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"Cystic Fibrosis"

These pubmed results were generated on 2016/06/02

PubMed comprises more than 24 million citations for biomedical literature from MEDLINE, life science journals, and online books. Citations may include links to full-text content from PubMed Central and publisher web sites.

11 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results:

"Systems Biology"[Title/Abstract] AND ("2005/01/01"[PDAT] : "3000"[PDAT])

These pubmed results were generated on 2016/06/02

PubMed comprises more than 24 million citations for biomedical literature from MEDLINE, life science journals, and online books. Citations may include links to full-text content from PubMed Central and publisher web sites.

The BioHub Knowledge Base: Ontology and Repository for Sustainable Biosourcing.

J Biomed Semantics. 2016;7(1):30

Authors: Read WJ, Demetriou G, Nenadic G, Ruddock N, Stevens R, Winter J

Abstract
BACKGROUND: The motivation for the BioHub project is to create an Integrated Knowledge Management System (IKMS) that will enable chemists to source ingredients from bio-renewables, rather than from non-sustainable sources such as fossil oil and its derivatives.
METHOD: The BioHubKB is the data repository of the IKMS; it employs Semantic Web technologies, especially OWL, to host data about chemical transformations, bio-renewable feedstocks, co-product streams and their chemical components. Access to this knowledge base is provided to other modules within the IKMS through a set of RESTful web services, driven by SPARQL queries to a Sesame back-end. The BioHubKB re-uses several bio-ontologies and bespoke extensions, primarily for chemical feedstocks and products, to form its knowledge organisation schema.
RESULTS: Parts of plants form feedstocks, while various processes generate co-product streams that contain certain chemicals. Both chemicals and transformations are associated with certain qualities, which the BioHubKB also attempts to capture. Of immediate commercial and industrial importance is to estimate the cost of particular sets of chemical transformations (leading to candidate surfactants) performed in sequence, and these costs too are captured. Data are sourced from companies' internal knowledge and document stores, and from the publicly available literature. Both text analytics and manual curation play their part in populating the ontology. We describe the prototype IKMS, the BioHubKB and the services that it supports for the IKMS.
AVAILABILITY: The BioHubKB can be found via http://biohub.cs.manchester.ac.uk/ontology/biohub-kb.owl .

PMID: 27246819 [PubMed - in process]

ODMedit: uniform semantic annotation for data integration in medicine based on a public metadata repository.

BMC Med Res Methodol. 2016;16(1):65

Authors: Dugas M, Meidt A, Neuhaus P, Storck M, Varghese J

Abstract
BACKGROUND: The volume and complexity of patient data - especially in personalised medicine - is steadily increasing, both regarding clinical data and genomic profiles: Typically more than 1,000 items (e.g., laboratory values, vital signs, diagnostic tests etc.) are collected per patient in clinical trials. In oncology hundreds of mutations can potentially be detected for each patient by genomic profiling. Therefore data integration from multiple sources constitutes a key challenge for medical research and healthcare.
METHODS: Semantic annotation of data elements can facilitate to identify matching data elements in different sources and thereby supports data integration. Millions of different annotations are required due to the semantic richness of patient data. These annotations should be uniform, i.e., two matching data elements shall contain the same annotations. However, large terminologies like SNOMED CT or UMLS don't provide uniform coding. It is proposed to develop semantic annotations of medical data elements based on a large-scale public metadata repository. To achieve uniform codes, semantic annotations shall be re-used if a matching data element is available in the metadata repository.
RESULTS: A web-based tool called ODMedit ( https://odmeditor.uni-muenster.de/ ) was developed to create data models with uniform semantic annotations. It contains ~800,000 terms with semantic annotations which were derived from ~5,800 models from the portal of medical data models (MDM). The tool was successfully applied to manually annotate 22 forms with 292 data items from CDISC and to update 1,495 data models of the MDM portal.
CONCLUSION: Uniform manual semantic annotation of data models is feasible in principle, but requires a large-scale collaborative effort due to the semantic richness of patient data. A web-based tool for these annotations is available, which is linked to a public metadata repository.

PMID: 27245222 [PubMed - in process]

Acceptability of a mobile health exercise-based cardiac rehabilitation intervention: a randomized trial.

