Towards a more positive view of healthcare in Ireland.

Ir J Med Sci. 2018 May 31;:

Authors: Nicholson A

Abstract
Ireland has a population of just over one million children, the highest birth rate in the European Union, significant income inequalities and an increasing non-national population. Our under five mortality figures have shown a steady decline to 3.6 per 1000 and are amongst the best in the world. Examples of high-quality healthcare results include neonatal intensive care outcomes, paediatric cancer survival rates, surgical outcomes in congenital heart disease, improved survival in cystic fibrosis and renal transplantation results. Positivity alone is not enough and I propose a 10-point plan for future healthcare for children and young people. We should first and foremost aim for health not care and prevention plays a key role. Parents and families should play an active role in decisions around their children's health and should be aware of results of treatment. Care should be delivered as close to home as possible and we should strengthen both primary and community care and provide additional support to general practitioners to manage childhood illness closer to home. We need to plan for new morbidities such as type 1 diabetes, obesity, mental health issues and inflammatory bowel disease. General paediatrics is a key enabler of better healthcare for children. We should advocate for a future system focussed on quality, reducing geographical variation and supporting local care, thereby keeping children out of hospital as much as possible.

PMID: 29855859 [PubMed - as supplied by publisher]

Unmet needs in cystic fibrosis: the next steps in improving outcomes.

Expert Rev Respir Med. 2018 Jun 01;:

Authors: West NE, Flume PA

Abstract
INTRODUCTION: Cystic fibrosis (CF) outcomes and survival have improved over the last century primarily due to advancements in antibiotics, nutritional and pulmonary therapies. Reviewed here are the significant unmet needs that exist for individuals with CF. Areas Covered: With the recent development of medications that address the underlying defect in the CF protein, there is hope that there will be continued improvement in CF outcomes. However, there remains a need to prevent or stop progression of CF related complications, as the CF protein is important to several body systems. As end stage lung disease is the primary cause of mortality in CF, a need exists for advancements in pulmonary therapies to reduce time burden, identification of best practices for the treatment of pulmonary exacerbations, further development of anti-infective and anti-inflammatory therapies, and appropriately-timed referral for lung transplantation at end stage lung disease. Extra-pulmonary complications are increasingly recognized and better understanding of such problems as CF related liver disease is needed. Expert Commentary: While CFTR modulators are available for the majority of CF patients, there remains a need for effective therapies to address infection, inflammation, irreversible lung disease, and extrapulmonary complications of CF.

PMID: 29855230 [PubMed - as supplied by publisher]

Airway Inflammatory/Immune Responses in COPD and Cystic Fibrosis.

Mediators Inflamm. 2018;2018:7280747

Authors: De Rose V, Burgel PR, Gaggar A, Greene C

PMID: 29853791 [PubMed - in process]

Nitrogen multiple breath washout test for infants with cystic fibrosis.

Eur Respir J. 2018 May 31;:

Authors: Koucký V, Skalická V, Pohunek P

PMID: 29853492 [PubMed - as supplied by publisher]

The mucin bundles responsible for airway cleaning are retained in cystic fibrosis and by cholinergic stimulation.

Eur Respir J. 2018 May 31;:

Authors: Ermund A, Meiss LN, Dolan B, Bähr A, Klymiuk N, Hansson GC

Abstract
The beneficial effect of anti-cholinergic therapy for chronic obstructive pulmonary diseases like COPD is well-documented although cholinergic stimulation paradoxically inhibits liquid absorption, increases cilia beat frequency, and increases airway surface liquid transport.Using pig tracheobronchial explants, we quantified basal mucus transport as well as after incubation with by the clinically used anti-muscarinic compound ipratropium bromide (Atrovent) and stimulation with acetylcholine.As expected the surface liquid transport was increased by acetylcholine and carbachol. In contrast, the mucus bundles secreted from the submucosal glands normally transported on the cilia were stopped from moving by acetylcholine, an effect inhibited by ipratropium bromide. Interestingly, in pigs lacking a functional CFTR channel, the mucin bundles were almost immobile. As in wild-type pigs the cystic fibrosis (CF) surface liquid transport increased after carbachol stimulation. The stagnant CF mucin bundles were trapped on the tracheal surface attached to the surface goblet cells. Pseudomonas aeruginosa bacteria were moved by the mucus bundles in wild-type, but not CF pigs.Acetylcholine thus uncouples airway surface liquid transport from transport of the surface mucin bundles as the bundles are dynamically inhibited by acetylcholine and the CFTR channel, explaining initiation of CF and COPD and opening novel therapeutic windows.

