Combating Ebola with Repurposed Therapeutics Using the CANDO Platform

Ebola virus disease (EVD) is extremely virulent with an estimated mortality rate of up to 90%. However, the state-of-the-art treatment for EVD is limited to quarantine and supportive care. The 2014 Ebola epidemic in West Africa, the largest in history, is believed to have caused more than 11,000 fatalities. The countries worst affected are also among the poorest in the world. Given the complexities, time, and resources required for a novel drug development, finding efficient drug discovery pathways is going to be crucial in the fight against future outbreaks. We have developed a Computational Analysis of Novel Drug Opportunities (CANDO) platform based on the hypothesis that drugs function by interacting with multiple protein targets to create a molecular interaction signature that can be exploited for rapid therapeutic repurposing and discovery. We used the CANDO platform to identify and rank FDA-approved drug candidates that bind and inhibit all proteins encoded by the genomes of five different Ebola virus strains. Top ranking drug candidates for EVD treatment generated by CANDO were compared to in vitro screening studies against Ebola virus-like particles (VLPs) by Kouznetsova et al. and genetically engineered Ebola virus and cell viability studies by Johansen et al. to identify drug overlaps between the in virtuale and in vitro studies as putative treatments for future EVD outbreaks. Our results indicate that integrating computational docking predictions on a proteomic scale with results from in vitro screening studies may be used to select and prioritize compounds for further in vivo and clinical testing. This approach will significantly reduce the lead time, risk, cost, and resources required to determine efficacious therapies against future EVD outbreaks

Construção de ontologia na prática: um estudo de caso aplicado ao domínio obstétrico

O volume de informação e a variedade de fontes de informação gera desafios para a integração informacional. A necessidade de integração de informação entre sistemas de informação distintos alavancou pesquisas para identificar alternativas capazes de proporcionar interoperabilidade semântica entre sistemas, ou seja, a especificação da informação sem gerar ambiguidades. Como contribuição da Ciência da Informação, as ontologias servem como alternativa de padronização semântica das informações. Entretanto, o processo de construção de ontologias ainda gera muita dúvida entre pesquisadores. Muitos autores descrevem metodologias para a construção de ontologias, mas observa-se uma lacuna entre os métodos descritos e a sua aplicação na prática. Busca-se demonstrar na prática a construção de uma ontologia que adotou duas consolidadas metodologias: o realismo ontológico e a metodologia NeOn. Em relação aos métodos e procedimentos técnicos realizados, esta pesquisa é um estudo de caso que investiga a prática da construção de uma ontologia biomédica no domínio obstétrico, com o objetivo de descrever e explicar o processo de construção da ontologia praticado. Espera-se contribuir com o avanço da pesquisa em construção de ontologias no campo da Ciência da Informação, dada sua aplicação na solução problemas de organização e recuperação de informações em ambientes informacionais de diversos campos científicos

Physicians' Attitudes Toward Complementary and Alternative Medicine and Their Knowledge of Specific Therapies: A Survey at an Academic Medical Center

The purpose of this study was to evaluate the attitudes of physicians at an academic medical center toward complementary and alternative medicine (CAM) therapies and the physicians' knowledge base regarding common CAM therapies. A link to a Web-based survey was e-mailed to 660 internists at Mayo Clinic in Rochester, MN, USA. Physicians were asked about their attitudes toward CAM in general and their knowledge regarding specific CAM therapies. The level of evidence a physician would require before incorporating such therapies into clinical care was also assessed. Of the 233 physicians responding to the survey, 76% had never referred a patient to a CAM practitioner. However, 44% stated that they would refer a patient if a CAM practitioner were available at their institution. Fifty-seven percent of physicians thought that incorporating CAM therapies would have a positive effect on patient satisfaction, and 48% believed that offering CAM would attract more patients. Most physicians agreed that some CAM therapies hold promise for the treatment of symptoms or diseases, but most of them were not comfortable in counseling their patients about most CAM treatments. Prospective, randomized controlled trials were considered the level of evidence required for most physicians to consider incorporating a CAM therapy into their practice. The results of this survey provide insight into the attitudes of physicians toward CAM at an academic medical center. This study highlights the need for educational interventions and the importance of providing physicians ready access to evidence-based information regarding CAM

Bilateral Mastectomy versus Breast-Conserving Surgery for Early-Stage Breast Cancer: The Role of Breast Reconstruction

BACKGROUND: Although breast-conserving surgery is oncologically safe for women with early-stage breast cancer, mastectomy rates are increasing. The objective of this study was to examine the role of breast reconstruction in the surgical management of unilateral early-stage breast cancer. METHODS: A retrospective cohort study of women diagnosed with unilateral early-stage breast cancer (1998 to 2011) identified in the National Cancer Data Base was conducted. Rates of breast-conserving surgery, unilateral and bilateral mastectomy with contralateral prophylactic procedures (per 1000 early-stage breast cancer cases) were measured in relation to breast reconstruction. The association between breast reconstruction and surgical treatment was evaluated using a multinomial logistic regression, controlling for patient and disease characteristics. RESULTS: A total of 1,856,702 patients were included. Mastectomy rates decreased from 459 to 360 per 1000 from 1998 to 2005 (p < 0.01), increasing to 403 per 1000 in 2011 (p < 0.01). The mastectomy rates rise after 2005 reflects a 14 percent annual increase in contralateral prophylactic mastectomies (p < 0.01), as unilateral mastectomy rates did not change significantly. Each percentage point of increase in reconstruction rates was associated with a 7 percent increase in the probability of contralateral prophylactic mastectomies, with the greatest variation explained by young age(32 percent), breast reconstruction (29 percent), and stage 0 (5 percent). CONCLUSIONS: Since 2005, an increasing proportion of early-stage breast cancer patients have chosen mastectomy instead of breast-conserving surgery. This trend reflects a shift toward bilateral mastectomy with contralateral prophylactic procedures that may be facilitated by breast reconstruction availability