J Cardiopulm Rehabil Prev. 2015 Sep-Oct;35(5):312-9

Authors: Pfaeffli Dale L, Whittaker R, Dixon R, Stewart R, Jiang Y, Carter K, Maddison R

Abstract
BACKGROUND: Mobile technologies (mHealth) have recently been used to deliver behavior change interventions; however, few have investigated the application of mHealth for treatment of ischemic heart disease (IHD). The Heart Exercise And Remote Technologies trial examined the effectiveness of an mHealth intervention to increase exercise behavior in adults with IHD. As a part of this trial, a process evaluation was conducted.
METHODS: One hundred seventy-one adults with IHD were randomized to receive a 6-month mHealth intervention (n = 85) plus usual care or usual care alone (n = 86). The intervention delivered a theory-based, automated package of exercise prescription and behavior change text messages and a supporting Web site. Three sources of data were triangulated to assess intervention participant perceptions: (1) Web site usage statistics; (2) feedback surveys; and (3) semistructured exit interviews. Descriptive information from survey and Web data were merged with qualitative data and analyzed using a semantic thematic approach.
RESULTS: At 24 weeks, all intervention participants provided Web usage statistics, 75 completed the feedback survey, and 17 were interviewed. Participants reported reading the text messages (70/75; 93%) and liked the content (55/75; 73%). The program motivated participants to exercise. Several suggestions to improve the program included further tailoring of the content (7/75; 7%) and increased personal contact (10/75; 13%).
CONCLUSIONS: Adults with IHD were able to use an mHealth program and reported that text messaging is a good way to deliver exercise information. While mHealth is designed to be automated, programs might be improved if content and delivery were tailored to individual needs.

PMID: 26181037 [PubMed - indexed for MEDLINE]

An ontology for Autism Spectrum Disorder (ASD) to infer ASD phenotypes from Autism Diagnostic Interview-Revised data.

J Biomed Inform. 2015 Aug;56:333-47

Authors: Mugzach O, Peleg M, Bagley SC, Guter SJ, Cook EH, Altman RB

Abstract
OBJECTIVE: Our goal is to create an ontology that will allow data integration and reasoning with subject data to classify subjects, and based on this classification, to infer new knowledge on Autism Spectrum Disorder (ASD) and related neurodevelopmental disorders (NDD). We take a first step toward this goal by extending an existing autism ontology to allow automatic inference of ASD phenotypes and Diagnostic & Statistical Manual of Mental Disorders (DSM) criteria based on subjects' Autism Diagnostic Interview-Revised (ADI-R) assessment data.
MATERIALS AND METHODS: Knowledge regarding diagnostic instruments, ASD phenotypes and risk factors was added to augment an existing autism ontology via Ontology Web Language class definitions and semantic web rules. We developed a custom Protégé plugin for enumerating combinatorial OWL axioms to support the many-to-many relations of ADI-R items to diagnostic categories in the DSM. We utilized a reasoner to infer whether 2642 subjects, whose data was obtained from the Simons Foundation Autism Research Initiative, meet DSM-IV-TR (DSM-IV) and DSM-5 diagnostic criteria based on their ADI-R data.
RESULTS: We extended the ontology by adding 443 classes and 632 rules that represent phenotypes, along with their synonyms, environmental risk factors, and frequency of comorbidities. Applying the rules on the data set showed that the method produced accurate results: the true positive and true negative rates for inferring autistic disorder diagnosis according to DSM-IV criteria were 1 and 0.065, respectively; the true positive rate for inferring ASD based on DSM-5 criteria was 0.94.
DISCUSSION: The ontology allows automatic inference of subjects' disease phenotypes and diagnosis with high accuracy.
CONCLUSION: The ontology may benefit future studies by serving as a knowledge base for ASD. In addition, by adding knowledge of related NDDs, commonalities and differences in manifestations and risk factors could be automatically inferred, contributing to the understanding of ASD pathophysiology.

PMID: 26151311 [PubMed - indexed for MEDLINE]

Comparing image search behaviour in the ARRS GoldMiner search engine and a clinical PACS/RIS.