PMID: 29853489 [PubMed - as supplied by publisher]

Perinatal Lethal Gaucher Disease due to RecNcil Recombinant Mutation in the GBA Gene Presenting with Hydrops Fetalis and Severe Congenital Anemia.

Case Rep Pathol. 2018;2018:2549451

Authors: Bhutada E, Pyragius T, Petersen SG, Niemann F, Matsika A

Abstract
A 35-year-old woman presented at 27-week gestation with hypertension and pedal edema. Antenatal scan showed hydrops fetalis and growth restriction. Cordocentesis showed severe fetal anemia. This was treated with multiple in utero blood transfusions with no clinically significant improvement and intrauterine death occurred at 28 weeks. Perinatal autopsy confirmed severe hydrops with hepatosplenomegaly and visceral effusions. Microscopic examination of the reticuloendothelial organs showed widespread infiltration by large mono- and multinucleate histiocytic cells with fibrillary appearance ("Gaucher cells"). DNA extracted from fetal tissue was submitted for analysis by next generation sequencing which revealed homozygosity for the RecNcil mutation in the GBA gene. Both parents were found to be heterozygous for the variant. The case report highlights a severe form of Gaucher disease with histopathological and molecular confirmation that presents with hydrops fetalis and severe refractory anemia. It also emphasizes the importance of perinatal autopsy coupled with exome sequencing in confirming syndromic diagnosis in the modern area.

PMID: 29854527 [PubMed]

Addressing the Side Effects of Contemporary Antidepressant Drugs: A Comprehensive Review.

Chonnam Med J. 2018 May;54(2):101-112

Authors: Wang SM, Han C, Bahk WM, Lee SJ, Patkar AA, Masand PS, Pae CU

Abstract
Randomized trials have shown that selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs) have better safety profiles than classical tricyclic antidepressants (TCAs). However, an increasing number of studies, including meta-analyses, naturalistic studies, and longer-term studies suggested that SSRIs and SNRIs are no less safe than TCAs. We focused on comparing the common side effects of TCAs with those of newer generation antidepressants including SSRIs, SNRIs, mirtazapine, and bupropion. The main purpose was to investigate safety profile differences among drug classes rather than the individual antidepressants, so studies containing comparison data on drug groups were prioritized. In terms of safety after overdose, the common belief on newer generation antidepressants having fewer side effects than TCAs appears to be true. TCAs were also associated with higher drop-out rates, lower tolerability, and higher cardiac side-effects. However, evidence regarding side effects including dry mouth, gastrointestinal side effects, hepatotoxicity, seizure, and weight has been inconsistent, some studies demonstrated the superiority of SSRIs and SNRIs over TCAs, while others found the opposite. Some other side effects such as sexual dysfunction, bleeding, and hyponatremia were more prominent with either SSRIs or SNRIs.

PMID: 29854675 [PubMed]

Drug repositioning for prostate cancer: using a data-driven approach to gain new insights.

AMIA Annu Symp Proc. 2017;2017:1724-1733

Authors: Wang Q, Xu R

Abstract
Prostate cancer (PC) is the most common cancer and the third leading cause of cancer death in men worldwide. Despite its high incidence and mortality, the likelihood of a cure is low for late-stages of PC. There is an unmet need for more effective agents for treating PC. Here, we present a drug repositioning system, GenoPredict, for finding innovative drug candidates for treating PC. GenoPredict leverages upon a large amount of disease genomics data and a large-scale drug treatment knowledge base (TreatKB) that we recently constructed. We first constructed a genetic disease network (GDN) that comprised of 882 nodes and 200,758 edges and applied a network-based ranking algorithm to find diseases from GDN that are genetically related to PC. We developed a drug prioritization algorithm to reposition drugs from PC-related diseases to treat PC. When evaluated in a de-novo prediction setting using 27 FDA- approved PC drugs, GenoPredict found 25 of 27 FDA-approved PC drugs and ranked them highly (recall: 0.925, mean ranking: 27.3%, median ranking: 15.6%). When compared to PREDICT, a comprehensive drug repositioning system, in novel predictions, GenoPredict performed better than PREDICT across two evaluation datasets. GenoPredict achieved a mean average precision (MAP) of 0.447 when evaluated with 172 PC drugs extracted from 172,888 clinical trial reports, representing a 164.5% improvement as compared to a MAP of 0.169 for PREDICT. When evaluated with 72 PC drugs extracted from 43,811 ongoing clinical trial reports, GenoPredict achieved a MAP of 0.278, representing a 231.1% improvement as compared to a MAP of 0.084 for PREDICT. The data is publicly available at: http://nlp.
CASE: edu/public/data/PC_GenoPredict and http: //nlp.
CASE: edu/public/data/treatKB.