Original Article Dietary Soy Supplement on Fibromyalgia Symptoms: A Randomized, Double-Blind, Placebo-Controlled, Early Phase Trial

Most patients with fibromyalgia use complementary and alternative medicine (CAM). Properly designed controlled trials are necessary to assess the effectiveness of these practices. This study was a randomized, double-blind, placebo-controlled, early phase trial. Fifty patients seen at a fibromyalgia outpatient treatment program were randomly assigned to a daily soy or placebo (casein) shake. Outcome measures were scores of the Fibromyalgia Impact Questionnaire (FIQ) and the Center for Epidemiologic Studies Depression Scale (CES-D) at baseline and after 6 weeks of intervention. Analysis was with standard statistics based on the null hypothesis, and separation test for early phase CAM comparative trials. Twenty-eight patients completed the study. Use of standard statistics with intent-to-treat analysis showed that total FIQ scores decreased by 14% in the soy group (P = .02) and by 18% in the placebo group (P &lt; .001). The difference in change in scores between the groups was not significant (P = .16). With the same analysis, CES-D scores decreased in the soy group by 16% (P = .004) and in the placebo group by 15% (P = .05). The change in scores was similar in the groups (P = .83). Results of statistical analysis using the separation test and intent-to-treat analysis revealed no benefit of soy compared with placebo. Shakes that contain soy and shakes that contain casein, when combined with a multidisciplinary fibromyalgia treatment program, provide a decrease in fibromyalgia symptoms. Separation between the effects of soy and casein (control) shakes did not favor the intervention. Therefore, large-sample studies using soy for patients with fibromyalgia are probably not indicated

Characteristics of the National Applicant Pool for Clinical Informatics Fellowships (2016-2017)

We conducted a national study to assess the numbers and diversity of applicants for 2016 and 2017 clinical informatics fellowship positions. In each year, we collected data on the number of applications that programs received from candidates who were ultimately successful vs. unsuccessful. In 2017, we also conducted an anonymous applicant survey. Successful candidates applied to an average of 4.2 and 5.5 programs for 2016 and 2017, respectively. In the survey, unsuccessful candidates reported applying to fewer programs. Assuming unsuccessful candidates submitted between 2-5 applications each, the total applicant pool numbered 42-69 for 2016 (competing for 24 positions) and 52-85 for 2017 (competing for 30 positions). Among survey respondents (n=33), 24% were female, 1 was black and none were Hispanic. We conclude that greater efforts are needed to enhance interest in clinical informatics among medical students and residents, particularly among women and members of underrepresented minority groups

Automation of a problem list using natural language processing

BACKGROUND: The medical problem list is an important part of the electronic medical record in development in our institution. To serve the functions it is designed for, the problem list has to be as accurate and timely as possible. However, the current problem list is usually incomplete and inaccurate, and is often totally unused. To alleviate this issue, we are building an environment where the problem list can be easily and effectively maintained. METHODS: For this project, 80 medical problems were selected for their frequency of use in our future clinical field of evaluation (cardiovascular). We have developed an Automated Problem List system composed of two main components: a background and a foreground application. The background application uses Natural Language Processing (NLP) to harvest potential problem list entries from the list of 80 targeted problems detected in the multiple free-text electronic documents available in our electronic medical record. These proposed medical problems drive the foreground application designed for management of the problem list. Within this application, the extracted problems are proposed to the physicians for addition to the official problem list. RESULTS: The set of 80 targeted medical problems selected for this project covered about 5% of all possible diagnoses coded in ICD-9-CM in our study population (cardiovascular adult inpatients), but about 64% of all instances of these coded diagnoses. The system contains algorithms to detect first document sections, then sentences within these sections, and finally potential problems within the sentences. The initial evaluation of the section and sentence detection algorithms demonstrated a sensitivity and positive predictive value of 100% when detecting sections, and a sensitivity of 89% and a positive predictive value of 94% when detecting sentences. CONCLUSION: The global aim of our project is to automate the process of creating and maintaining a problem list for hospitalized patients and thereby help to guarantee the timeliness, accuracy and completeness of this information

Localization of type 1 diabetes susceptibility to the MHC class I genes HLA-B and HLA-A

The major histocompatibility complex (MHC) on chromosome 6 is associated with susceptibility to more common diseases than any other region of the human genome, including almost all disorders classified as autoimmune. In type 1 diabetes the major genetic susceptibility determinants have been mapped to the MHC class II genes HLA-DQB1 and HLA-DRB1 (refs 1-3), but these genes cannot completely explain the association between type 1 diabetes and the MHC region. Owing to the region's extreme gene density, the multiplicity of disease-associated alleles, strong associations between alleles, limited genotyping capability, and inadequate statistical approaches and sample sizes, which, and how many, loci within the MHC determine susceptibility remains unclear. Here, in several large type 1 diabetes data sets, we analyse a combined total of 1,729 polymorphisms, and apply statistical methods - recursive partitioning and regression - to pinpoint disease susceptibility to the MHC class I genes HLA-B and HLA-A (risk ratios >1.5; Pcombined = 2.01 × 10-19 and 2.35 × 10-13, respectively) in addition to the established associations of the MHC class II genes. Other loci with smaller and/or rarer effects might also be involved, but to find these, future searches must take into account both the HLA class II and class I genes and use even larger samples. Taken together with previous studies, we conclude that MHC-class-I-mediated events, principally involving HLA-B*39, contribute to the aetiology of type 1 diabetes. ©2007 Nature Publishing Group