J Biomed Inform. 2015 Aug;56:57-64

Authors: De-Arteaga M, Eggel I, Do B, Rubin D, Kahn CE, Müller H

Abstract
Information search has changed the way we manage knowledge and the ubiquity of information access has made search a frequent activity, whether via Internet search engines or increasingly via mobile devices. Medical information search is in this respect no different and much research has been devoted to analyzing the way in which physicians aim to access information. Medical image search is a much smaller domain but has gained much attention as it has different characteristics than search for text documents. While web search log files have been analysed many times to better understand user behaviour, the log files of hospital internal systems for search in a PACS/RIS (Picture Archival and Communication System, Radiology Information System) have rarely been analysed. Such a comparison between a hospital PACS/RIS search and a web system for searching images of the biomedical literature is the goal of this paper. Objectives are to identify similarities and differences in search behaviour of the two systems, which could then be used to optimize existing systems and build new search engines. Log files of the ARRS GoldMiner medical image search engine (freely accessible on the Internet) containing 222,005 queries, and log files of Stanford's internal PACS/RIS search called radTF containing 18,068 queries were analysed. Each query was preprocessed and all query terms were mapped to the RadLex (Radiology Lexicon) terminology, a comprehensive lexicon of radiology terms created and maintained by the Radiological Society of North America, so the semantic content in the queries and the links between terms could be analysed, and synonyms for the same concept could be detected. RadLex was mainly created for the use in radiology reports, to aid structured reporting and the preparation of educational material (Lanlotz, 2006) [1]. In standard medical vocabularies such as MeSH (Medical Subject Headings) and UMLS (Unified Medical Language System) specific terms of radiology are often underrepresented, therefore RadLex was considered to be the best option for this task. The results show a surprising similarity between the usage behaviour in the two systems, but several subtle differences can also be noted. The average number of terms per query is 2.21 for GoldMiner and 2.07 for radTF, the used axes of RadLex (anatomy, pathology, findings, …) have almost the same distribution with clinical findings being the most frequent and the anatomical entity the second; also, combinations of RadLex axes are extremely similar between the two systems. Differences include a longer length of the sessions in radTF than in GoldMiner (3.4 and 1.9 queries per session on average). Several frequent search terms overlap but some strong differences exist in the details. In radTF the term "normal" is frequent, whereas in GoldMiner it is not. This makes intuitive sense, as in the literature normal cases are rarely described whereas in clinical work the comparison with normal cases is often a first step. The general similarity in many points is likely due to the fact that users of the two systems are influenced by their daily behaviour in using standard web search engines and follow this behaviour in their professional search. This means that many results and insights gained from standard web search can likely be transferred to more specialized search systems. Still, specialized log files can be used to find out more on reformulations and detailed strategies of users to find the right content.

PMID: 26002820 [PubMed - indexed for MEDLINE]

Pharmacogenomics, Pharmacokinetics, and Pharmacodynamics in the Era of Targeted Therapies.

Am Soc Clin Oncol Educ Book. 2016;35:e175-e184

Authors: Calvo E, Walko C, Dees EC, Valenzuela B

Abstract
The complex nature of the pharmacologic aspects of cancer therapeutics has become more apparent in the past several years with the arrival of a cascade of target-based agents and the difficult challenge of bringing individualized precision medicine to oncology. Interpatient variability in drug action, singularly in novel agents, is in part caused by pharmacogenomic (PG), pharmacokinetic, and pharmacodynamic (PD) factors, and drug selection and dosing should take this into consideration to optimize the benefit for our patients in terms of antitumor activity and treatment tolerance. In this regard, somatic genetic evaluation of tumors is useful in not only predicting response to initial targeted therapies but also in anticipating and guiding therapy after the development of acquired resistance; therapeutic drug monitoring of novel small molecules and monoclonal antibodies must be incorporated in our day-to-day practice to minimize the negative effect on clinical outcome of interindividual variability on pharmacokinetic processes of these drugs for all patients, but especially for fragile patient populations and those with organ dysfunction or comorbidities. For these populations, incorporating frailty assessment tools into trials of newer agents and validating frailty-based dose adjustment should be an important part of further drug development.

PMID: 27249721 [PubMed - as supplied by publisher]

Evidence for extensive pleiotropy among pharmacogenes.