PMID: 29854243 [PubMed - in process]

Word-of-Mouth Innovation: Hypothesis Generation for Supplement Repurposing based on Consumer Reviews.

AMIA Annu Symp Proc. 2017;2017:689-695

Authors: Fan JW, Lussier YA

Abstract
Dietary supplements remain a relatively underexplored source for drug repurposing. A systematic approach to soliciting responses from a large consumer population is desirable to speed up innovation. We tested a workflow that mines unexpected benefits of dietary supplements from massive consumer reviews. A (non-exhaustive) list of regular expressions was used to screen over 2 million reviews on health and personal care products. The matched reviews were manually analyzed, and one supplement-disease pair was linked to biological databases for enriching the hypothesized association. The regular expressions found 169 candidate reviews, of which 45.6% described unexpected benefits of certain dietary supplements. The manual analysis showed some of the supplement-disease associations to be novel or in agreement with evidence published later in the literature. The hypothesis enrichment was able to identify meaningful function similarity between the supplement and the disease. The results demonstrated value of the workflow in identifying candidates for supplement repurposing.

PMID: 29854134 [PubMed - in process]

Repurposing Lesogaberan to Promote Human Islet Cell Survival and β-Cell Replication.

J Diabetes Res. 2017;2017:6403539

Authors: Tian J, Dang H, Hu A, Xu W, Kaufman DL

Abstract
The activation of β-cell's A- and B-type gamma-aminobutyric acid receptors (GABAA-Rs and GABAB-Rs) can promote their survival and replication, and the activation of α-cell GABAA-Rs promotes their conversion into β-cells. However, GABA and the most clinically applicable GABA-R ligands may be suboptimal for the long-term treatment of diabetes due to their pharmacological properties or potential side-effects on the central nervous system (CNS). Lesogaberan (AZD3355) is a peripherally restricted high-affinity GABAB-R-specific agonist, originally developed for the treatment of gastroesophageal reflux disease (GERD) that appears to be safe for human use. This study tested the hypothesis that lesogaberan could be repurposed to promote human islet cell survival and β-cell replication. Treatment with lesogaberan significantly enhanced replication of human islet cells in vitro, which was abrogated by a GABAB-R antagonist. Immunohistochemical analysis of human islets that were grafted into immune-deficient mice revealed that oral treatment with lesogaberan promoted human β-cell replication and islet cell survival in vivo as effectively as GABA (which activates both GABAA-Rs and GABAB-Rs), perhaps because of its more favorable pharmacokinetics. Lesogaberan may be a promising drug candidate for clinical studies of diabetes intervention and islet transplantation.

PMID: 29018828 [PubMed - indexed for MEDLINE]

Spark-MCA: Large-scale, Exhaustive Formal Concept Analysis for Evaluating the Semantic Completeness of SNOMED CT.

AMIA Annu Symp Proc. 2017;2017:1931-1940

Authors: Wei Z, Licong C, Guo-Qiang Z

Abstract
The completeness of a medical terminology system consists of two parts: complete content coverage and complete semantics. In this paper, we focus on semantic completeness and present a scalable approach, called Spark-MCA, for evaluating the semantic completeness of SNOMED CT. We formulate the SNOMED CT contents into an FCA-based formal context, in which SNOMED CT concepts are used for extents, while their attributes are used as intents. We applied Spark-MCA to the 201403 US edition of SNOMED CT to exhaustively compute all the formal concepts and sub concept relationships in about 2 hours with 96 processors using an Amazon Web Service cluster. We found a total of 799,868 formal concepts, within which 500,583 are not contained in the 201403 release. We compared these concepts with the cumulative addition of 22,687 concepts from the 5 "delta" files from the 201403 release to the 201609 release. 3,231 matches were found between those suggested by FCA and those from cumulative concept addition by the SNOMED CT Editorial Panel. This result provides encouraging evidence that our approach could be useful for enhancing the semantic completeness of SNOMED CT.

