions in two patients required repeat embolization because of a greater than 2 cm increase in size. The median time interval from embolization to recurrence was 78.7 months (range, 13-132 months). Statistical testing with use of the Fisher exact test demonstrated that patients with TS were significantly more likely to develop recurrence than those without TS (P = .01). CONCLUSIONS Transarterial embolization is effective in preventing hemorrhage in patients with renal AMLs. However, long-term follow-up revealed a high AML recurrence rate in patients with TS. Lifelong surveillance for recurrence after AML embolization is essential in patients with TS.

Risk Factors for Liver Abscess Formation after Hepatic Chemoembolization

PURPOSE To assess the frequency and risk factors for liver abscess after hepatic chemoembolization. MATERIALS AND METHODS The authors performed retrospective analysis of 397 chemoembolization procedures in 157 patients. All patients received prophylactic intravenous antibiotics before the procedure and 5 days of oral antibiotics after the procedure. The association between abscess formation and risk factors was determined with use of chi(2) analysis and the Fisher exact test and expressed as an odds ratio. RESULTS Liver abscess occurred in seven of 157 patients (4.5%) after eight of 397 procedures (2.0%) at a mean of 19 d +/- 7 after chemoembolization. No patients had neutropenia. Organisms isolated reflected intestinal flora. Six patients required percutaneous drainage for 35 d +/- 29. The seventh patient required drainage for the remainder of life as a result of a nonhealing biliary fistula. Three of 24 patients with neuroendocrine tumors had abscesses (12.5%; odds ratio, 4.6; 95% CI, 0.96-22.1; P =.07), as did three of 14 patients with gastrointestinal sarcomas (21%; odds ratio, 9.5; 95% CI, 1.9-47.8; P =.016), and one of two with pancreatic adenocarcinoma. Six of the seven patients with abscesses underwent a Whipple procedure before chemoembolization. Only one patient with a history of a Whipple procedure did not develop an hepatic abscess. In the absence of a bilioenteric anastomosis, abscess occurred in only one of 150 patients (0.7%), or one of 383 procedures (0.3%). The odds ratio for liver abscess among patients with a bilioenteric anastomosis was 894 (95% CI, 50-16,000; P <.0001). CONCLUSION Earlier bilioenteric anastomosis is the major determinant of liver abscess formation after hepatic chemoembolization. The prophylaxis regimen used failed to prevent abscess formation in patients with earlier bilioenteric anastomosis.

Effects of Gender on Nigral Gene Expression and Parkinson Disease

To identify gene expression patterns in human dopamine (DA) neurons in the substantia nigra pars compacta (SNc) of male and female control and Parkinson disease (PD) patients, we harvested DA neurons from frozen SNc from 16 subjects (4 male PDs, 4 female PDs, 4 male and 4 female controls) using Laser Capture microdissection and microarrays. We assessed for enrichment of functional categories with a hypergeometric distribution. The data were validated with QPCR. We observed that gender has a pervasive effect on gene expression in DA neurons. Genes upregulated in females relative to males are mainly involved in signal transduction and neuronal maturation, while in males some of the upregulated genes (alpha-synuclein and PINK1) were previously implicated in the pathogenesis of PD. In females with PD we found alterations in genes with protein kinase activity, genes involved in proteolysis and WNT signaling pathway, while in males with PD there were alterations in protein-binding proteins and copper-binding proteins. Our data reveal broad gender-based differences in gene expression in human dopaminergic neurons of SNc that may underlie the predisposition of males to PD. Moreover, we show that gender influences the response to PD, suggesting that the nature of the disease and the response to treatment may be gender-dependent.

Assessment of Tumor Necrosis of Hepatocellular Carcinoma After Chemoembolization: Diffusion-Weighted and Contrast-Enhanced MRI With Histopathologic Correlation of the Explanted Liver