Pharmacogenomics. 2016 Jun 1;:0

Authors: Oetjens MT, Bush WS, Denny JC, Birdwell K, Kodaman N, Verma A, Dilks HH, Pendergrass SA, Ritchie MD, Crawford DC

Abstract
AIM: We sought to identify potential pleiotropy involving pharmacogenes.
METHODS: We tested 184 functional variants in 34 pharmacogenes for associations using a custom grouping of International Classification and Disease, Ninth Revision billing codes extracted from deidentified electronic health records of 6892 patients.
RESULTS: We replicated several associations including ABCG2 (rs2231142) and gout (p = 1.73 × 10(-7); odds ratio [OR]: 1.73; 95% CI: 1.40-2.12); and SLCO1B1 (rs4149056) and jaundice (p = 2.50 × 10(-4); OR: 1.67; 95% CI: 1.27-2.20).
CONCLUSION: In this systematic screen for phenotypic associations with functional variants, several novel genotype-phenotype combinations also achieved phenome-wide significance, including SLC15A2 rs1143672 and renal osteodystrophy (p = 2.67 × 10(-) (6); OR: 0.61; 95% CI: 0.49-0.75).

PMID: 27249515 [PubMed - as supplied by publisher]

Requirements for comprehensive pharmacogenetic genotyping platforms.

Pharmacogenomics. 2016 Jun 1;:0

Authors: Lauschke VM, Ingelman-Sundberg M

Abstract
Recent research highlighted the large extent of rare variants in pharmacogenes and, on this basis, it was estimated that rare variants account for 30-40% of the functional variability in pharmacogenes. It has been proposed that comprehensive next-generation sequencing (NGS)-based sequencing of pharmacogenes could soon be a cost-effective methodology for clinical routine genotyping. Yet, multiple challenges on technical, interpretative and ethical levels need to be overcome to enable the reasonable dissemination of comprehensive pharmacogenetic genotyping, that includes rare genetic variation, into clinical practice. We argue that current pre-emptive pharmacogenetic testing cannot be based on comprehensive approaches but needs to be restricted to validated variants. Rather, comprehensive strategies should only be used for retrospective analyses of patients exhibiting unanticipated drug responses. Thereby, subsequent to computational analyses and functional validations, emerging variants with confirmed functional relevance can be incorporated into candidate genotyping strategies, thus refining and enhancing future pre-emptive genetic testing.

PMID: 27248710 [PubMed - as supplied by publisher]

Identifying genetic loci affecting antidepressant drug response in depression using drug-gene interaction models.

Pharmacogenomics. 2016 Jun 1;

Authors: Noordam R, Avery CL, Visser LE, Stricker BH

Abstract
Antidepressants are often only moderately successful in decreasing the severity of depressive symptoms. In part, antidepressant treatment response in patients with depression is genetically determined. However, although a large number of studies have been conducted aiming to identify genetic variants associated with antidepressant drug response in depression, only a few variants have been repeatedly identified. Within the present review, we will discuss the methodological challenges and limitations of the studies that have been conducted on this topic to date (e.g., 'treated-only design', statistical power) and we will discuss how specifically drug-gene interaction models can be used to be better able to identify genetic variants associated with antidepressant drug response in depression.

PMID: 27248517 [PubMed - as supplied by publisher]

Pharmacogenomics of platinum-based chemotherapy response in NSCLC: a genotyping study and a pooled analysis.

Oncotarget. 2016 May 29;

Authors: Chen J, Wang Z, Zou T, Cui J, Yin J, Zheng W, Jiang W, Zhou H, Liu Z

Abstract
Published data showed inconsistent results about associations of extensively studied polymorphisms with platinum-based chemotherapy response. Our study aimed to provide reliable conclusions of these associations by detecting genotypes of the SNPs in a larger sample size and summarizing a comprehensive pooled analysis. 13 SNPs in 8 genes were genotyped in 1024 NSCLC patients by SequenomMassARRAY. 39 published studies and our study were included in meta-analysis. Patients with GA or GG genotypes of XRCC1 G1196 had better response than AA genotype carriers (Genotyping study: OR = 0.72, 95%CI: 0.53-0.96, P = 0.028; Meta-analysis: OR = 0.74, 95%CI: 0.62-0.89, P = 0.001). Patients carrying CT or TT genotypes of XRCC1 C580T could be more sensitive to platinum-based chemotherapy compared to patients with CC genotype (OR = 0.54, 95%CI: 0.37-0.80, P = 0.002). CC genotype of XRCC3 C18067T carriers showed more resistance to platinum-based chemotherapy when compared to those with CT or TT genotypes (OR = 0.69, 95%CI: 0.52-0.91, P = 0.009). Our study indicated that XRCC1 G1196A/ C580T and XRCC3 C18067T should be paid attention for personalized platinum-based chemotherapy in NSCLC patients.