PMID: 29854265 [PubMed - in process]

Modeling Contextual Knowledge for Clinical Decision Support.

AMIA Annu Symp Proc. 2017;2017:1617-1624

Authors: Sordo M, Tokachichu P, Vitale CJ, Maviglia SM, Rocha RA

Abstract
In theory, the logic of decision rules should be atomic. In practice, this is not always possible; initially simple logic statements tend to be overloaded with additional conditions restricting the scope of such rules. By doing so, the original logic soon becomes encumbered with contextual knowledge. Contextual knowledge is re-usable on its own and could be modeled separately from the logic of a rule without losing the intended functionality. We model constraints to explicitly define the context where knowledge of decision rules is actionable. We borrowed concepts from Semantic Web, Complex Adaptive Systems, and Contextual Reasoning. The proposed approach provides the means for identifying and modeling contextual knowledge in a simple, sound manner. The methodology presented herein facilitates rule authoring, fosters consistency in rules implementation and maintenance; facilitates developing authoritative knowledge repositories to promote quality, safety and efficacy of healthcare; and paves the road for future work in knowledge discovery.

PMID: 29854232 [PubMed - in process]

Reconciliation of multiple guidelines for decision support: a case study on the multidisciplinary management of breast cancer within the DESIREE project.

AMIA Annu Symp Proc. 2017;2017:1527-1536

Authors: Séroussi B, Guézennec G, Lamy JB, Muro N, Larburu N, Sekar BD, Prebet C, Bouaud J

Abstract
Breast cancer is the most common cancer among women. DESIREE is a European project which aims at developing web-based services for the management of primary breast cancer by multidisciplinary breast units (BUs). We describe the guideline-based decision support system (GL-DSS) of the project. Various breast cancer clinical practice guidelines (CPGs) have been selected to be concurrently applied to provide state-of-the-art patient-specific recommendations. The aim is to reconcile CPG recommendations with the objective of complementarity to enlarge the number of clinical situations covered by the GL-DSS. Input and output data exchange with the GL-DSS is performed using FHIR. We used a knowledge model of the domain as an ontology on which relies the reasoning process performed by rules that encode the selected CPGs. Semantic web tools were used, notably the Euler/EYE inference engine, to implement the GL-DSS. "Rainbow boxes" are a synthetic tabular display used to visualize the inferred recommendations.

PMID: 29854222 [PubMed - in process]

Evaluation of Semantic Web Technologies for Storing Computable Definitions of Electronic Health Records Phenotyping Algorithms.

AMIA Annu Symp Proc. 2017;2017:1352-1361

Authors: Papež V, Denaxas S, Hemingway H

Abstract
Electronic Health Records are electronic data generated during or as a byproduct of routine patient care. Structured, semi-structured and unstructured EHR offer researchers unprecedented phenotypic breadth and depth and have the potential to accelerate the development of precision medicine approaches at scale. A main EHR use-case is defining phenotyping algorithms that identify disease status, onset and severity. Phenotyping algorithms utilize diagnoses, prescriptions, laboratory tests, symptoms and other elements in order to identify patients with or without a specific trait. No common standardized, structured, computable format exists for storing phenotyping algorithms. The majority of algorithms are stored as human-readable descriptive text documents making their translation to code challenging due to their inherent complexity and hinders their sharing and re-use across the community. In this paper, we evaluate the two key Semantic Web Technologies, the Web Ontology Language and the Resource Description Framework, for enabling computable representations of EHR-driven phenotyping algorithms.

PMID: 29854204 [PubMed - in process]

Mechanism-based Pharmacovigilance over the Life Sciences Linked Open Data Cloud.