OBJECTIVE The purpose of this study was to compare, with histopathologic examination of the liver explant as the reference standard, diffusion-weighted MRI with contrast-enhanced subtraction MRI in the assessment of necrosis of hepatocellular carcinoma (HCC) after trans arterial chemoembolization (TACE). MATERIALS AND METHODS The cases of 21 patients with HCC who underwent MRI after TACE were evaluated. Two independent observers calculated the apparent diffusion coefficient (ADC) of HCC and measured percentage tumor necrosis on subtraction images. The ADCs of necrotic and viable tumor tissues were compared. ADC and percentage necrosis on subtraction images were correlated with percentage necrosis found at pathologic examination. Receiver operating characteristics analysis was performed on the diagnosis of complete tumor necrosis. RESULTS Twenty-eight HCCs (mean diameter, 2.3 cm) were evaluated. There were significant differences between the ADC of viable tissue and that of necrotic tumor tissue (1.33 +/- 0.41 vs 2.04 +/- 0.38 x 10(-3) mm(2)/s, p < 0.0001). There was significant moderate correlation between ADC and the pathologic finding of percentage necrosis (r = 0.64, p < 0.001) and significant strong correlation between subtraction image and pathologic percentage necrosis (r = 0.89-0.91, depending on the phase; p < 0.001). In the diagnosis of complete tumor necrosis, ADC had an area under the curve, sensitivity, and specificity of 0.85, 75%, and 87.5% compared with 0.82-0.89, 100%, and 58.3-79.1% for subtraction imaging (p > 0.5 between ADC and subtraction imaging). CONCLUSION Compared with diffusion-weighted imaging, contrast-enhanced MRI with subtraction technique had more significant correlation with the histopathologic findings in the evaluation of necrosis of HCC after TACE. There was no difference, however, between the two methods in diagnosis of complete tumor necrosis.

Outcome and Prognostic Factors of Restenosis after Percutaneous Treatment of Native Hemodialysis Fistulas

PURPOSE To assess patency after percutaneous treatment of dysfunctional and thrombosed native arteriovenous fistulas and to examine predictors of patency after intervention. MATERIALS AND METHODS A cohort of 65 consecutive patients with dysfunctional (n = 53) or occluded (n = 12) native fistulas who underwent 96 percutaneous interventions over an 18-month period was retrospectively analyzed. Fistula locations were radiocephalic (n = 37), brachiocephalic (n = 10), or brachiobasilic (n = 18). Primary interventions consisted of angioplasty (n = 50), stent placement (n = 3), or percutaneous thrombolysis/thrombectomy (n = 12). Additional interventions during follow-up consisted of angioplasty (n = 22), stent placement (n = 6), or percutaneous thrombolysis/thrombectomy (n = 3). Duration of fistula function was assessed clinically and examined as a function of anatomic and clinical variables with use of Cox hazards models and the Kaplan-Meier method. RESULTS Clinical success with resumption of at least one session of normal dialysis occurred in 94% (90 of 96) of interventions. The 30-day morbidity rate was 2.1%; no procedure-related deaths occurred. Primary, assisted primary, and secondary patency rates (+/- SE) of dysfunctional fistulas after intervention at 12 months were 26% +/- 11%, 80% +/- 6%, and 82% +/- 6%. Occluded fistulas after intervention had 3-month primary, assisted primary, and secondary patency rates of 60% +/- 15%, 60% +/- 15%, and 80% +/- 13%. Lesions 2.0 cm or more in length were five times more likely to have loss of patency than lesions smaller than 2.0 cm. The presence of at least one comorbid factor--diabetes, coronary artery disease, or peripheral vascular disease--was associated with nearly twice the risk of patency loss after any intervention. CONCLUSION Despite modest primary patency rates in our experience, high assisted and secondary patency rates can be achieved with percutaneous intervention in native arteriovenous fistulas. These findings emphasize the need for close surveillance of native fistulas and a low threshold for diagnostic fistulography after initial intervention. The most detrimental determinant of outcome was lesion length > or =2 cm.

Huntingtin modulates transcription, occupies gene promoters in vivo and binds directly to DNA in a polyglutamine-dependent manner

Transcriptional dysregulation is a central pathogenic mechanism in Huntingtons disease, a fatal neurodegenerative disorder associated with polyglutamine (polyQ) expansion in the huntingtin (Htt) protein. In this study, we show that mutant Htt alters the normal expression of specific mRNA species at least partly by disrupting the binding activities of many transcription factors which govern the expression of the dysregulated mRNA species. Chromatin immunoprecipitation (ChIP) demonstrates Htt occupation of gene promoters in vivo in a polyQ-dependent manner, and furthermore, ChIP-on-chip and ChIP subcloning reveal that wild-type and mutant Htt exhibit differential genomic distributions. Exon 1 Htt binds DNA directly in the absence of other proteins and alters DNA conformation. PolyQ expansion increases Htt–DNA interactions, with binding to recognition elements of transcription factors whose function is altered in HD. Together, these findings suggest mutant Htt modulates gene expression through abnormal interactions with genomic DNA, altering DNA conformation and transcription factor binding.