PMID: 27248474 [PubMed - as supplied by publisher]

Pharmacogenetics of ribavirin-induced anemia in HCV patients.

Pharmacogenomics. 2016 Jun 1;

Authors: D'Avolio A, Cusato J, De Nicolò A, Allegra S, Di Perri G

Abstract
Dual therapy (pegylated interferon plus ribavirin) was considered the standard of care for hepatitis C virus (HCV) treatment until 2011, when the first-wave direct-acting antivirals were added to this regimen for HCV genotype-1 patients to increase the sustained virological response rate. The second-wave direct-acting antivirals entered the clinical use also in some ribavirin (RBV)- and/or interferon-free combinations. Nevertheless, since some of the new therapeutic regimens also include RBV and its use results still associated with hemolytic anemia, this requires countermeasures to be prevented. These include the identification of several host predictive factors involved in RBV absorption, distribution, metabolism, elimination and many others that might influence this toxic effect. For this reason, we provided an overview of the potential role of pharmacogenomics in predisposing RBV-treated HCV patients to anemia.

PMID: 27248282 [PubMed - as supplied by publisher]

Evaluation of methodology for the analysis of 'time-to-event' data in pharmacogenomic genome-wide association studies.

Pharmacogenomics. 2016 Jun 1;:0

Authors: Syed H, Jorgensen AL, Morris AP

Abstract
AIM: To evaluate the power to detect associations between single nucleotide polymorphisms and time-to-event outcomes across a range of pharmacogenomic study designs while comparing alternative regression approaches.
MATERIALS & METHODS: Simulations were conducted to compare Cox proportional hazards modeling accounting for censoring and logistic regression modeling of a dichotomized outcome at the end of the study.
RESULTS: The Cox proportional hazards model was demonstrated to be more powerful than the logistic regression analysis. The difference in power between the approaches was highly dependent on the rate of censoring.
CONCLUSION: Initial evaluation of single nucleotide polymorphism association signals using computationally efficient software with dichotomized outcomes provides an effective screening tool for some design scenarios, and thus has important implications for the development of analytical protocols in pharmacogenomic studies.

PMID: 27248145 [PubMed - as supplied by publisher]

Pharmacogenomics of long-acting β2-agonists.

Expert Opin Drug Metab Toxicol. 2015;11(11):1733-51

Authors: Blake K, Lima J

Abstract
INTRODUCTION: Long-acting β2-agonists are an effective class of drugs, when combined with inhaled corticosteroids, for reducing symptoms and exacerbations in patients with asthma that is not adequately controlled by inhaled corticosteroids alone. However, because this class of drugs has been associated with severe adverse events, including hospitalization and death in small numbers of patients, efforts to identify a pharmacogenetic profile for patients at risk has been diligently investigated.
AREAS COVERED: The PubMed search engine of the National Library of Medicine was used to identify English-language and non-English language articles published from 1947 to March 2015 pertinent to asthma, pharmacogenomics, and long-acting β2-agonists. Keywords and topics included: asthma, asthma control, long-acting β2-agonists, salmeterol, formoterol, pharmacogenetics, and pharmacogenomics. This strategy was also used for the Cochrane Library Database and CINAHL. Reference types were randomized controlled trials, reviews, and editorials. Additional publications were culled from reference lists. The publications were reviewed by the authors and those most relevant were used to support the topics covered in this review.
EXPERT OPINION: Children, who carry the ADRB2 Arg16Arg genotype, may be at greater risk than adults for severe adverse events. Rare ADRB2 variants appear to provide better clues for identifying the at-risk population of asthmatics.

PMID: 26235677 [PubMed - indexed for MEDLINE]

On the creation of a clinical gold standard corpus in Spanish: Mining adverse drug reactions.