AMIA Annu Symp Proc. 2017;2017:1014-1023

Authors: Kamdar MR, Musen MA

Abstract
Adverse drug reactions (ADR) result in significant morbidity and mortality in patients, and a substantial proportion of these ADRs are caused by drug-drug interactions (DDIs). Pharmacovigilance methods are used to detect unanticipated DDIs and ADRs by mining Spontaneous Reporting Systems, such as the US FDA Adverse Event Reporting System (FAERS). However, these methods do not provide mechanistic explanations for the discovered drug-ADR associations in a systematic manner. In this paper, we present a systems pharmacology-based approach to perform mechanism-based pharmacovigilance. We integrate data and knowledge from four different sources using Semantic Web Technologies and Linked Data principles to generate a systems network. We present a network-based Apriori algorithm for association mining in FAERS reports. We evaluate our method against existing pharmacovigilance methods for three different validation sets. Our method has AUROC statistics of 0.7-0.8, similar to current methods, and event-specific thresholds generate AUROC statistics greater than 0.75 for certain ADRs. Finally, we discuss the benefits of using Semantic Web technologies to attain the objectives for mechanism-based pharmacovigilance.

PMID: 29854169 [PubMed - in process]

Negative selection in tumor genome evolution acts on essential cellular functions and the immunopeptidome.

Genome Biol. 2018 May 31;19(1):67

Authors: Zapata L, Pich O, Serrano L, Kondrashov FA, Ossowski S, Schaefer MH

Abstract
BACKGROUND: Natural selection shapes cancer genomes. Previous studies used signatures of positive selection to identify genes driving malignant transformation. However, the contribution of negative selection against somatic mutations that affect essential tumor functions or specific domains remains a controversial topic.
RESULTS: Here, we analyze 7546 individual exomes from 26 tumor types from TCGA data to explore the portion of the cancer exome under negative selection. Although we find most of the genes neutrally evolving in a pan-cancer framework, we identify essential cancer genes and immune-exposed protein regions under significant negative selection. Moreover, our simulations suggest that the amount of negative selection is underestimated. We therefore choose an empirical approach to identify genes, functions, and protein regions under negative selection. We find that expression and mutation status of negatively selected genes is indicative of patient survival. Processes that are most strongly conserved are those that play fundamental cellular roles such as protein synthesis, glucose metabolism, and molecular transport. Intriguingly, we observe strong signals of selection in the immunopeptidome and proteins controlling peptide exposition, highlighting the importance of immune surveillance evasion. Additionally, tumor type-specific immune activity correlates with the strength of negative selection on human epitopes.
CONCLUSIONS: In summary, our results show that negative selection is a hallmark of cell essentiality and immune response in cancer. The functional domains identified could be exploited therapeutically, ultimately allowing for the development of novel cancer treatments.

PMID: 29855388 [PubMed - in process]

Identification of a Novel BRCA1 Pathogenic Mutation in Korean Patients Following Reclassification of BRCA1 and BRCA2 Variants According to the ACMG Standards and Guidelines Using Relevant Ethnic Controls.

Cancer Res Treat. 2017 Oct;49(4):1012-1021

Authors: Park JS, Nam EJ, Park HS, Han JW, Lee JY, Kim J, Kim TI, Lee ST

Abstract
PURPOSE: Comparison of variant frequencies in the general population has become an essential part of the American College of Medical Genetics and Genomics (ACMG) standards and guidelines for interpreting sequence variants. We determined the optimal number of relevant ethnic controls that should be used to accurately calculate the odds ratio (OR) of genetic variants.
MATERIALS AND METHODS: Using the ACMG guidelines, we reclassified BRCA1 and BRCA2 mutations and variants of unknown significance in 745 Korean patients susceptible to hereditary breast and ovarian cancer compared with 1,314 Korean population controls.
RESULTS: We observed that the ORs were falsely inflated when we analyzed several variants using non-Korean population data. Our simulation indicated that the number of controls needed for the lower limit of a 95% confidence interval to exceed 1.0 varied according to the frequency of the variant in each patient group, with more than 820 controls needed for a variant existing in 1% of cases. Using a sufficient number of relevant population data, we could efficiently classify variants and identified the BRCA1 p.Leu1780Pro mutation as a possible pathogenic founder mutation in Korean patients.
CONCLUSION: Our study suggests that BRCA1 p.Leu1780Pro is a novel pathogenic mutation found in Korean patients. We also determined the optimal number of relevant ethnic controls needed for accurate variant classification according to the ACMG guidelines.