Predictors of Long-term Patency after Femoropopliteal Angioplasty: Results from the STAR Registry

PURPOSE To identify variables predictive of long-term patency after femoropopliteal angioplasty. MATERIALS AND METHODS The primary patency of 219 limbs in 205 patients from a multicenter registry who underwent femoropopliteal angioplasty between January 1, 1992, and December 31, 1994, was prospectively monitored with a combination of angiography, noninvasive hemodynamic testing, and clinical outcome. Patient demographic, angiographic, and hemodynamic variables were examined alone and in combination to determine effect on long-term primary patency. Each limb was graded as Category 1-4 according to the American Heart Association (AHA) criteria for arterial lesions, and differences in outcome for each category were examined. Primary patency and intergroup analysis were determined with use of the Kaplan-Meier method and log-rank test, respectively. Cox proportional hazards models were used to calculate relative risks for predictive variables. RESULTS Primary patency rates for all limbs (on an intent-to-treat basis) at 12, 24, and 36 months were 87% +/- 3%, 80% +/- 3%, and 69% +/- 5%, respectively. Primary patency at 48 and 60 months was 55% +/- 7%. Poor tibial runoff (single tibial vessel with 50%-99% stenosis or occlusion) was most predictive of occlusion (relative risk 8.5, P <.0001). The presence of diabetes or renal failure was associated with lower long-term patency (relative risk 5.5 and 4.0, P <.0001 and.0002, respectively). Long-term patency was higher with AHA Category 1 lesions (P =.006), and no significant difference in patency was observed between Category 2 and 3 lesions (P =.65). A multivariate Cox proportional hazards model showed only the stratified runoff score and the presence of diabetes to be significant determinants of long-term patency. CONCLUSION Poor tibial runoff is most predictive of lower long-term patency rates. Diabetes is also independently associated with lower long-term patency rates. The criteria that distinguish Category 2 and 3 lesions do not predict differences in long-term patency, nor do they serve to identify lesions best treated with surgical bypass. This suggests that indications for femoral angioplasty can be extended to include longer and more complex Category 3 lesions.

Experience with the recovery filter as a retrievable inferior vena cava filter.

PURPOSE This study evaluates clinical experience with the Recovery filter as a retrievable inferior vena cava (IVC) filter. MATERIALS AND METHODS One hundred seven Recovery filters were placed in 106 patients with an initial clinical indication for temporary caval filtration. Patients were followed up to assess filter efficacy, complications, eventual need for filter removal, time to retrieval, and ability to remove the filter. RESULTS The patient cohort consisted of 62 men and 44 women with a mean age of 48 years (range, 18-90 y). Mean implantation time was 165 days. Indications for filter placement in patients with deep vein thrombosis (DVT) and/or pulmonary embolism (PE) included contraindication to anticoagulation (n = 33), complications of anticoagulation (n = 8), poor cardiopulmonary reserve (n = 6), large clot burden (n = 3), and PE while receiving anticoagulation (n = 1). Indications for filter placement in patients without proven PE or DVT included immobility after trauma (n = 35); recent intracranial hemorrhage, neurosurgery, or brain tumor (n = 18); and other surgical or invasive procedure (n = 3). Three patients (2.8%) had symptomatic PE after placement of the Recovery filter. No caval thromboses were detected. No symptomatic filter migrations occurred. Recovery filter removal was attempted in 15 of 106 patients (14%) at a mean of 150 days after placement. The Recovery filter was successfully retrieved in 14 of 15 patients (93%); one removal was unsuccessful at 210 days after placement. Ninety-two filters (87%) currently remain in place. CONCLUSIONS Although all the filters were placed with the intention of being removed, a large percentage of filters were not retrieved. The Recovery filter was safe and effective in preventing PE when used as a retrievable IVC filter.

The SWAN biomedical discourse ontology

Developing cures for highly complex diseases, such as neurodegenerative disorders, requires extensive interdisciplinary collaboration and exchange of biomedical information in context. Our ability to exchange such information across sub-specialties today is limited by the current scientific knowledge ecosystems inability to properly contextualize and integrate data and discourse in machine-interpretable form. This inherently limits the productivity of research and the progress toward cures for devastating diseases such as Alzheimers and Parkinsons. SWAN (Semantic Web Applications in Neuromedicine) is an interdisciplinary project to develop a practical, common, semantically structured, framework for biomedical discourse initially applied, but not limited, to significant problems in Alzheimer Disease (AD) research. The SWAN ontology has been developed in the context of building a series of applications for biomedical researchers, as well as in extensive discussions and collaborations with the larger bio-ontologies community. In this paper, we present and discuss the SWAN ontology of biomedical discourse. We ground its development theoretically, present its design approach, explain its main classes and their application, and show its relationship to other ongoing activities in biomedicine and bio-ontologies.