J Biomed Inform. 2015 Aug;56:318-32

Authors: Oronoz M, Gojenola K, Pérez A, de Ilarraza AD, Casillas A

Abstract
The advances achieved in Natural Language Processing make it possible to automatically mine information from electronically created documents. Many Natural Language Processing methods that extract information from texts make use of annotated corpora, but these are scarce in the clinical domain due to legal and ethical issues. In this paper we present the creation of the IxaMed-GS gold standard composed of real electronic health records written in Spanish and manually annotated by experts in pharmacology and pharmacovigilance. The experts mainly annotated entities related to diseases and drugs, but also relationships between entities indicating adverse drug reaction events. To help the experts in the annotation task, we adapted a general corpus linguistic analyzer to the medical domain. The quality of the annotation process in the IxaMed-GS corpus has been assessed by measuring the inter-annotator agreement, which was 90.53% for entities and 82.86% for events. In addition, the corpus has been used for the automatic extraction of adverse drug reaction events using machine learning.

PMID: 26141794 [PubMed - indexed for MEDLINE]

Identifying synonymy between relational phrases using word embeddings.

J Biomed Inform. 2015 Aug;56:94-102

Authors: Nguyen NT, Miwa M, Tsuruoka Y, Tojo S

Abstract
Many text mining applications in the biomedical domain benefit from automatic clustering of relational phrases into synonymous groups, since it alleviates the problem of spurious mismatches caused by the diversity of natural language expressions. Most of the previous work that has addressed this task of synonymy resolution uses similarity metrics between relational phrases based on textual strings or dependency paths, which, for the most part, ignore the context around the relations. To overcome this shortcoming, we employ a word embedding technique to encode relational phrases. We then apply the k-means algorithm on top of the distributional representations to cluster the phrases. Our experimental results show that this approach outperforms state-of-the-art statistical models including latent Dirichlet allocation and Markov logic networks.

PMID: 26004792 [PubMed - indexed for MEDLINE]

Automatic endpoint detection to support the systematic review process.

J Biomed Inform. 2015 Aug;56:42-56

Authors: Blake C, Lucic A

Abstract
Preparing a systematic review can take hundreds of hours to complete, but the process of reconciling different results from multiple studies is the bedrock of evidence-based medicine. We introduce a two-step approach to automatically extract three facets - two entities (the agent and object) and the way in which the entities are compared (the endpoint) - from direct comparative sentences in full-text articles. The system does not require a user to predefine entities in advance and thus can be used in domains where entity recognition is difficult or unavailable. As with a systematic review, the tabular summary produced using the automatically extracted facets shows how experimental results differ between studies. Experiments were conducted using a collection of more than 2million sentences from three journals Diabetes, Carcinogenesis and Endocrinology and two machine learning algorithms, support vector machines (SVM) and a general linear model (GLM). F1 and accuracy measures for the SVM and GLM differed by only 0.01 across all three comparison facets in a randomly selected set of test sentences. The system achieved the best performance of 92% for objects, whereas the accuracy for both agent and endpoints was 73%. F1 scores were higher for objects (0.77) than for endpoints (0.51) or agents (0.47). A situated evaluation of Metformin, a drug to treat diabetes, showed system accuracy of 95%, 83% and 79% for the object, endpoint and agent respectively. The situated evaluation had higher F1 scores of 0.88, 0.64 and 0.62 for object, endpoint, and agent respectively. On average, only 5.31% of the sentences in a full-text article are direct comparisons, but the tabular summaries suggest that these sentences provide a rich source of currently underutilized information that can be used to accelerate the systematic review process and identify gaps where future research should be focused.

PMID: 26003938 [PubMed - indexed for MEDLINE]

Association of a Locus in the CAMTA1 Gene With Survival in Patients With Sporadic Amyotrophic Lateral Sclerosis.