PMID: 28111427 [PubMed - indexed for MEDLINE]

Two novel mutations in PRPF3 causing autosomal dominant retinitis pigmentosa.

Sci Rep. 2016 11 25;6:37840

Authors: Zhong Z, Yan M, Sun W, Wu Z, Han L, Zhou Z, Zheng F, Chen J

Abstract
Retinitis pigmentosa (RP) is a heterogeneous set of hereditary eye diseases, characterized by selective death of photoreceptor cells in the retina, resulting in progressive visual impairment. Approximately 20-40% of RP cases are autosomal dominant RP (ADRP). In this study, a Chinese ADRP family previously localized to the region between D1S2819 and D1S2635 was sequenced via whole-exome sequencing and a variant c.1345C > G (p.R449G) was identified in PRPF3. The Sanger sequencing was performed in probands of additional 95 Chinese ADRP families to investigate the contribution of PRPF3 to ADRP in Chinese population and another variant c.1532A > C (p.H511P) was detected in one family. These two variants, co-segregate with RP in two families respectively and both variants are predicted to be pathological. This is the first report about the spectrum of PRPF3 mutations in Chinese population, leading to the identification of two novel PRPF3 mutations. Only three clustered mutations in PRPF3 have been identified so far in several populations and all are in exon 11. Our study expands the spectrum of PRPF3 mutations in RP. We also demonstrate that PRPF3 mutations are responsible for 2.08% of ADRP families in this cohort indicating that PRPF3 mutations might be relatively rare in Chinese ADRP patients.

PMID: 27886254 [PubMed - indexed for MEDLINE]

Complete androgen insensitivity syndrome caused by a deep intronic pseudoexon-activating mutation in the androgen receptor gene.

Sci Rep. 2016 09 09;6:32819

Authors: Känsäkoski J, Jääskeläinen J, Jääskeläinen T, Tommiska J, Saarinen L, Lehtonen R, Hautaniemi S, Frilander MJ, Palvimo JJ, Toppari J, Raivio T

Abstract
Mutations in the X-linked androgen receptor (AR) gene underlie complete androgen insensitivity syndrome (CAIS), the most common cause of 46,XY sex reversal. Molecular genetic diagnosis of CAIS, however, remains uncertain in patients who show normal coding region of AR. Here, we describe a novel mechanism of AR disruption leading to CAIS in two 46,XY sisters. We analyzed whole-genome sequencing data of the patients for pathogenic variants outside the AR coding region. Patient fibroblasts from the genital area were used for AR cDNA analysis and protein quantification. Analysis of the cDNA revealed aberrant splicing of the mRNA caused by a deep intronic mutation (c.2450-118A>G) in the intron 6 of AR. The mutation creates a de novo 5' splice site and a putative exonic splicing enhancer motif, which leads to the preferential formation of two aberrantly spliced mRNAs (predicted to include a premature stop codon). Patient fibroblasts contained no detectable AR protein. Our results show that patients with CAIS and normal AR coding region need to be examined for deep intronic mutations that can lead to pseudoexon activation.

PMID: 27609317 [PubMed - indexed for MEDLINE]

Reducing the Toxicity Risk in Antibiotic Prescriptions by Combining Ontologies with a Multiple Criteria Decision Model.

AMIA Annu Symp Proc. 2017;2017:1625-1634

Authors: Souissi SB, Abed M, Elhiki L, Fortemps P, Pirlot M

Abstract
We consider the risk of adverse drug events caused by antibiotic prescriptions. Antibiotics are the second most common cause of drug related adverse events and one of the most common classes of drugs associated with medical malpractice claims. To cope with this serious issue, physicians rely on guidelines, especially in the context of hospital prescriptions. Unfortunately such guidelines do not offer sufficient support to solve the problem of adverse events. To cope with these issues our work proposes a clinical decision support system based on expert medical knowledge, which combines semantic technologies with multiple criteria decision models. Our model links and assesses the adequacy of each treatment through the toxicity risk of side effects, in order to provide and explain to physicians a sorted list of possible antibiotics. We illustrate our approach through carefully selected case studies in collaboration with the EpiCURA Hospital Center in Belgium.

PMID: 29854233 [PubMed - in process]