JAMA Neurol. 2016 May 31;

Authors: Fogh I, Lin K, Tiloca C, Rooney J, Gellera C, Diekstra FP, Ratti A, Shatunov A, van Es MA, Proitsi P, Jones A, Sproviero W, Chiò A, McLaughlin RL, Sorarù G, Corrado L, Stahl D, Del Bo R, Cereda C, Castellotti B, Glass JD, Newhouse S, Dobson R, Smith BN, Topp S, van Rheenen W, Meininger V, Melki J, Morrison KE, Shaw PJ, Leigh PN, Andersen PM, Comi GP, Ticozzi N, Mazzini L, D'Alfonso S, Traynor BJ, Van Damme P, Robberecht W, Brown RH, Landers JE, Hardiman O, Lewis CM, van den Berg LH, Shaw CE, Veldink JH, Silani V, Al-Chalabi A, Powell J

Abstract
Importance: Amyotrophic lateral sclerosis (ALS) is a devastating adult-onset neurodegenerative disorder with a poor prognosis and a median survival of 3 years. However, a significant proportion of patients survive more than 10 years from symptom onset.
Objective: To identify gene variants influencing survival in ALS.
Design, Setting, and Participants: This genome-wide association study (GWAS) analyzed survival in data sets from several European countries and the United States that were collected by the Italian Consortium for the Genetics of ALS and the International Consortium on Amyotrophic Lateral Sclerosis Genetics. The study population included 4256 patients with ALS (3125 [73.4%] deceased) with genotype data extended to 7 174 392 variants by imputation analysis. Samples of DNA were collected from January 1, 1993, to December 31, 2009, and analyzed from March 1, 2014, to February 28, 2015.
Main Outcomes and Measures: Cox proportional hazards regression under an additive model with adjustment for age at onset, sex, and the first 4 principal components of ancestry, followed by meta-analysis, were used to analyze data. Survival distributions for the most associated genetic variants were assessed by Kaplan-Meier analysis.
Results: Among the 4256 patients included in the analysis (2589 male [60.8%] and 1667 female [39.2%]; mean [SD] age at onset, 59 [12] years), the following 2 novel loci were significantly associated with ALS survival: at 10q23 (rs139550538; P = 1.87 × 10-9) and in the CAMTA1 gene at 1p36 (rs2412208, P = 3.53 × 10-8). At locus 10q23, the adjusted hazard ratio for patients with the rs139550538 AA or AT genotype was 1.61 (95% CI, 1.38-1.89; P = 1.87 × 10-9), corresponding to an 8-month reduction in survival compared with TT carriers. For rs2412208CAMTA1, the adjusted hazard ratio for patients with the GG or GT genotype was 1.17 (95% CI, 1.11-1.24; P = 3.53 × 10-8), corresponding to a 4-month reduction in survival compared with TT carriers.
Conclusions and Relevance: This GWAS robustly identified 2 loci at genome-wide levels of significance that influence survival in patients with ALS. Because ALS is a rare disease and prevention is not feasible, treatment that modifies survival is the most realistic strategy. Therefore, identification of modifier genes that might influence ALS survival could improve the understanding of the biology of the disease and suggest biological targets for pharmaceutical intervention. In addition, genetic risk scores for survival could be used as an adjunct to clinical trials to account for the genetic contribution to survival.

PMID: 27244217 [PubMed - as supplied by publisher]

How can clinical ethics guide the management of comorbidities in the child with Rett syndrome?

J Paediatr Child Health. 2016 May 31;

Authors: Downs J, Forbes D, Johnson M, Leonard H

Abstract
Rett syndrome is a rare disorder caused by a mutation in the MECP2 gene. Those affected generally have severe functional impairments, and medical comorbidities such as scoliosis and poor growth are common. There is a paucity of information on the natural history of many rare disorders and an even greater deficit of evidence to guide best practice. The population-based and longitudinal Australian Rett Syndrome Database established in 1993 has supported investigations of the natural history of Rett syndrome and effectiveness of treatments. This paper reviews the disorder Rett syndrome and evidence for the management of scoliosis and poor growth within a clinical ethics framework. Compared with conservative management, we have shown that spinal fusion is associated with reduced mortality and better respiratory health. We have also shown that gastrostomy insertion is associated with subsequent weight gain. Family counselling for both procedures necessarily must include family perspectives and careful clinical attention to their needs and wishes. Vignettes describing family decision-making and experiences are presented to illustrate the principals of beneficence and autonomy in determining the best interests of the child and family. A blend of evidence-based practice with a strong clinical ethics framework has capacity to build existing strengths in families and reduce the negative impacts of disability and in so doing, optimise the health and wellbeing of those with Rett syndrome.

PMID: 27243819 [PubMed - as supplied by publisher]